Translocation

Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

Staff Sylvie Yau Chun Wan - Senon Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation.

http://AtlasGeneticsOncology.org

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1)

Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Scope

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

Staff Sylvie Yau Chun Wan - Senon Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation.

http://AtlasGeneticsOncology.org

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.

CMKOR1 (chemokine orphan receptor 1) Broberg K

Editor-in-Chief

Jean-Loup Huret (Poitiers, France)

Editorial Board

Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukemia Sections Vasantha Brito-Babapulle (London, UK) Leukemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Anne Marie Capodano (Marseille, France) Solid Tumors Section Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections Antonio Cuneo (Ferrara, Italy) Leukemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumors Sections Louis Dallaire (Montreal, Canada) Education Section François Desangles (Paris, France) Leukemia / Solid Tumors Sections Gordon Dewald (Rochester, Minnesota) Leukemia / Deep Insights Sections Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Oskar Haas (Vienna, Austria) Genes / Leukemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumors Section Lisa Lee-Jones (Newcastle, UK) Solid Tumors Section Edmond Ma (Hong Kong, China) Leukemia Section Cristina Mecucci (Perugia, Italy) Genes / Leukemia Sections Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section Fredrik Mertens (Lund, Sweden) Solid Tumors Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukemia Section Florence Pedeutour (Nice, France) Genes / Solid Tumors Sections Susana Raimondi (Memphis, Tennesse) Genes / Leukemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumors Section Franck Viguié (Paris, France) Leukemia Section Thomas Wan (Hong Kong, China) Genes / Leukemia Sections Bernhard Weber (Würzburg, Germany) Education Section

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1)

Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Volume 9, Number 1, January - March 2005

Table of contents

Gene Section

CMKOR1 (chemokine orphan receptor 1) 1 Karin Broberg MAPRE1 (Microtubule-associated protein, RP/EB family, member 1) 3 Jennifer S Tirnauer ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) 6 Patrizia Casalini, Marilena V Iorio TOP1 (topoisomerase (DNA) 1) 13 Junko Horiguchi Yamada WISP2 (Wnt-1-inducible signaling parthway protein-2) 15 Sushanta K Banerjee, Snigdha Banerjee LHFP (lipoma HMGIC fusion partner) 17 Marleen Petit TFPT (TCF3/E2A fusion partner) 19 Enrica Privitera, Andrea Biondi VAV1 (vav 1 oncogene) 21 Shulamit Katzav

Leukaemia Section del(13q) in ALL 24 David Betts t(14;21)(q11;q22) 26 Jacques Boyer t(1;14)(q21;q32) IRTA1/IGH 28 Mary Callanan, Dominique Leroux t(1;14)(q21;q32) MUC1/IGH 30 Jacques Boyer t(1;6)(p35;p25) 32 Jean-Loup Huret t(16;21)(p11;q22) 34 Jean Loup Huret t(9;11)(q34;p15) 37 Jean-Loup Huret t(X;20)(q13;q13.3) 39 Kavita S Reddy, Kathy E Richkind

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1)

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Solid Tumour Section

Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma 41 Manuel Sánchez-Martín, Ines González-Herrero, Isidro Sánchez-García Uterus Tumours: an Overview 45 Roberta Vanni, Giuseppina Parodo Soft Tissue Tumors: Low grade fibromyxoid sarcoma 52 Ioannis Panagopoulos, Fredrik Mertens, Nils Mandahl, Clelia Tiziana Storlazzi Soft Tissue Tumors: Soft Tissue Leiomyosarcoma 55 Jian-Hua Luo Soft tissue tumors: Lipoblastoma 57 Cristina Morerio, Claudio Panarello t(16;21)(p11;q22) 60 Jean Loup Huret

Cancer Prone Disease Section

LEOPARD syndrome 63 Maria Cristina Digilio

Deep Insight Section

The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! 66 Eric Engel

Case Report Section

A new case of t(1;11)(q21;q23) in a child with M1 ANLL 75 Katell Le Du, Eric Jeandidier, Francine Garnache, Pierre Rohrlich, Jean-Luc Bresson, Marie-Agnès Collonge-Rame Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 1 78 Kavita S Reddy, Kathy E Richkind Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 2 80 Kavita S Reddy, Kathy E Richkind Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 3 82 Kavita S Reddy, Kathy E Richkind Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 4 84 Kavita S Reddy, Kathy E Richkind

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1)

Atlas of Genetics and Cytogenetics

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Educational Items Section

Genetics and Public Health 86 Anne-Marie Laberge Glossary of Medical and Molecular Genetics 92 Louis Dallaire

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1)

Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

CMKOR1 (chemokine orphan receptor 1) Karin Broberg Department of Occupational and Environmental Medicine, Lund University Hospital, Lund, Sweden (KB)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Genes/CMKOR1ID40108ch2q37.html DOI: 10.4267/2042/38146 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

bladder, spleen, heart, skeletal muscle, peripheral Identity nervous system and placenta. Other names: CMKOR1; RDC1; GPRN159; G Localisation protein-coupled receptor; chemokine orphan receptor 1; G protein-coupled receptor RDC1 homolog Integral membrane protein. HGNC (Hugo): CXCR7 Function Location: 2q37.3 Orphan receptor, but its endogenous ligand has not yet been identified. The protein is also a coreceptor for Local order: Telomeric to IQCA. Centromeric to human immunodeficiency viruses (HIV). RDC1 COPS8. belongs to a family of G-protein coupled receptors, Note: RDC1 was originally thought to be the receptor which includes hormone, neurotransmitter and light for VIP. receptors, all of which transduce extracellular signals through interaction with guanine nucleotide (G) DNA/RNA binding proteins. Description Homology The genomic size has been estimated to approximately RDC1 displays homology to other members of the 12.5-13.5 kb. RDC1 has previously been reported to large family of G-protein coupled receptors. contain only one exon of 1,09 kbp. However, the finding of a RDC1 transcript corresponding to four Mutations different regions with exon/intron boundaries in the BAC 514f21 suggests a more complex gene structure. Germinal The predicted amino acid sequence of exon 3 and 4 Single nucleotide polymorphisms. does not show any homology to the protein databases Somatic and, since they both contribute with stop codons, it could be questioned whether these sequences represent Translocations involving RDC1 and HMGA2 has been exons, or are part of an alternatively spliced 3' reported in three lipomas (see below). untranslated region of the gene. Implicated in Pseudogene None. Lipoma Disease Protein Benign adipocyte tumor. Description 362 amino acids; 41522 Da. Expression Prognosis RDC1 is expressed in embryological, juvenile as well Good. as adult tissues. Expression has been reported in e.g. Cytogenetics

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CXCR7 (chemokine (C-X-C motif) receptor 7) Broberg K

Translocations involving 2q35-37 and 12q13-15 have been reported in six lipomas. References Hybrid/Mutated gene Sreedharan SP, Robichon A, Peterson KE, Goetzl EJ. Cloning and expression of the human vasoactive intestinal peptide Fusion between RDC1 and HMGA2 has been reported receptor. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4986- in three lipomas with rearrangement involving 2q35-37 90 and 12q13-15. The breakpoint occurred after the third Nagata S, Ishihara T, Robberecht P, Libert F, Parmentier M, exon of HMGA2, the most common breakpoint of this Christophe J, Vassart G. RDC1 may not be VIP receptor. gene, and in a previously unknown 3' part of the RDC1 Trends Pharmacol Sci. 1992 Mar;13(3):102-3 gene. The RDC1 part of the fusion was over 300 bp. Shimizu N, Soda Y, Kanbe K, Liu HY, Mukai R, Kitamura T, Abnormal protein Hoshino H. A putative G protein-coupled receptor, RDC1, is a novel coreceptor for human and simian immunodeficiency The functional impact of this fusion is most likely a viruses. J Virol. 2000 Jan;74(2):619-26 truncation of HMGA2, since the RDC1 part contributes Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M, with a stop codon one amino acid downstream of the Mertens F, Mandahl N, Panagopoulos I. Fusion of RDC1 with breakpoint. HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15. Int J Oncol. 2002 Oncogenesis Aug;21(2):321-6 Not yet established. Nilsson M, Höglund M, Panagopoulos I, Sciot R, Dal Cin P, Tenosynovial giant cell tumours Debiec-Rychter M, Mertens F, Mandahl N. Molecular cytogenetic mapping of recurrent chromosomal breakpoints in Disease tenosynovial giant cell tumors. Virchows Arch. 2002 Nov;441(5):475-80 Benign tumor of synovium and tendon sheath. Madden SL, Cook BP, Nacht M, Weber WD, Callahan MR, Prognosis Jiang Y, Dufault MR, Zhang X, Zhang W, Walter-Yohrling J, Good. Rouleau C, Akmaev VR, Wang CJ, Cao X, St Martin TB, Roberts BL, Teicher BA, Klinger KW, Stan RV, Lucey B, Cytogenetics Carson-Walter EB, Laterra J, Walter KA. Vascular gene Translocations involving 1p11-13 and 2q35-37 have expression in nonneoplastic and malignant brain. Am J Pathol. been reported in eight cases of tenosynovial giant cell 2004 Aug;165(2):601-8 tumours. This article should be referenced as such: Hybrid/Mutated gene Broberg K. CMKOR1 (chemokine orphan receptor 1). Atlas Four out of seven cases of tenosynovial giant cell Genet Cytogenet Oncol Haematol. 2005; 9(1):1-2. tumours with aberrations of 2q35-37 had breakpoints in a BAC probe 260J21 (BACPAC, Oakland), which contains the RDC1 gene.

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 2

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Gene Section Mini Review

MAPRE1 (Microtubule-associated protein, RP/EB family, member 1) Jennifer S Tirnauer Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, E1032, Farmington, CT 06030-3101, USA (JST)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPRE1ID455ch20q11.html DOI: 10.4267/2042/38147 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: EB1 Description HGNC (Hugo): MAPRE1 22 Kb genomic locus, 5 introns. Location : 20q11.1-11.23 Transcription Location (base pair) : 32,123,450 - 32,153,886 bp. 2540 bp open reading frame. Protein Description 268 amino acids; 35 kDa; EB1 was cloned in yeast two-hybrid screen as binding partner for the tumor suppressor APC (Adenomatous Polyposis Coli); EB1 is a microtubule plus end tracking protein (+tip). It contains a calponin homology domain and a leucine zipper. Expression EB1 is ubiquitously expressed. Protein levels remain similar throughout the cell cycle. Localisation EB1 targets to the plus ends of microtubules when they are polymerizing, producing a "comet tail" pattern.

(Figure 1). The mechanism is treadmilling, in which EB1-GFP fluorescence on polymerizing microtubule plus ends new subunits are continually added at the tip. in a living PtK1 cell. EB1 also shows additional weak binding to the Note microtubule lattice (along the length of the The original name EB1 came from a yeast two hybrid microtubule). EB1 targets to kinetochores moving anti- screen "End Binding 1" is a nickname that was later poleward. This is suspected to be due to binding to applied when the protein was found to target to kinetochore microtubule plus ends rather than the microtubule plus ends. kinetochore itself. Through its carboxyl terminus, EB1 localizes to centrosomes and spindle poles.

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MAPRE1 (Microtubule-associated protein, RP/EB family, member 1) Tirnauer JS

Function binds to the APC C-terminus, so its binding is lost in most truncations. Also lost are other APC binding The primary function identified to date is regulation of partners including the transcription factor beta-catenin. microtubule dynamic instability. Microtubules The role of APC as a tumor suppressor is thought to be dynamically convert between growth (polymerization) through the beta-catenin pathway. Some evidence in and shrinkage (depolymerization). The transition from the mouse suggests that this is true. growth to shrinkage is called catastrophe, while the However, there is increasing evidence that connections conversion from shrinkage to growth is called rescue. between APC and the cytoskeleton are important in cell Microtubules also pause in their polymerization. EB1 migration, which could have an important role in colon reduces these pauses and reduces the frequency of cancer. One Italian FAP family has been reported in catastrophes. EB1 increases the frequency of rescues. which APC is truncated distal to the beta-catenin The net result is more stable, longer microtubules. This binding site but including the EB1 binding site. There effect is predominantly seen during mitosis. is no direct evidence of EB1 mutation in colon cancer, EB1 is important in maintaining the structure of the and a single report found no evidence of somatic mitotic spindle. This is thought to be mediated by its mutations by reverse transcriptase single-strand effects on spindle microtubule dynamic instability. conformational polymorphism (SSCP) analysis in 21 EB1 is important in spindle positioning within the cell. sporadic colorectal cancers and seven colorectal This is thought to be due to its effects on astral adenomas. microtubule dynamic instability. In budding yeast, EB1 also plays a role in positioning the mitotic spindle Meduloblastoma through the bud neck. In this case, it is through Disease microtubule dynamics as well direct binding to a A single report showed that EB1 is transcriptionally protein at the bud tip, creating a physical link between elevated in pediatric meduloblastoma. There is no the microtubule end and the cell cortex. direct evidence of EB1 mutation in meduloblastoma. EB1 plays a role in linking kinetochores to kinetochore microtubules, which is important for chromosome stability. It is not known whether it regulates Breakpoints kinetochore microtubule dynamics or end-on Note attachment. None known. EB1 also has an independent role in anchoring microtubule minus ends to centrosomes References Protein-protein interactions: Adenomatous Polyposis Coli (APC) tumor suppressor, polymerized tubulin Su LK, Burrell M, Hill DE, Gyuris J, Brent R, Wiltshire R, Trent (microtubules), p150glued/dynactin, CLIP-170, mDia, J, Vogelstein B, Kinzler KW. APC binds to the novel protein Pin2/TRF1, RhoGEF2 (drosophila), shortstop EB1. Cancer Res. 1995 Jul 15;55(14):2972-7 (drosophila). Renner C, Pfitzenmeier JP, Gerlach K, Held G, Ohnesorge S, Sahin U, Bauer S, Pfreundschuh M. RP1, a new member of Homology the adenomatous polyposis coli-binding EB1-like gene family, is differentially expressed in activated T cells. J Immunol. 1997 MAPRE2, MAPRE3. Aug 1;159(3):1276-83 Schwartz K, Richards K, Botstein D. BIM1 encodes a Mutations microtubule-binding protein in yeast. Mol Biol Cell. 1997 Note Dec;8(12):2677-91 None known. Berrueta L, Kraeft SK, Tirnauer JS, Schuyler SC, Chen LB, Hill DE, Pellman D, Bierer BE. The adenomatous polyposis coli- binding protein EB1 is associated with cytoplasmic and spindle Implicated in microtubules. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10596-601 Colon cancer Jaïs P, Sabourin JC, Bombled J, Rougier P, Lasser P, Disease Duvillard P, Bénard J, Bressac-de Paillerets B. Absence of somatic alterations of the EB1 gene adenomatous polyposis Truncation of the Adenomatous Polyposis Coli (APC) coli-associated protein in human sporadic colorectal cancers. protein is seen in Familial Adenomatous Polyposis Br J Cancer. 1998 Nov;78(10):1356-60 (FAP) as well as most sporadic colon cancers. EB1

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MAPRE1 (Microtubule-associated protein, RP/EB family, member 1) Tirnauer JS

Morrison EE, Wardleworth BN, Askham JM, Markham AF, Rogers SL, Rogers GC, Sharp DJ, Vale RD. Drosophila EB1 is Meredith DM. EB1, a protein which interacts with the APC important for proper assembly, dynamics, and positioning of tumour suppressor, is associated with the microtubule the mitotic spindle. J Cell Biol. 2002 Sep 2;158(5):873-84 cytoskeleton throughout the cell cycle. Oncogene. 1998 Dec 31;17(26):3471-7 Tirnauer JS, Canman JC, Salmon ED, Mitchison TJ. EB1 targets to kinetochores with attached, polymerizing Muhua L, Adames NR, Murphy MD, Shields CR, Cooper JA. A microtubules. Mol Biol Cell. 2002 Dec;13(12):4308-16 cytokinesis checkpoint requiring the yeast homologue of an APC-binding protein. Nature. 1998 Jun 4;393(6684):487-91 Tirnauer JS, Grego S, Salmon ED, Mitchison TJ. EB1- microtubule interactions in Xenopus egg extracts: role of EB1 Berrueta L, Tirnauer JS, Schuyler SC, Pellman D, Bierer BE. in microtubule stabilization and mechanisms of targeting to The APC-associated protein EB1 associates with components microtubules. Mol Biol Cell. 2002 Oct;13(10):3614-26 of the dynactin complex and cytoplasmic dynein intermediate chain. Curr Biol. 1999 Apr 22;9(8):425-8 Bu W, Su LK. Characterization of functional domains of human EB1 family proteins. J Biol Chem. 2003 Dec 12;278(50):49721- Juwana JP, Henderikx P, Mischo A, Wadle A, Fadle N, 31 Gerlach K, Arends JW, Hoogenboom H, Pfreundschuh M, Renner C. EB/RP gene family encodes tubulin binding Goodson HV, Skube SB, Stalder R, Valetti C, Kreis TE, proteins. Int J Cancer. 1999 Apr 12;81(2):275-84 Morrison EE, Schroer TA. CLIP-170 interacts with dynactin complex and the APC-binding protein EB1 by different Tirnauer JS, O'Toole E, Berrueta L, Bierer BE, Pellman D. mechanisms. Cell Motil Cytoskeleton. 2003 Jul;55(3):156-73 Yeast Bim1p promotes the G1-specific dynamics of microtubules. J Cell Biol. 1999 May 31;145(5):993-1007 Hayashi I, Ikura M. Crystal structure of the amino-terminal microtubule-binding domain of end-binding protein 1 (EB1). J Askham JM, Moncur P, Markham AF, Morrison EE. Regulation Biol Chem. 2003 Sep 19;278(38):36430-4 and function of the interaction between the APC tumour suppressor protein and EB1. Oncogene. 2000 Apr Ligon LA, Shelly SS, Tokito M, Holzbaur EL. The microtubule 6;19(15):1950-8 plus-end proteins EB1 and dynactin have differential effects on microtubule polymerization. Mol Biol Cell. 2003 Korinek WS, Copeland MJ, Chaudhuri A, Chant J. Molecular Apr;14(4):1405-17 linkage underlying microtubule orientation toward cortical sites in yeast. Science. 2000 Mar 24;287(5461):2257-9 Mathur J, Mathur N, Kernebeck B, Srinivas BP, Hülskamp M. A novel localization pattern for an EB1-like protein links Lee L, Tirnauer JS, Li J, Schuyler SC, Liu JY, Pellman D. microtubule dynamics to endomembrane organization. Curr Positioning of the mitotic spindle by a cortical-microtubule Biol. 2003 Nov 11;13(22):1991-7 capture mechanism. Science. 2000 Mar 24;287(5461):2260-2 Subramanian A, Prokop A, Yamamoto M, Sugimura K, Uemura Mimori-Kiyosue Y, Shiina N, Tsukita S. The dynamic behavior T, Betschinger J, Knoblich JA, Volk T. Shortstop recruits of the APC-binding protein EB1 on the distal ends of EB1/APC1 and promotes microtubule assembly at the muscle- microtubules. Curr Biol. 2000 Jul 13;10(14):865-8 tendon junction. Curr Biol. 2003 Jul 1;13(13):1086-95 Tirnauer JS, Bierer BE. EB1 proteins regulate microtubule Louie RK, Bahmanyar S, Siemers KA, Votin V, Chang P, dynamics, cell polarity, and chromosome stability. J Cell Biol. Stearns T, Nelson WJ, Barth AI. Adenomatous polyposis coli 2000 May 15;149(4):761-6 and EB1 localize in close proximity of the mother centriole and EB1 is a functional component of centrosomes. J Cell Sci. Nakamura M, Zhou XZ, Lu KP. Critical role for the EB1 and 2004 Mar 1;117(Pt 7):1117-28 APC interaction in the regulation of microtubule polymerization. Curr Biol. 2001 Jul 10;11(13):1062-7 Rogers SL, Wiedemann U, Häcker U, Turck C, Vale RD. Drosophila RhoGEF2 associates with microtubule plus ends in Su LK, Qi Y. Characterization of human MAPRE genes and an EB1-dependent manner. Curr Biol. 2004 Oct their proteins. Genomics. 2001 Jan 15;71(2):142-9 26;14(20):1827-33 Askham JM, Vaughan KT, Goodson HV, Morrison EE. Wen Y, Eng CH, Schmoranzer J, Cabrera-Poch N, Morris EJ, Evidence that an interaction between EB1 and p150(Glued) is Chen M, Wallar BJ, Alberts AS, Gundersen GG. EB1 and APC required for the formation and maintenance of a radial bind to mDia to stabilize microtubules downstream of Rho and microtubule array anchored at the centrosome. Mol Biol Cell. promote cell migration. Nat Cell Biol. 2004 Sep;6(9):820-30 2002 Oct;13(10):3627-45 Barth AI, Siemers KA, Nelson WJ. Dissecting interactions This article should be referenced as such: between EB1, microtubules and APC in cortical clusters at the Tirnauer JS. MAPRE1 (Microtubule-associated protein, plasma membrane. J Cell Sci. 2002 Apr 15;115(Pt 8):1583-90 RP/EB family, member 1). Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):3-5.

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Gene Section Review

ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)) Patrizia Casalini, Marilena V Iorio Molecular Targeting Unit, Experimental Oncology Dept., Istituto Nazionale Tumori, Via Venezian, 1. 20133 Milano, Italy (PC, MVI)

Published in Atlas Database: December 2004 Online updated version : http://AtlasGeneticsOncology.org/Genes/ERBB2ID162ch17q11.html DOI: 10.4267/2042/38148 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

been reported, with the most common Allele B1 (Ile- Identity 654/Ile-655); allele B2 (Ile-654/Val-655); allele B3 Other names: v-erb-b2; HER2; NEU; TKR1; NGL; (Val-654/Val-655). This nucleotide polymorphism Her-2/neu; C-erbB-2 could be associated with development of gastric HGNC (Hugo): ERBB2 carcinoma and with breast cancer risk, particularly among younger women. Location: 17q11.2-q12 Transcription Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. mRNA Transcript Variant : This variant (1) represents the shorter transcript but encodes the longer isoform (a) (protein: erbB-2 isoform (a)). mRNA Transcript Variant : This variant (2) (protein: erbB-2 isoform (b) contains additional exons at its 5' end and lacks an alternate 5' noncoding exon, compared Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. to variant (1). These differences result in translation Note initiation at an in-frame, downstream AUG and an isoform (b) with a shorter N-terminus compared to Tyrosine-kinase receptor (RTK). The HER family of isoform (a). RTKs consists of four receptors: epidermal growth mRNA Transcript Variant : herstatin HER2-ECD factor receptor (EGFR, also called HER-1 or erbB-1), 1300 bp alternative erbB-2 transcript that retains intron HER-2 (also called erbB-2 or Neu), HER-3 and HER-4 8. This alternative transcript specifies 340 residues (also called erbB-3 and erbB-4, respectively). identical to subdomains I and II from the extracellular domain of p185erbB-2 followed by a unique C- DNA/RNA terminal sequence of 79 aa encoded by intron 8. The Description herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to Sequence length 30528; CDS 3768. 27 exons; total p185erbB-2 mRNA in carcinoma cells that contain an exon length 4477, max. exon length 969, min exon amplified erbB-2 gene. length 48. Number of SNPs 11. Polymorphisms: allelic mRNA Transcript Variant : An alternative transcript variations at amino acid positions 654 and 655 of form of the human homologous gene isoform (a) (positions 624 and 625 of isoform (b)) have

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ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived Casalini P, Iorio MV oncogene homolog (avian) )

HER2 protein: schematic representation Receptor tyrosin-kinases (RTKs) are cell surface allosteric enzymes consisting of: - an extracellular ligand-binding domain (blue) - a single transmembrane (TM) domain has an extensive homology to the epidermal grow factor receptor (brown) - a cytoplasmic domain with catalityc activity (green). erbB-2, containing an in-frame deletion encompassing Function exon 19, has been detected in human breast ACTIVATION AND INTERACTIONS : carcinomas. For the other member of the HER family, ligand binding induces receptor homo- or heterodimerization, Protein which is essential for TKs activation and subsequent Description recruitment of target proteins, in turns initiating a complex signaling cascade that leads into distinct erbB2 encodes an 185-kDa, 1255 amino acids, orphan transcriptional programs. There are several HER- receptor tyrosine kinase, it displays potent oncogenic specific ligands. HER2, which apparently has no direct activity when overexpressed. The protooncogene or specific ligand, plays a major coordinating role in consists of three domains: a single transmembrane the HER network because of its ability to enhance and domain that separates an intracellular kinase domain stabilize the dimerization: each receptor with a specific from an extracellular ligand-binding domain. ligand appears in fact to prefer HER-2 as its Expression heterodimeric partner. HER-2-containing heterodimers HER2 protein is expressed in several human organs and are characterized by extremely high signaling potency tissues: normal epithelium, endometrium and ovarian because HER-2 dramatically reduces the rate of ligand epithelium and at neuromuscular level; prostate, dissociation, allowing strong and prolonged activation pancreas, lung, kidney, liver, heart, hematopoietic cells. of downstream signalling pathways. HER2 expression is low in mononuclear cells from SIGNALING AND CELLULAR: bone marrow, peripheral blood (PB) and mobilized PB. The most important intracellular pathways activated by The higher expression has been found in cord blood- HER2 are those involving mitogen activated protein derived cells. Quiescent CD34+ progenitor cells from kinase and phosphatidylinositol-3 kinase. HER2 all blood sources and resting lymphocytes are HER2 expression in cancer, besides its role in proliferation, negative, but the expression of this receptor is up- enhances and prolongs those survivals signals, regulated during cell-cycle recruitment of progenitor associating up-regulation of this receptor to the cells. Similarly, it increases in mature, hematopoietic malignant phenotype. At the same time, and depending proliferating cells, underlying the correlation between on cellular status, the role of this receptor in controlling HER2 and the proliferating status of hematopoietic cell fate can also lead to differentiation and apoptosis. cells. PHYSIOLOGICAL : Role in development and differentiation: Localisation HER2 has several non-oncogenic roles in regulating Plasma membrane. growth, differentiation, apoptosis and/or remodeling in

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ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived Casalini P, Iorio MV oncogene homolog (avian) )

normal mammary glands. Dominant-negative forms of acute lymphoblastic leukemia (ALL). It could be used HER2 have significant defects in mammary as a potential target for the application of HER2- development and lactation. directed treatment strategies in ALL including HER2 has an important role in development and vaccination approaches. function of heart. Cre-Lox technology to mutate erbB-2 Bladder cancer specifically in ventricular cardiomyocytes leads to a severe cardiomyopathy. This is inferred also by the Prognosis adverse cardiac side effects observed in breast cancer HER2 is overexpressed in 25% to 40% of several patients treated with the monoclonal anti-HER2 Ab human tumors and associated with the malignancy of Trastuzumab. the disease, high mitotic index and a shorter survival HER2 has a role in control of Schwann cell time for the patient. Overexpression of ErbB-2 is myelination and it has been demonstrated that HER2 associated with transitional cell carcinoma of the signaling is also critical for oligodendrocyte bladder. HER2 overexpression occurs in muscle- differentiation in vivo. invasive urothelial carcinomas of the bladder and is HER2 has a dual role in both muscle spindle associated with worse survival; amplifications of erbB- maintenance and survival of myoblasts. Muscle- 2 gene are also frequently linked to alterations of the specific HER2 KO results in fact in viable mice with a TOP2A gene in bladder cancer. progressive defect in proprioception due to loss of Breast carcinoma muscles spindles. Prognosis Homology HER-2 overexpression, occurring in 25-30% of human Homolog to Avian erythroblastic leukemia viral (v-erb- breast cancers, is associated to shorter time to relapse b) oncogen 2. and lower overall survival. Overexpression of the erbB- 2 gene, is associated with tumor aggressiveness, and Mutations with patient responsiveness to doxorubicin, cyclophosphamide, methotrexate, fluorouracil (CMF), Somatic and to paclitaxel, whereas tamoxifen was found to be The Cancer Genome Project and Collaborative Group ineffective and even detrimental in patients with sequenced the erbB-2 gene from 120 primary lung HER2-positive tumors. In Paget's disease of breast, tumors and identified 4% that had mutations within the HER2 protein overexpression is caused by kinase domain; in the adenocarcinoma subtype of lung amplification of the erbB-2 gene. HER2 has a role in cancer, 10% of cases hadmutations. this disease of the breast, where the epidermis of the In non small cell lung cancer (adenocarcinoma) the nipple is infiltrated by large neoplastic cells of following erbB-2 mutations were found: glandular origin. It seems that binding of heregulin-alfa insertion/duplication of GCATACGTGATG at to the receptor complex on Paget cells results in nucleotide 2322 of the erbB-2 gene, resulting in a 4- chemotaxis of these breast cancer cells. amino acid insertion (AYVM) at codon 774. insertion of CTGTGGGCT at nucleotide 2335 of the erbB-2 Cervical cancer gene, resulting in a 3-amino acid insertion (VGS) Prognosis starting at codon 779; a 2-bp substitution in the erbB-2 HER2 may be activated in the early stage of gene, TT-CC at nucleotides 2263 and 2264, resulting in pathogenesis of cervical carcinoma in geriatric patients a leu755-to-pro (L755P) substitution. In a glioblastoma and is frequently amplified in squamous cell carcinoma a 2740G-A transition in the erbB-2 gene that caused a of the uterine cervix. glu914-to-lys substitution(E914K). In a gastric tumor a 2326G-A transition in the erbB-2 Childhood Medulloblastoma gene that caused a gly776-to-ser (G776S) substitution. Prognosis In an ovarian tumor, a 2570A-G transition in the erbB- Overexpression of HER2 in medulloblastoma is 2 gene that caused an asn857-to-ser (N857S) associated with poor prognosis and metastasis and substitution. HER2-HER4 receptor heterodimerization is of particular biological significance in this disease. Implicated in Colorectal cancer Hematological malignancies Prognosis Disease Overexpression of HER2 occurs in a significant HER2 expression can be detected in blast cells from number of colorectal cancers. It was significantly patients with hematological malignancies including associated with poor survival and related to tumor progression in colorectal cancer.

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ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived Casalini P, Iorio MV oncogene homolog (avian) )

Oral squamous cell carcinoma Overexpression of HER-2 in pancreatic adenocarcinoma seems to be a result of increased Prognosis transcription rather than gene amplification. The E6/E7 proteins of HPV type 16 and HER2 cooperate to coexpression of HER2 oncogene protein, epidermal induce neoplastic transformation of primary normal growth factor receptor, and TGF-beta1 in pancreatic oral epithelial cells. Overexpression of HER2 receptor ductal adenocarcinoma is related to the is a frequent event in oral squamous cell carcinoma and histopathological grades and clinical stages of tumors. is correlated with poor survival. Primary Fallopian tube carcinoma Gastric cancer Prognosis Prognosis This disease is a rare form of female cancer where the HER2 amplification/overexpression does not seem to HER2 overexpression plays a role in tumorigenesis. play a role in the molecular pathogenesis of most gastrinomas. However, mild gene amplification occurs Prostate cancer in a subset of them, and overexpression of this receptor Prognosis is associated with aggressiveness of the disease. HER2 The expression of ERBB2 in prostate cancer is is correlated with tumor histological differentiation and relatively low, but is up-modulated at onset of hormone is associated with poor prognosis in well-differentiated resistance. gastric adenocarcinoma. Salivary gland tumor Germ-cell testicular tumor Prognosis Prognosis Several results demonstrated significant positive A significant correlation was observed between HER2 staining of HER2 in the salivary tumorigenic tissue but overexpression and clinical outcome in germ-cell not in the surrounding non-tumorigenic tissue, pointing testicular tumors. to a biological role in the tumorigenic process. Cholangiocarcinoma Synovial sarcoma Prognosis Prognosis Increased HER2 expression contributes to the The presence of increased levels of HER2 in synovial development of cholangiocarcinogenesis into an sarcoma is associated with a more favorable clinical advanced stage associated with tumor metastasis. In course. addition, overexpression of HER2 and COX-2 correlated directly with tumor differentiation. To be noted Lung cancer Note Prognosis Possible therapeutic strategies: 1) growth inhibitory HER2 is overexpressed in less than 20% of patients antibodies (like Trastuzumab), used alone or in with non-small cell lung cancer (NSCLC) and studies combination with standard chemotherapeutics; 2) have shown that overexpression of this receptor is tyrosin kinase inhibitors (TKI); 3) active correlated with a poor prognosis in both resected and immunotherapy, because the HER2 oncoprotein is advanced NSCLC. immunogenic in some breast carcinoma patients. Osteosarcoma Prognosis References Higher frequency of HER2 expression has been Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival observed in samples from patients with metastatic with amplification of the HER-2/neu oncogene. Science. 1987 disease at presentation and at the time of relapse, and it Jan 9;235(4785):177-82 correlates with worse histologic response and decreased Di Fiore PP, Segatto O, Taylor WG, Aaronson SA, Pierce JH. event-free survival. EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling. Science. 1990 Apr Ovarian cancer 6;248(4951):79-83 Prognosis Papewalis J, Nikitin AYu, Rajewsky MF. G to A polymorphism Patients with HER2-overexpression have a at amino acid codon 655 of the human erbB-2/HER2 gene. significantly worse prognosis compared to patients with Nucleic Acids Res. 1991 Oct 11;19(19):5452 HER2-negative tumors. Tateishi M, Toda T, Minamisono Y, Nagasaki S. Clinicopathological significance of c-erbB-2 protein expression Pancreatic adenocarcinoma in human gastric carcinoma. J Surg Oncol. 1992 Prognosis Apr;49(4):209-12

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ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived Casalini P, Iorio MV oncogene homolog (avian) )

Kolodziejczyk P, Yao T, Oya M, Nakamura S, Utsunomiya T, Kwong KY, Hung MC. A novel splice variant of HER2 with Ishikawa T, Tsuneyoshi M. Long-term follow-up study of increased transformation activity. Mol Carcinog. 1998 patients with gastric adenomas with malignant transformation. Oct;23(2):62-8 An immunohistochemical and histochemical analysis. Cancer. 1994 Dec 1;74(11):2896-907 Olayioye MA, Graus-Porta D, Beerli RR, Rohrer J, Gay B, Hynes NE. ErbB-1 and ErbB-2 acquire distinct signaling Mitra AB, Murty VV, Pratap M, Sodhani P, Chaganti RS. properties dependent upon their dimerization partner. Mol Cell ERBB2 (HER2/neu) oncogene is frequently amplified in Biol. 1998 Sep;18(9):5042-51 squamous cell carcinoma of the uterine cervix. Cancer Res. 1994 Feb 1;54(3):637-9 Balsari A, Casalini P, Tagliabue E, Greco M, Pilotti S, Agresti R, Giovanazzi R, Alasio L, Rumio C, Cascinelli N, Colnaghi MI, Motojima K, Furui J, Kohara N, Izawa K, Kanematsu T, Shiku Ménard S. 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Binding of Neu differentiation factor with the assessment of 6 cases. Neoplasma. 1999;46(2):128-31 extracellular domain of Her2 and Her3. J Biol Chem. 1995 Oct 13;270(41):24604-8 Chung TK, Cheung TH, To KF, Wong YF. Overexpression of p53 and HER-2/neu and c-myc in primary fallopian tube Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C. carcinoma. Gynecol Obstet Invest. 2000;49(1):47-51 Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature. 1995 Nov 23;378(6555):394-8 Garratt AN, Voiculescu O, Topilko P, Charnay P, Birchmeier C. A dual role of erbB2 in myelination and in expansion of the Carlomagno C, Perrone F, Gallo C, De Laurentiis M, Lauria R, schwann cell precursor pool. J Cell Biol. 2000 Mar Morabito A, Pettinato G, Panico L, D'Antonio A, Bianco AR, De 6;148(5):1035-46 Placido S. c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB lymph node metastases. J Clin Oncol. 1996 Oct;14(10):2702-8 signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000 Jul 3;19(13):3159-67 Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y. A hierarchical network of Schelfhout VR, Coene ED, Delaey B, Thys S, Page DL, De interreceptor interactions determines signal transduction by Potter CR. Pathogenesis of Paget's disease: epidermal Neu differentiation factor/neuregulin and epidermal growth heregulin-alpha, motility factor, and the HER receptor family. J factor. Mol Cell Biol. 1996 Oct;16(10):5276-87 Natl Cancer Inst. 2000 Apr 19;92(8):622-8 Gilbertson RJ, Perry RH, Kelly PJ, Pearson AD, Lunec J. Xie D, Shu XO, Deng Z, Wen WQ, Creek KE, Dai Q, Gao YT, Prognostic significance of HER2 and HER4 coexpression in Jin F, Zheng W. Population-based, case-control study of HER2 childhood medulloblastoma. Cancer Res. 1997 Aug genetic polymorphism and breast cancer risk. J Natl Cancer 1;57(15):3272-80 Inst. 2000 Mar 1;92(5):412-7 Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the Casalini P, Botta L, Menard S. Role of p53 in HER2-induced preferred heterodimerization partner of all ErbB receptors, is a proliferation or apoptosis. J Biol Chem. 2001 Apr mediator of lateral signaling. EMBO J. 1997 Apr 1;16(7):1647- 13;276(15):12449-53 55 Kim YS, Konoplev SN, Montemurro F, Hoy E, Smith TL, Xia W, Lau YK, Zhang HZ, Liu AR, Li L, Kiyokawa N, Clayman Rondón G, Champlin RE, Sahin AA, Ueno NT. HER-2/neu GL, Katz RL, Hung MC. Strong correlation between c-erbB-2 overexpression as a poor prognostic factor for patients with overexpression and overall survival of patients with oral metastatic breast cancer undergoing high-dose chemotherapy squamous cell carcinoma. Clin Cancer Res. 1997 Jan;3(1):3-9 with autologous stem cell transplantation. 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methotrexate, and fluorouracil in lymph node-positive breast in primary tumor and metastases of colorectal cancer according to HER2 overexpression and other tumor adenocarcinoma. Bull Exp Biol Med. 2003 May;135(5):489-94 biologic variables. J Clin Oncol. 2001 Jan 15;19(2):329-35 Junttila TT, Laato M, Vahlberg T, Söderström KO, Visakorpi T, Yarden Y, Sliwkowski MX. Untangling the ErbB signalling Isola J, Elenius K. Identification of patients with transitional cell network. Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37 carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR Aishima SI, Taguchi KI, Sugimachi K, Shimada M, Sugimachi analysis in estimation of ErbB receptor status from cancer K, Tsuneyoshi M. c-erbB-2 and c-Met expression relates to patients. Clin Cancer Res. 2003 Nov 1;9(14):5346-57 cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. 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Hum Ménard S, Balsari A, Casalini P, Tagliabue E, Campiglio M, Pathol. 2003 Jul;34(7):639-45 Bufalino R, Cascinelli N. HER-2-positive breast carcinomas as Simon R, Atefy R, Wagner U, Forster T, Fijan A, Bruderer J, a particular subset with peculiar clinical behaviors. Clin Cancer Wilber K, Mihatsch MJ, Gasser T, Sauter G. HER-2 and Res. 2002 Feb;8(2):520-5 TOP2A coamplification in urinary bladder cancer. Int J Cancer. Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, 2003 Dec 10;107(5):764-72 Hübner N, Chien KR, Birchmeier C, Garratt AN. Conditional Tan D, Deeb G, Wang J, Slocum HK, Winston J, Wiseman S, mutation of the ErbB2 (HER2) receptor in cardiomyocytes Beck A, Sait S, Anderson T, Nwogu C, Ramnath N, Loewen G. leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 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J Pediatr Hematol Oncol. 2003 Jan;25(1):27-32 Int. 2002 Nov;1(4):620-3 Al Moustafa AE, Foulkes WD, Benlimame N, Wong A, Yen L, Delektorskaya VV, Perevoshchikov AG, Kushlinskii NE. Bergeron J, Batist G, Alpert L, Alaoui-Jamali MA. E6/E7 Immunohistological study of NM 23 and C-erbB-2 expression proteins of HPV type 16 and ErbB-2 cooperate to induce

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ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived Casalini P, Iorio MV oncogene homolog (avian) )

neoplastic transformation of primary normal oral epithelial cells. Konecny GE, Thomssen C, Lück HJ, Untch M, Wang HJ, Kuhn Oncogene. 2004 Jan 15;23(2):350-8 W, Eidtmann H, du Bois A, Olbricht S, Steinfeld D, Möbus V, von Minckwitz G, Dandekar S, Ramos L, Pauletti G, Pegram Bernard C, Corzo G, Adachi-Akahane S, Foures G, Kanemaru MD, Jänicke F, Slamon DJ. Her-2/neu gene amplification and K, Furukawa Y, Nakajima T, Darbon H. Solution structure of response to paclitaxel in patients with metastatic breast ADO1, a toxin extracted from the saliva of the assassin bug, cancer. J Natl Cancer Inst. 2004 Aug 4;96(15):1141-51 Agriosphodrus dohrni. Proteins. 2004 Feb 1;54(2):195-205 Lassus H, Leminen A, Vayrynen A, Cheng G, Gustafsson JA, Camilleri-Broët S, Hardy-Bessard AC, Le Tourneau A, Paraiso Isola J, Butzow R. ERBB2 amplification is superior to protein D, Levrel O, Leduc B, Bain S, Orfeuvre H, Audouin J, Pujade- expression status in predicting patient outcome in serous Lauraine E. HER-2 overexpression is an independent marker ovarian carcinoma. Gynecol Oncol. 2004 Jan;92(1):31-9 of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. Ann Oncol. 2004 Mándoky L, Géczi L, Bodrogi I, Tóth J, Csuka O, Kásler M, Bak Jan;15(1):104-12 M. Clinical relevance of HER-2/neu expression in germ-cell testicular tumors. Anticancer Res. 2004 Jul-Aug;24(4):2219-24 Casalini P, Iorio MV, Galmozzi E, Ménard S. Role of HER receptors family in development and differentiation. J Cell Onn A, Correa AM, Gilcrease M, Isobe T, Massarelli E, Bucana Physiol. 2004 Sep;200(3):343-50 CD, O'Reilly MS, Hong WK, Fidler IJ, Putnam JB, Herbst RS. Synchronous overexpression of epidermal growth factor Chung GG, Zerkowski MP, Ocal IT, Dolled-Filhart M, Kang JY, receptor and HER2-neu protein is a predictor of poor outcome Psyrri A, Camp RL, Rimm DL. beta-Catenin and p53 analyses in patients with stage I non-small cell lung cancer. Clin Cancer of a breast carcinoma tissue microarray. Cancer. 2004 May Res. 2004 Jan 1;10(1 Pt 1):136-43 15;100(10):2084-92 Riener EK, Arnold N, Kommoss F, Lauinger S, Pfisterer J. The Cianciulli A, Cosimelli M, Marzano R, Merola R, Piperno G, prognostic and predictive value of immunohistochemically Sperduti I, de la Iglesia F, Leonardo G, Graziano F, Mancini R, detected HER-2/neu overexpression in 361 patients with Guadagni F. Genetic and pathologic significance of 1p, 17p, ovarian cancer: a multicenter study. Gynecol Oncol. 2004 and 18q aneusomy and the ERBB2 gene in colorectal cancer Oct;95(1):89-94 and related normal colonic mucosa. Cancer Genet Cytogenet. 2004 May;151(1):52-9 Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O'Meara S, Smith R, Parker A, Barthorpe A, Essapen S, Thomas H, Green M, De Vries C, Cook MG, Marks Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, C, Topham C, Modjtahedi H. The expression and prognostic Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, significance of HER-2 in colorectal cancer and its relationship Greenman C, Halliday K, Hills K, Kosmidou V, Lugg R, with clinicopathological parameters. Int J Oncol. 2004 Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Feb;24(2):241-8 Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Hermanová M, Lukás Z, Nenutil R, Brázdil J, Kroupová I, Kren Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, L, Pazourková M, R ůzicka M, Díte P. Amplification and Leung SY, Louis DN, Looijenga LH, Malkowicz B, Pierotti MA, overexpression of HER-2/neu in invasive ductal carcinomas of Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, the pancreas and pancreatic intraepithelial neoplasms and the Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton relationship to the expression of p21(WAF1/CIP1). Neoplasma. MR. Lung cancer: intragenic ERBB2 kinase mutations in 2004;51(2):77-83 tumours. Nature. 2004 Sep 30;431(7008):525-6 Hirsch FR, Langer CJ. The role of HER2/neu expression and This article should be referenced as such: trastuzumab in non-small cell lung cancer. Semin Oncol. 2004 Feb;31(1 Suppl 1):75-82 Casalini P, Iorio MV. ERBB2 (erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived Hughes DP, Thomas DG, Giordano TJ, Baker LH, McDonagh oncogene homolog (avian) ). Atlas Genet Cytogenet Oncol KT. Cell surface expression of epidermal growth factor Haematol. 2005; 9(1):6-12. receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res. 2004 Mar 15;64(6):2047-53

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Gene Section Mini Review

TOP1 (topoisomerase (DNA) 1) Junko Horiguchi Yamada Department of Oncology, Institute of DNA Medicine, The Jikei University, School of Medicine, Tokyo, Japan (JHY)

Published in Atlas Database: December 2004 Online updated version : http://AtlasGeneticsOncology.org/Genes/TOP1ID320ch20q11.html DOI: 10.4267/2042/38149 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity HGNC (Hugo): TOP1 Location: 20q12-q13.1 Location (base pair): 39090K-39190K on chromosome 20 The arrow indicates the breaking point of translocation, and the Local order: centromer to telomer. star denotes the sites of point mutation. DNA/RNA Description 765 amino acids, about 100kDa; contains NLS in the Note N-term, a core domain which recognizes its binding The sequence is split into 21 exons over 85kbp. Introns sequences, a link domain which connects the core and are 0.2-30 kbp in size. catalytic domains, and the catalytic domain in the C- Description term. 21 exons with 20 introns. Expression Transcription Ubiquitous. The expression level is up-regulated along with cell proliferation signals. 3.8 kb (single band). Localisation Pseudogene Nucleus. 2 pseudogenes: TOP1P1 on chromosome 1q23-q24, and TOP1P2 on chromosome 22q12-q13.1. Function TOP1 catalyzes the breaking and rejoining of single Protein DNA strand. Note Homology Type I DNA topoisomerase, EC (5.99.1.2). The core and catalytic domains are conserved between the human and S.cerevisiae enzyme.

The star denotes intron 7 where chromosome translocation occurs.

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TOP1 (topoisomerase (DNA) 1) Yamada JH

Mutations References Somatic Kunze N, Yang GC, Dölberg M, Sundarp R, Knippers R, Richter A. Structure of the human type I DNA topoisomerase Translocation of chromosome t(11;20)(p15;q12) has gene. J Biol Chem. 1991 May 25;266(15):9610-6 been reported in hematological malignancies (see Ahuja HG, Felix CA, Aplan PD. The t(11;20)(p15;q11) below). chromosomal translocation associated with therapy-related Point mutations with amino acid substitution in the myelodysplastic syndrome results in an NUP98-TOP1 fusion. catalytic domain have been implicated in irinotecan- Blood. 1999 Nov 1;94(9):3258-61 resistance. Ahuja HG, Felix CA, Aplan PD. Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) Implicated in translocations. Genes Chromosomes Cancer. 2000 Oct;29(2):96-105 t(11;20)(p15;q12) Panagopoulos I, Fioretos T, Isaksson M, Larsson G, Billström Disease R, Mitelman F, Johansson B. Expression of NUP98/TOP1, but de novo acute myeloid leukemia, acute monocytic not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15). Genes leukemia, therapy-related myelodysplastic Chromosomes Cancer. 2002 Jun;34(2):249-54 syndrome/leukemia(t-MDS/AML). Tsurutani J, Nitta T, Hirashima T, Komiya T, Uejima H, Tada H, Prognosis Syunichi N, Tohda A, Fukuoka M, Nakagawa K. Point Poor (?) mutations in the topoisomerase I gene in patients with non- small cell lung cancer treated with irinotecan. Lung Cancer. Hybrid/Mutated gene 2002 Mar;35(3):299-304 NUP98/TOP1. Chen S, Xue Y, Chen Z, Guo Y, Wu Y, Pan J. Generation of Oncogenesis the NUP98-TOP1 fusion transcript by the t(11;20) (p15;q11) in NUP98-TOP1 fusion protein has been proved to have a case of acute monocytic leukemia. Cancer Genet Cytogenet. 2003 Jan 15;140(2):153-6 leukemogenic activities independent of topoisomerase activity. Iwase S, Akiyama N, Sekikawa T, Saito S, Arakawa Y, Horiguchi-Yamada J, Yamada H. Both NUP98/TOP1 and TOP1/NUP98 transcripts are detected in a de novo AML with Breakpoints t(11;20)(p15;q11). Genes Chromosomes Cancer. 2003 Sep;38(1):102-5 Gurevich RM, Aplan PD, Humphries RK. NUP98- topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation. Blood. 2004 Aug 15;104(4):1127-36 The breakpoints locate in intron 7, causing the fusion protein to Potenza L, Sinigaglia B, Luppi M, Morselli M, Saviola A, Ferrari lack the N-terminal 169 amino acids.The breakpoints locate in A, Riva G, Zucchini P, Giacobbi F, Emilia G, Temperani P, the repetitive elements or close to them which exist in intron 7 Torelli G. A t(11;20)(p15;q11) may identify a subset of of TOP1 gene. nontherapy-related acute myelocytic leukemia. Cancer Genet Cytogenet. 2004 Mar;149(2):164-8 To be noted This article should be referenced as such: Note Yamada JH. TOP1 (topoisomerase (DNA) 1). Atlas Genet Point mutations W736stop and G737S were detected in Cytogenet Oncol Haematol. 2005; 9(1):13-14. lung non-small cell carcinoma. The significance of mutations in catalytic domain has been suspected to be relevant to susceptibility to irinotecan.

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Gene Section Mini Review

WISP2 (Wnt-1-inducible signaling parthway protein-2) Sushanta K. Banerjee, Snigdha Banerjee Division of Hematology/Oncology, Depatment of Medicine, and Department of Anatomy and Cell Biology University of Kansas Medical Center and Research Director, Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA (SKB, SB)

Published in Atlas Database: December 2004 Online updated version : http://AtlasGeneticsOncology.org/Genes/WISP2ID42814ch20q12.html DOI: 10.4267/2042/38150 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

predominant in the non-invasive carcinoma lesions as Identity well as benign hyperplastic areas adjacent to the Other names: CCN5; rCop-1; CT58; CTGF-L invasive tumors. Together, these findings suggest that HGNC (Hugo): WISP2 bi-phasic regulation of WISP-2 signaling may be critical for initial events of growth, survivability and Location: 20q12-13 invasion of breast tumor cells. Note: WISP-2 is a member of the connective tissue WISP-2 also acts as a negative regulator in some cells growth factor/cysteine-rich 61/nephroblastoma including vascular smooth muscle cells. overexpressed (nov) (CCN) family and is upregulated in the mouse mammary epithelial cell line C57MG DNA/RNA transformed by Wnt-1 and in several non-invasive human breast tumor cell lines. WISP-2 is a serum and PMA (phorbol 12-myristate 13- acetate)-induced early responsive gene. Blocking the expression of this gene by WISP-2 antisense oligos or siRNA drastically reduce serum or PMA-induced cell proliferation in MCF-7 cells. Therefore, these studies suggest that WISP-2 signaling may be essential for mitogen-induced breast tumor cell proliferation. WISP-2 expression is enhanced by important modulators of human breast cancer cell proliferation such as estrogen, progesterone and epidermal growth factor (EGF) in MCF-7 cells. These effects, inhibited by appropriate antagonists, indicate that steroids and growth factor-induced upregulation of WISP-2 may be mediated through receptors. Modular structure of individual genes of WISP sub-family of The expression profile of WISP-2 gene in breast tumor CCN family. Module shown with color boxes are the predicted primary translational. biopsy tissue specimens are similar with that of in vitro studies and suggest that WISP-2 mRNA and protein Note levels are significantly higher in tumor samples as Until now, three genes have been identified and compared to the normal breast samples, and this isolated as members of WISP sub-family. WISP- expression is significantly correlated with the 1/CCN4, WISP-2/CCN5 and WISP-3/CCN6 genes expression of estrogen receptor protein. However, were localized in human chromosomes 8q24.1-q24.3, within the tumor specimens, expression was 20q12-q13 and 6q22-23, respectively and exhibit tissue

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WISP2 (Wnt-1-inducible signaling parthway protein-2) Banerjee SK, Banerjee S

specific patterns of expression. Nucleotide and protein Disease sequence alignment studies have demonstrated a 30- Macronodular adrenal hyperplasia. 40% sequence homology within WISP genes and their modular architecture is similar except in their C- References terminal domains, which is absent in the WISP-2 gene. Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Protein Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D, Levine AJ. WISP genes are Description members of the connective tissue growth factor family that are The translation products of most of the CCN family up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci U S A. members are secreted proteins of 35-40 kDa and have 1998 Dec 8;95(25):14717-22 been shown to contain four distinct structural modules: Kumar S, Hand AT, Connor JR, Dodds RA, Ryan PJ, Trill JJ, 1) an IGF-binding protein type (IGFBP) domain, 2) a Fisher SM, Nuttall ME, Lipshutz DB, Zou C, Hwang SM, Votta Von Willebrand type C (VWC) domain; 3) a BJ, James IE, Rieman DJ, Gowen M, Lee JC. Identification Thrombospondin-1 (TSP-1) domain and 4) a C- and cloning of a connective tissue growth factor-like cDNA terminal Cysteine-knot (CT) domain (10). from human osteoblasts encoding a novel regulator of osteoblast functions. J Biol Chem. 1999 Jun 11;274(24):17123- Although the functional roles of these multiple modules 31 are unclear, they raise interesting questions as to the contribution of each individual module to the biological Saxena N, Banerjee S, Sengupta K, Zoubine MN, Banerjee SK. Differential expression of WISP-1 and WISP-2 genes in properties of the full-length proteins. normal and transformed human breast cell lines. Mol Cell Expression Biochem. 2001 Dec;228(1-2):99-104 Epithelial cells and vascular smooth muscle cells. Banerjee S, Saxena N, Sengupta K, Tawfik O, Mayo MS, Banerjee SK. WISP-2 gene in human breast cancer: estrogen Localisation and progesterone inducible expression and regulation of tumor cell proliferation. Neoplasia. 2003 Jan-Feb;5(1):63-73 Adrenal gland, breast, colon, pancreas, uterus and ovary. Inadera H. Estrogen-induced genes, WISP-2 and pS2, respond divergently to protein kinase pathway. Biochem Biophys Res Function Commun. 2003 Sep 19;309(2):272-8 Positive regulator of epithelial cells and negative Bourdeau I, Antonini SR, Lacroix A, Kirschner LS, Matyakhina regulator of vascular smooth muscle cells. L, Lorang D, Libutti SK, Stratakis CA. Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as Mutations molecular mediators. Oncogene. 2004 Feb 26;23(8):1575-85 Mason HR, Lake AC, Wubben JE, Nowak RA, Castellot JJ Jr. Somatic The growth arrest-specific gene CCN5 is deficient in human Amplified in breast tumor cells. leiomyomas and inhibits the proliferation and motility of cultured human uterine smooth muscle cells. Mol Hum Reprod. Implicated in 2004 Mar;10(3):181-7 This article should be referenced as such: Disease Banerjee SK, Banerjee S. WISP2 (Wnt-1-inducible signaling Breast cancer. parthway protein-2). Atlas Genet Cytogenet Oncol Haematol. Disease 2005; 9(1):15-16. Colon cancer.

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Gene Section Short Communication

LHFP (lipoma HMGIC fusion partner) Marleen Petit Laboratory for Molecular Oncology, Department of Human Genetics, University of Leuven (K.U.Leuven) & VIB, Herestraat 49, B-3000 Leuven, Belgium (MP)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Genes/LHFPID248ch13q12.html DOI: 10.4267/2042/38151 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Mutations HGNC (Hugo): LHFP Somatic Location: 13q12 HMGA2/LHFP fusion gene encoding the three DNA- binding domains of HMGA2 followed by 69 amino DNA/RNA acids encoded by frame-shifted LHFP sequences. Description Implicated in Exon-intron structure not described. Transcription Solitary lipomas. Disease mRNA: ubiquitously: 2.4 kb; The ATG start codon is immediately preceded by an in-frame stop codon, and Benign tumors of adipose tissue. matches the most important positions of the Kozak Prognosis consensus sequence; the 3'-UTR contains a CA-repeat. Can be surgically removed with no recurrence in most Pseudogene cases. No pseudogenes according to pseudogene.org. Cytogenetics More than 60% of solitary lipomas have an aberrant Protein karyotype: 2/3 of these carry 12q15 rearrangements, most often translocations, affecting the HMGA2 gene: Description 1/4 of the latter have chromosomal region 3q27-q28 Database searches with the predicted LHFP amino acid (containing LPP) as 12q15 translocation partner sequences revealed no significant similarity to any (creating a HMGA2/LPP fusiongene). known gene or protein or any known protein motif. In the 3/4 others, multiple chromosomes have been Expression found as translocation partner of 12q15, one of these being chromosomal region 13q12 (containing, amongst Not known. others, the LHFP gene). Localisation Hybrid/Mutated gene Not known. HMGA2/LHFP hybrid gene containing the first three Function exons of HMGA2, which are followed by exon(s) of LHFP; under the regulation of the HMGA2 promoter. Not known. Abnormal protein Homology No known LHFP fusion protein. (HMGA2/LHFP LHFP is a member of a family of proteins, which fusion transcripts encode the three DNA-binding contains 6 members: LHFP, LHFPL1, LHFPL2, domains of HMGA2 followed by 69 amino acids LHFPL3, LHFPL4, LHFPL5. encoded by frame-shifted LHFP sequences).

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LHFP (lipoma HMGIC fusion partner) Petit MM

Dahlén A, Debiec-Rychter M, Pedeutour F, Domanski HA, References Höglund M, Bauer HC, Rydholm A, Sciot R, Mandahl N, Mertens F. Clustering of deletions on chromosome 13 in Petit MM, Schoenmakers EF, Huysmans C, Geurts JM, benign and low-malignant lipomatous tumors. Int J Cancer. Mandahl N, Van de Ven WJ. LHFP, a novel translocation 2003 Feb 20;103(5):616-23 partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes. Genomics. 1999 May 1;57(3):438- This article should be referenced as such: 41 Petit MM. LHFP (lipoma HMGIC fusion partner). Atlas Genet Rogalla P, Lemke I, Bullerdiek J. Absence of HMGIC-LHFP Cytogenet Oncol Haematol. 2005; 9(1):17-18. fusion in pulmonary chondroid hamartomas with aberrations involving chromosomal regions 12q13 through 15 and 13q12 through q14. Cancer Genet Cytogenet. 2002 Feb;133(1):90-3

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Gene Section Short Communication

TFPT (TCF3/E2A fusion partner) Enrica Privitera, Andrea Biondi Dipartimento di Scienze Biomolecolari e Biotecnologie, Via Celoria 26, 20133 Milano, Italy (EP, AB)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Genes/TFPTID495ch19q13.html DOI: 10.4267/2042/38152 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Function Overexpression of TFPT/Amida in cultured cells Other names: FB1 induces arrest in G2-M and apoptosis. Biochemical HGNC (Hugo): TFPT studies indicate that TFPT/Amida interacts with Location: 19q13.4 Cdc2/CDK1 in mitosis and its overexpression results in a decrease of Cdc2/CDK1 activity (5).It is also suggested that the TFPT/Amida DNA binding activity is necessary for cell cycle inhibition and that Amida phophorylation by Cdc2/CDK1, detected "in vitro", might decrease this DNA binding activity. Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Homology Very high homology with mouse and rat orthologs. DNA/RNA Mutations Description Genomic structure of six exons and five introns Somatic spanning about 10 kb. Involved in chromosome rearrangement in leukaemia. Transcription Implicated in Two transcripts of 1.1 kb and 1.2 kb, expressed mainly in brain and in hemopoietic cell lines. The rat ortholog, Childhood pre-B ALL Amida, was found highly expressed also in rat testis. Note TATA less promoter, that can be transactivated "in vitro" by PU.1 and Ikaros 2. Orientation, minus strand. We detected 8 cases out of 200: incidence about 4% of childhood pre-B ALL. Protein Cytogenetics Description Following the position of the two involved genes, E2A on 19p13 and FB1 on 19q13 an inv(19)(p13q13) Conserved protein of 253 amino acids (in man) with appears more likely but a translocation two nuclear localization signals (NLS) (n.68-75 and t(19;19)(p13;q13) cannot be yet ruled out. Still n.190-194) and a DNA binding domain located pending. between the two NLSs. Hybrid/Mutated gene Expression E2A-FB1. Constitutive. Abnormal protein Localisation Since the chimeric transcripts so far analyzed contain Nuclear.

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TFPT (TCF3/E2A fusion partner) Privitera E, Biondi A

the FB1 sequence fused out of frame to E2A and no early gene product arc, contains novel nuclear localization truncated E2A protein was detected by Western blot, signals, and causes cell death in cultured cells. J Biol Chem. 2000 Jan 28;275(4):2647-53 we suggest that no fusion protein is produced. Brambillasca F, Mosna G, Ballabio E, Biondi A, Boulukos KE, Privitera E. Promoter analysis of TFPT (FB1), a molecular Breakpoints partner of TCF3 (E2A) in childhood acute lymphoblastic leukemia. Biochem Biophys Res Commun. 2001 Nov Note 16;288(5):1250-7 We detected different joining points in the transcripts Roettgers S, Brambillasca F, Giudici G, Harbott J, Privitera E, of the different analyzed cases indicating different Biondi A. Heterozygous targeted disruption of E2A gene by an breakpoints in a genomic region spanning exons 15-17 Inv(19)(p13;q13). The American Society of Hematology 44th on TCF3 and exons 5-6 on TFPT. Annual Meeting, Philadelphia, 2002. Gan Y, Taira E, Irie Y, Fujimoto T, Miki N. Arrest of cell cycle References by amida which is phosphorylated by Cdc2 kinase. Mol Cell Biochem. 2003 Apr;246(1-2):179-85 Brambillasca F, Mosna G, Colombo M, Rivolta A, Caslini C, Minuzzo M, Giudici G, Mizzi L, Biondi A, Privitera E. This article should be referenced as such: Identification of a novel molecular partner of the E2A gene in childhood leukemia. Leukemia. 1999 Mar;13(3):369-75 Privitera E, Biondi A. TFPT (TCF3/E2A fusion partner). Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):19-20. Irie Y, Yamagata K, Gan Y, Miyamoto K, Do E, Kuo CH, Taira E, Miki N. Molecular cloning and characterization of Amida, a novel protein which interacts with a neuron-specific immediate

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Gene Section Mini Review

VAV1 (vav 1 oncogene) Shulamit Katzav Experimental Medicine & Cancer Research, The Hebrew University/Hadassah Medical School, Ein-Karem, P.O.Box 12272, Jerusalem 91120, Israel (SK)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Genes/VAV1ID195ch19p13.html DOI: 10.4267/2042/38153 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Description Vav1 encodes a highly unique protein that contains Other names: VAV numerous modular motifs known to play a role in HGNC (Hugo): VAV1 tyrosine-mediated signal transduction cascades, such as Location: 19p13.2 a dbl homology (DH) region, which exhibits a guanine nucleotide exchange factor (GEF) activity towards the DNA/RNA Rho family GTPases; a pleckstrin homology (PH) domain which interacts with polyphosphoinositides; a Transcription Src Homology 2 (SH2) and two Src Homology 3 (SH3) 2535 mRNA complete codons. domains that mediate protein-protein interactions; a proline- rich motif that enables binding to SH3 - Protein containing proteins, an acidic-rich (Ac) region and a Note 'calponin-homology' (CH) region, which functions as an actin-binding domain in other proteins and two Vav1 was discovered when DNA from five esophageal nuclear localization signals (NLS). carcinomas were tested for their transforming activity. In fact, Vav1 is the only known Rho GEF that This newly identified gene represented the sixth combines in the same protein the DH/PH motifs and oncogene detected in Dr. Barbacid's laboratory and it the structural hallmark of signal transducer proteins, the was thus designated Vav1, after the sixth letter of the SH2 and SH3 domains. Hebrew alphabet. Vav1 was activated as an oncogene in vitro by replacement of 67 amino-acid residues of its Expression amino-terminus (CH region) with 19 amino-acids Vav1 is specifically expressed in the hematopoietic residues of pSV2neo sequences, co-transfected as a system. selectable marker. Function Wild-type Vav1 produces minimal transformation of NIH3T3 murine fibroblasts only when the protein is The Vav1 protein (95 kDa) is rapidly tyrosine- grossly over-expressed. phosphorylated following stimulation of various Removal of its amino terminus sequences (65 residues), receptors on hematopoietic cells (TCR, BCR, IgE, etc). thus mimicking its original mode of activation, is Vav1 can then function in various signaling cascades. sufficient to induce Vav1 transformation.

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VAV1 (vav 1 oncogene) Katzav S

First, as a tyrosine-phosphorylated protein, Vav1 involvement of this protein in the neoplastic process in operates as a guanine nucleotide exchange factor (GEF) a subset of neuroblastomas. Furthermore, it was for Rac1, Rac2 and RhoG. It is the only known GEF recently found to be involved in a large number of protein whose activity is regulated by tyrosine Pancreatic tumors. phosphorylation. As a regulator of activation of the Rho/Rac GTPases, Implicated in Vav1 participates in several processes that require cytoskeletal reorganization, such as the formation of Disease the immunological synapse (IS), phagocytosis, platelet Neuroblastoma. aggregation and spreading. Vav1 can also function in Disease GEF-independent pathways through its association Pancreatic tumors. with other proteins such as ZAP-70, SLP-76, Ly-GDI (an inhibitor of Rho/RacGTPases), Grb2 and References cytoseketal proteins such as Zyxin. Vav1 plays a critical role in stimulation of NFAT Katzav S, et al. vav, a novel human oncogene derived from a (Nuclear Factor of Activated T cells), culminating in locus ubiquitously expressed in hematopoietic cells. EMBO J. the production of numerous vital cytokines. Vav1 also 1989 Aug;8(8):2283-90 leads to the induction of an intracellular calcium flux Martinerie C, et al. The human VAV proto-oncogene maps to by regulating the activation of phospholipase Cg1 chromosome region 19p12----19p13.2. Hum Genet. 1990 Nov;86(1):65-8 (PLCg1) via phosphoinositide 3-kinase (PI3K) dependent and -independent pathways. The activity of Bustelo XR, Ledbetter JA, Barbacid M. Product of vav proto- oncogene defines a new class of tyrosine protein kinase Vav1 also leads to the activation of NF-kB and the substrates. Nature. 1992 Mar 5;356(6364):68-71 extracellular signal regulated kinase (ERK) mitogen- activated protein kinase (MAPK) signaling cascade. Margolis B, Hu P, Katzav S, Li W, Oliver JM, Ullrich A, Weiss A, Schlessinger J. Tyrosine phosphorylation of vav proto- There is compelling evidence from studies of gene- oncogene product containing SH2 domain and transcription targeted mice to indicate that Vav1 participates in the factor motifs. Nature. 1992 Mar 5;356(6364):71-4 development and function of many types of immune Wu J, Katzav S, Weiss A. A functional T-cell receptor signaling cell such as the positive- and negative-selection events pathway is required for p95vav activity. Mol Cell Biol. 1995 that are imposed on double-positive thymocytes. Aug;15(8):4337-46 Homology Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR. Phosphotyrosine-dependent activation of Rac-1 GDP/GTP Vav1 is one of a larger family of proteins that include exchange by the vav proto-oncogene product. Nature. 1997 Vav2 and Vav3 which unlike Vav1 are also Jan 9;385(6612):169-72 ubiquitously expressed and the Vav homologues in Bustelo XR. Vav proteins, adaptors and cell signaling. Drosophila Melanogaster and in the nematode, C. Oncogene. 2001 Oct 1;20(44):6372-81 elegans. These proteins are similar in their structure to Manetz TS, Gonzalez-Espinosa C, Arudchandran R, Xirasagar Vav1, thus also functioning as signal transducer S, Tybulewicz V, Rivera J. Vav1 regulates phospholipase proteins. cgamma activation and calcium responses in mast cells. Mol Cell Biol. 2001 Jun;21(11):3763-74 Mutations Reynolds LF, Smyth LA, Norton T, Freshney N, Downward J, Kioussis D, Tybulewicz VL. Vav1 transduces T cell receptor Somatic signals to the activation of phospholipase C-gamma1 via Although, no mutants of Vav1 have been reported thus phosphoinositide 3-kinase-dependent and -independent far in "real" human tumors, it was recently found that pathways. J Exp Med. 2002 May 6;195(9):1103-14 Vav1 is expressed in the majority of 42 specimens of Turner M, Billadeau DD. VAV proteins as signal integrators for human neuroblastoma, suggesting a possible multi-subunit immune-recognition receptors. Nat Rev Immunol. 2002 Jul;2(7):476-86

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VAV1 (vav 1 oncogene) Katzav S

Jordan MS, Singer AL, Koretzky GA. Adaptors as central Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy mediators of signal transduction in immune cells. Nat Immunol. DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, 2003 Feb;4(2):110-6 Billadeau DD. Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Hornstein I, Alcover A, Katzav S. Vav proteins, masters of the Cell. 2005 Jan;7(1):39-49 world of cytoskeleton organization. Cell Signal. 2004 Jan;16(1):1-11 This article should be referenced as such: Katzav S. Vav1: an oncogene that regulates specific Katzav S. VAV1 (vav 1 oncogene). Atlas Genet Cytogenet transcriptional activation of T cells. Blood. 2004 Apr Oncol Haematol. 2005; 9(1):21-23. 1;103(7):2443-51

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Leukaemia Section Short Communication del(13q) in ALL David Betts Department of Oncology, University Children's Hospital, Steinwiesstr. 75, CH-8032 Zürich, Switzerland (DB)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del13qALLID1188.html DOI: 10.4267/2042/38154 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

sole event in approximately 10% of cases. There are Identity also rare reports of translocations also leading to a Note partial 13q deletion. Monosomy 13 is also reported but Deletions of chromosome 13q are a non-random occurs very rarely as a sole aberration. Under finding in a broad spectrum of haematological representation of chromosome 13 is often found in neoplasms, including B-cell chronic lymphocytic hypotriploid cases. leukemia (CLL), non-Hodgkin's lymphoma (NHL) and Additional anomalies multiple myeloma (MM) and acute myeloid leukaemia Most cases with del(13q) will have additional (AML). aberrations, but there is no consistent picture and the events can include the typical non-random events in Clinics and pathology ALL. Disease Genes involved and proteins Acute lymphoblastic leukaemia (ALL). Phenotype/cell stem origin Note Critical region in 13q14 appears to lie telomeric to No specific immunophenotype observed. RB1. Epidemiology A del(13q) chromosome is found in approximately 2% References of cases in both adult and childhood disease at Chung CY, Kantarjian H, Haidar M, Starostik P, Manshouri T, presentation. Up to 4% of cases may have some loss of Gidel C, Freireich E, Keating M, Albitar M. Deletions in the 13q material, either through full monosomy or 13q14 locus in adult lymphoblastic leukemia: rate of incidence unbalanced rearrangements. Incidence of chromosome and relevance. Cancer. 2000 Mar 15;88(6):1359-64 13 deletions is higher at relapse. Heerema NA, Sather HN, Sensel MG, Lee MK, Hutchinson RJ, Nachman JB, Reaman GH, Lange BJ, Steinherz PG, Bostrom Prognosis BC, Gaynon PS, Uckun FM. Abnormalities of chromosome May confer an increased risk of treatment failure but to bands 13q12 to 13q14 in childhood acute lymphoblastic leukemia. J Clin Oncol. 2000 Nov 15;18(22):3837-44 date has not been shown to be an independent prognostic indicator. Schneider NR, Carroll AJ, Shuster JJ, Pullen DJ, Link MP, Borowitz MJ, Camitta BM, Katz JA, Amylon MD. New recurring cytogenetic abnormalities and association of blast cell Cytogenetics karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a pediatric oncology group report of Cytogenetics morphological 343 cases. Blood. 2000 Oct 1;96(7):2543-9 Various breakpoints reported. The centromeric Cavé H, Avet-Loiseau H, Devaux I, Rondeau G, Boutard P, breakpoint is typically in the 13q12-14 region and Lebrun E, Méchinaud F, Vilmer E, Grandchamp B. Deletion of chromosomal region 13q14.3 in childhood acute lymphoblastic telomeric between 13q21 and 13qter. Loss of all or part leukemia. Leukemia. 2001 Mar;15(3):371-6 of 13q14 is common to almost all cases. Occurs as a

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Kovacs BZ, Niggli FK, Betts DR. Aberrations involving 13q12 This article should be referenced as such: approximately q14 are frequent secondary events in childhood acute lymphoblastic leukemia. Cancer Genet Cytogenet. 2004 Betts D. del(13q) in ALL. Atlas Genet Cytogenet Oncol Jun;151(2):157-61 Haematol. 2005; 9(1):24-25.

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Leukaemia Section Short Communication t(14;21)(q11;q22) Jacques Boyer Laboratoire d'Hématologie, CH du MANS, France (JB)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1421q11q22ID1180.html DOI: 10.4267/2042/38155 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Note Alias OLIG2. Disease DNA/RNA T-cell Acute lymphoblastic leukemia (T-ALL) This gene maps within a 9 to 12 Mb region of Epidemiology chromosome 21q22. Rare. Protein Clinics This gene was shown to possess a helix-loop-helix (bHLH) motif witch inhibits the E2A function in One case reported: The patient was a 7-years-old transfection assays. E2A is required for normal T-cell female with high white blood count with lymphoblasts differentiation. positive for T-cell antigens; cerebrospinal fluid negative for malignant cells; superior mediastinal mass. Result of the chromosomal Prognosis anomaly The patient attained a complete remission with standard chemotherapy but relapsed and died after 4 months of Hybrid gene therapy. Note Translocation of the BHLHB1 gene 130kb upstream of Cytogenetics the TCRA enhancer. This translocation activates the Cytogenetics morphological BHLHB1 gene and produces high levels of BHLHB1 mRNA. Expression of HLHB1 inhibits E2A-mediated The t(14;21)(q11.2;q22) was accompanied with transcription activation in vitro. del(6)(q21). Cryptic t(14;21) translocation cases may exist. Fusion protein Note Genes involved and proteins No fusion protein. TCRA Oncogenesis Location Several helix-loop-helix (HLH) proteins are proposed to function as transcriptionnal regulatory factors based 14q11.2 on their ability to bind in vitro the E-box motif of Protein transcriptional enhancers. T cell receptor. The observation that ectopic BHLHB1 expression can inhibit E2A activity suggests that BHLHB1 exerts its BHLHB1 leukemogenic effects through a functional inhibition of Location E2A. 21q22

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 26 t(14;21)(q11;q22) Boyer J

development and to rapid development of T-cell lymphomas. References Mol Cell Biol. 1997 Aug;17(8):4782-91 Whitlock JA, Raimondi SC, Harbott J, Morris SW, McCurley Wang J, Jani-Sait SN, Escalon EA, Carroll AJ, de Jong PJ, TL, Hansen-Hagge TE, Ludwig WD, Weimann G, Bartram CR. Kirsch IR, Aplan PD. The t(14;21)(q11.2;q22) chromosomal t(5;14)(q33-34;q11), a new recurring cytogenetic abnormality in translocation associated with T-cell acute lymphoblastic childhood acute leukemia. Leukemia. 1994 Sep;8(9):1539-43 leukemia activates the BHLHB1 gene. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3497-502 Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A This article should be referenced as such: Collaborative Study of the Group Français de Cytogénétique Hématologique. Blood. 1996 Apr 15;87(8):3135-42 Boyer J. t(14 ;21)(q11;q22). Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):26-27. Bain G, Engel I, Robanus Maandag EC, te Riele HP, Voland JR, Sharp LL, Chun J, Huey B, Pinkel D, Murre C. E2A deficiency leads to abnormalities in alphabeta T-cell

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Leukaemia Section Mini Review t(1;14)(q21;q32) IRTA1/IGH Mary Callanan, Dominique Leroux Lymphoma Research Group - Groupe de Recherche sur les Lymphomes - EMI0353, Institut Albert Bonniot, Université Joseph Fourier Grenoble 1, La Tronche 38706, France (MC, DL)

Published in Atlas Database: December 2004 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32ID1375.html DOI: 10.4267/2042/38156 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA IRTA1 localises to the IRTA gene locus. Three IRTA1 Note: transcripts of 2.5kb, 2.7kb and 3.5kb are possible due This translocation with IRTA1 involvement is different to alternate usage of 3 polyadenylation sites. from t(1;14)(q21;q32) with BCL9 involvement, from Protein the t(1;14)(q21;q32) with FCGR2B involvement, and The three alternate IRTA1 transcripts give rise to the from the t(1;14)(q21;q32) with MUC1 involvement. same putative 515 amino acid protein. The protein shows a signal peptide, four extracellular Clinics and pathology Ig-type domains carrying three potential asparagaine Disease (N)-linked glycosylation sites, a 16 amino acid transmmbrane and a 106 amino acid cytoplasmic Multiple Myeloma and B-cell non-Hodgkins domain with three putative consensus Src-homology 2 lymphoma. SH2 binding domains. Epidemiology These domains show similarity to both ITAM Rare. 2 published cases: 1 in a multiple myeloma cell (Immunoreceptor Tyrosine-based Activation Motifs) line. The second in a case of gastric diffuse large B-cell and ITIM (Immunoreceptor Tyrosine-based Inhibition lymphoma (DLBCL). Motifs). The function of the protein is unknown. It is expressed in marginal zone B cells. In the Prognosis extracellular domain IRTA1 protein shows homology Unknown. to Ig superfamily receptors (47% identity and 51% similarity) and Fc receptor family (37% identity and Genetics 50% similarity). In the intracellular domain, IRTA1 shows striking homology to PECAM1 (31% identity Note and 45% homology). The t(1;14) interrupts the IRTA gene locus IGH (Immunoglobulin superfamily Receptor Translocation Associated gene locus) which spans approximately Location 250kb, between the IRTA1 and IRTA2 genes. 14q32 Genes involved and proteins Result of the chromosomal IRTA1 anomaly Location Fusion protein 1q21 Description

Expression of IRTA1 fusion proteins. In the first case

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 28 t(1;14)(q21;q32) IRTA1/IGH Callanan M, Leroux D

described the t(1;14) juxtaposes the IRTA1 gene to the C alpha constant gene in the same transcriptional References orientation on the der(14) chromosome. An IRTA1/C Davis RS, Wang YH, Kubagawa H, Cooper MD. Identification alpha fusion protein results from this. The predicted of a family of Fc receptor homologs with preferential B cell expression. Proc Natl Acad Sci U S A. 2001 Aug fusion protein fuses the signal peptide and first two 14;98(17):9772-7 extracellular residues of IRTA1 to the C alpha encoded transmembrane and cytoplasmic domains. Hatzivassiliou G, Miller I, Takizawa J, Palanisamy N, Rao PH, Iida S, Tagawa S, Taniwaki M, Russo J, Neri A, Cattoretti G, Overexpression of IRTA1 was not observed in other Clynes R, Mendelsohn C, Chaganti RS, Dalla-Favera R. IRTA1 myeloma or lymphoma cell lines, regardless of the and IRTA2, novel immunoglobulin superfamily receptors status of its chromosomal band 1q21. expressed in B cells and involved in chromosome 1q21 More recently long distance inverse PCR cloning abnormalities in B cell malignancy. Immunity. 2001 Mar;14(3):277-89 identified a second case of IRTA1 translocation to IGH switch sequence (Switch gamma 3) in a case of gastric Falini B, Tiacci E, Pucciarini A, Bigerna B, Kurth J, DLBCL. Hatzivassiliou G, Droetto S, Galletti BV, Gambacorta M, Orazi A, Pasqualucci L, Miller I, Kuppers R, Dalla-Favera R, In contrast, IRTA2 gene (located telomeric of IRTA1 Cattoretti G. Expression of the IRTA1 receptor identifies in the IRTA gene locus) shows frequent deregulation in intraepithelial and subepithelial marginal zone B cells of the Burkitt lymphoma and Multiple Myeloma cell lines mucosa-associated lymphoid tissue (MALT). Blood. 2003 Nov with 1q21 abnormalities (mostly duplications or 15;102(10):3684-92 unbalanced translocations that lead to trisomy or Sonoki T, Willis TG, Oscier DG, Karran EL, Siebert R, Dyer tetrasomy 1q). MJ. Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse IRTA1 is normally expressed in marginal zone B cells PCR. Leukemia. 2004 Dec;18(12):2026-31 while IRTA2 is selectively expressed in centrocytes, marginal zone B cells and immunoblasts. This article should be referenced as such: IRTA1 and 2 have been independently cloned as Callanan M, Leroux D. t(1;14)(q21;q32) IRTA1/IGH. Atlas FcRH4 and FcRH5 (Fc Receptor Homologues) from a Genet Cytogenet Oncol Haematol. 2005; 9(1):28-29. human lymph node cDNA library.

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Leukaemia Section Short Communication t(1;14)(q21;q32) MUC1/IGH Jacques Boyer Laboratoire d'Hématologie, CH du MANS, France (JB)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32MUC1ID1342.html DOI: 10.4267/2042/38158 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Genes involved and proteins Note MUC1 The chromosomal band 1q21 is the third most frequent Location site of rearrangement in non-Hodgkin's lymphoma after 1q21. 14q32 and 18q21. Five genes mapped to this region (BCL9, MUC1, Note FCGR2B, MUM2, API2) some have been shown to be Located 8cM telomeric to BCL9; aliases of MUC1 are deregulated by juxtaposition with the IgH genes. EMA and CD227. Disease DNA/RNA B-cell non Hodgkin Lymphoma (NHL). 3.88 kb, 8 exons, 1721 bp, 2 transcripts. Epidemiology Protein The MUC1 region is rearranged in 6% of tumors with 122.1 kDa (1255 aa) Highly glycosylated protein. 1q21 cytogenetic aberration. The MUC1 protein can be expressed as a transmembrane or secretedprotein. May be playing a Cytology role in adhesive functions and in cell-cell interactions, No clear association with a particular NHL subtype has metastasis, signaling and is implicated in some been reported. adenocarcinomas. The EMA wich is equivalent to Prognosis MUC1 occurs in lymphocyte-predominant Hodgkin's Poor prognosis especially in diffuse large cell disease, plasmocytomas and T-cell lymphomas due to lymphoma. mechanisms other than 1q21 rearrangement. May be associated with tumor progression. IgH Cytogenetics Location 14q32. Cytogenetics morphological A number of 1q21 abnormalities result in an Result of the chromosomal unbalanced chromosome 1 translocation. anomaly Additional anomalies Caryotype of tencomplex.Usually detected with Hybrid gene t(14;18)(q32;q21) and t(8;14)(q24;q32) as a secondary Description chromosomal abnormalitie. The translocation links sequences 2.4 kpb 3' of the MUC1 gene on chromosome 1 to the IGH4 switch

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 30 t(1;14)(q21;q32) MUC1/IGH Boyer J

region on chromosome 14. MUC1 gene is intact. The In addition to activation of MUC1, haploid loss of MUC1 gene is brought into proximity with the C chromosome 1 long arm also contributes to gamma 4 and C alpha 2 loci. Downstream of C alpha 2 oncogenesis in some tumors. is an enhancer element implicated in the activation of MUC1 expression. References Fusion protein Dyomin VG, Palanisamy N, Lloyd KO, Dyomina K, Jhanwar SC, Houldsworth J, Chaganti RS. MUC1 is activated in a B-cell Description lymphoma by the t(1;14)(q21;q32) translocation and is No fusion protein. rearranged and amplified in B-cell lymphoma subsets. Blood. 2000 Apr 15;95(8):2666-71 Oncogenesis Gilles F, Goy A, Remache Y, Shue P, Zelenetz AD. MUC1 Chromosomal translocation involving class switch dysregulation as the consequence of a t(1;14)(q21;q32) recombination when DNA strand breaks are introduced translocation in an extranodal lymphoma. Blood. 2000 May into the switch regions of recombining CH genes. 1;95(9):2930-6 Activation of MUC1 translation and transcription. An Macintyre E, Willerford D, Morris SW. Non-Hodgkin's important role for MUC1 in tumorigenesis has been Lymphoma: Molecular Features of B Cell Lymphoma. demontrated in Muc-1 null mice. MUC1 is associated Hematology Am Soc Hematol Educ Program. 2000;:180-204 with delayed progression of the tumor (selective This article should be referenced as such: advantage, inhibition of cell adhesion). Boyer J. t(1;14)(q21;q32) MUC1/IGH. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):30-31.

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Leukaemia Section Short Communication t(1;6)(p35;p25) Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F- 86021 Poitiers, France (JLH)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0106p35p25ID1378.html DOI: 10.4267/2042/38157 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

t(1;6)(p35;p25) G- banding - Courtesy Melanie Zenger and Claudia Haferlach.

Clinics and pathology Prognosis Yet unknown (median follow up is only 28 months), Disease but 3 patients developed a diffuse large B-cell Chronic lymphocytic leukemia (CLL) lymphoma (DLBCL), and 3 patients (2 of which with Phenotype/cell stem origin DLBCL) died at 29, 76, and 95 months. Unmutated status of IgVH (an unfavourable prognostic Cytogenetics feature) was found in all cases. Epidemiology Additional anomalies Sole anomaly in three cases, with +12 in three cases, 8 patients to date, representing 0.5% of CLL cases in a with 9q anomalies in three, del(11q) in two, 17p country based survey; sex ratio: 6 male/2 female anomalies in two, 17q anomalies in two; del(11q), and patients, aged 33-81 years (med: 62.5 years). 17p anomalies are poor prognostic factors in CLL. Clinics Two cases in Binet stage A, 4 in stage B, 2 in stage C. Genes involved and proteins Normal LDH values in 7 of 8. Note

IRF4 (6p25.2) is possibly involved in the translocation. The gene in 1p35.3 is unknown.

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 32 t(1;6)(p35;p25) Huret JL

To be noted References Case Report Michaux L, Wlodarska I, Rack K, Stul M, Criel A, Maerevoet M, Marichal S, Demuynck H, Mineur P, Kargar Samani K, Van Translocation t(1;6)(p35;p25) in B-cell Hoof A, Ferrant A, Marynen P, Hagemeijer A. Translocation lymphoproliferative disorder with evolution to Diffuse t(1;6)(p35.3;p25.2): a new recurrent aberration in "unmutated" Large B-cell Lymphoma. B-CLL. Leukemia. 2005 Jan;19(1):77-82 Chronic lymphocytic leukaemia/Small lymphocytic This article should be referenced as such: lymphoma (CLL/SLL) associated with translocation t(1;6)(p35;p25) as part of complex karyotype. Huret JL. t(1;6)(p35;p25). Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):32-33.

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Leukaemia Section Short Communication t(16;21)(p11;q22) Jean Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F- 86021 Poitiers, France (JLH)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1621.html DOI: 10.4267/2042/38161 This article is an update of: Pérot C. t(16;21)(p11;q22). Atlas Genet Cytogenet Oncol Haematol.1998;2(2):62.

Identity

t(16;21)(p11;q22) G- banding - Courtesy Melanie Zenger and Claudia Haferlach.

Clinics and pathology Cytology Myelocytic and monocytoid features are often present; Disease eosinophils in the bone marrow are sometimes de novo acute non lymphocytic leukemia (ANLL); to abnormal and/or elevated; erythrophagocytosis may be be noted is one case of chronic myelogenous leukemia found. (CML) -blast crisis. Prognosis Phenotype/cell stem origin Seems poor: complete remission may not be achieved; ANLL cases: mainly M1, M2, M4, M5a, M5b, or M7 there is high incidence of relapse within a year and a ANLL; may be preceded by a myelodysplastic median of survival is about 22 months (cases herein syndrome (MDS). reviewed). Epidemiology Disease About 40 reported cases, mainly found in young adults; Ewing tumours children cases are described; median age is about 30 Note yrs; balanced sex ratio. t(16;21)(p11;q22) has been found in rare cases of Clinics Ewing tumours, a paediatric neoplasm with small Blood data: anemia, thrombocytopenia, mild round-cells derived from neural crests cells usually hyperleucocytosis; with high monocytic cell count at associated with translocations involving EWSR1. times.

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 34 t(16;21)(p11;q22) Huret JL

Cytogenetics bone marrow eosinophilia and structural anomaly of chromosome 16. Cancer Genet Cytogenet. 1985 Ewing tumours are usually associated with a Aug;17(4):359-63 t(11;22)(q24;q12) with 5' EWSR1 - 3' FLI1 Minamihisamatsu M, Ishihara T. Translocation (8;21) and its involvement, less often associated with variants in acute nonlymphocytic leukemia. The relative t(21;22)(q22;q12) with 5' EWSR1 - 3' ERG importance of chromosomes 8 and 21 to the genesis of the involvement, rarely associated with t(2;22)(q36; q12) disease. Cancer Genet Cytogenet. 1988 Jul 15;33(2):161-73 (5' EWSR1 - 3' FEV) or with t(17;22)(q21;q12) (5' Berkowicz M, Rosner E, Resnitzky P, Mamon Z, Ben-Bassat I, EWSR1-3' ETV4) Ramot B. Acute nonlymphocytic leukemia with t(16;21) Cancer Genet Cytogenet. 1990 Jul 1;47(1):139-40 Prognosis Sadamori N, Yao E, Tagawa M, Nakamura H, Sasagawa I, Recent treatments have improved the prognosis of Itoyama T, Tokunaga S, Ichimaru M, Nakamura I, Kamei T. Ewing's tumours. The prognosis is mainly determined 16;21 translocation in acute nonlymphocytic leukemia with by the presence of metastases at the time of diagnosis. abnormal eosinophils: a unique subtype. Acta Haematol. 1990;84(4):212-6 Cytogenetics Marosi C, Bettelheim P, Geissler K, Lechner K, Köller U, Haas OA, Chott A, Hagemeijer A. Translocation (16;21)(p11;q22) in acute monoblastic leukemia with erythrophagocytosis. Cancer Additional anomalies Genet Cytogenet. 1991 Jul 1;54(1):61-6 ANLL cases: found solely in about 60% of cases in at Morgan R, Riske CB, Meloni A, Ries CA, Johnson CH, Lemons least a subclone; associated with +10, +8, or de(9q)/-9 RS, Sandberg AA. t(16;21)(p11.2;q22): a recurrent primary in about 10% of cases each. rearrangement in ANLL. Cancer Genet Cytogenet. 1991 May;53(1):83-90 Genes involved and proteins Ferro MR, Cabello P, Garcia-Sagredo JM, Resino M, San Roman C, Larana JG. t(16;21) in a Ph positive CML. Cancer FUS Genet Cytogenet. 1992 Jun;60(2):210-1 Location Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai M, Kaneko Y. The 8;21 chromosome translocation in acute 16p11 myeloid leukemia is always detectable by molecular analysis Protein using AML1. Blood. 1993 Mar 15;81(6):1573-9 RNA binding protein; member of the TET family, like Nobbs MC, Chan-Lam D, Howell RT, Kitchen C, Copplestone EWSR1. JA. Acute non-lymphocytic leukemia with t(16;21). Cancer Genet Cytogenet. 1993 Oct 15;70(2):144-5 ERG Okada K, Takeichi M, Uchida H, Shirota T, Sakai N, Ito H. Location Translocation (16;21)(p11;q22) in acute nonlymphocytic leukemia. Cancer Genet Cytogenet. 1994 Jul 1;75(1):60-3 21q22 Panagopoulos I, Aman P, Fioretos T, Höglund M, Johansson Protein B, Mandahl N, Heim S, Behrendtz M, Mitelman F. Fusion of the ETS transcription factor. FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22). Genes Chromosomes Cancer. 1994 Result of the chromosomal Dec;11(4):256-62 Satoh K, Miura I, Chubachi A, Ohtani H, Hirokawa M, Niitsu H, anomaly Miura AB. [Acute monoblastic leukemia (M5a) with dysmegakaryocytopoiesis associated with t(16;21) (p11;q22)]. Hybrid gene Rinsho Ketsueki. 1994 Feb;35(2):160-4 Description Scott AA, Head DR, Kopecky KJ, Appelbaum FR, Theil KS, Grever MR, Chen IM, Whittaker MH, Griffith BB, Licht JD. HLA- 5' FUS including exons 1 to 6, 7 or 8 - 3' ERG from DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute exon 7, 8 or 9 to C-term. leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute Fusion protein myeloid leukemia-M3. Blood. 1994 Jul 1;84(1):244-55 Description Hiyoshi M, Koh KR, Yamane T, Tatsumi N. Acute non- N-term FUS transactivation domain fused to the C-term lymphoblastic leukaemia with t(16;21): case report with a review of the literature. Clin Lab Haematol. 1995 DNA binding ETS domain of ERG. Sep;17(3):243-6 Oncogenesis Hiyoshi M, Yamane T, Hirai M, Tagawa S, Hattori H, Nakao Y, Seems to act as a transcriptional activator. Yasui Y, Koh KR, Hino M, Tatsumi N. Establishment and characterization of IRTA17 and IRTA21, two novel acute nonlymphocytic leukaemia cell lines with t(16;21) translocation. Br References J Haematol. 1995 Jun;90(2):417-24 Mecucci C, Bosly A, Michaux JL, Broeckaert-Van Orshoven A, Harigae H, Kobayashi M, Mihara A, Watanabe N. Detection of Van den Berghe H. Acute nonlymphoblastic leukemia with minimal residual disease in cerebro-spinal fluid of a patient

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with acute myelogenous leukemia with t(16;21)(p11;q22) t(16;21)(p11;q22): frequent expression of CD56 and translocation by reverse transcriptase-polymerase chain interleukin-2 receptor alpha chain. Br J Haematol. 1999 reaction. Tohoku J Exp Med. 1997 Dec;183(4):297-302 Jun;105(3):711-9 Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Okita H, Umezawa A, Fukuma M, Ando T, Urano F, Sano M, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Nakata Y, Mori T, Hata J. Acute myeloid leukemia possessing Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, jumping translocation is related to highly elevated levels of Yanagisawa M, Hayashi Y. Consistent detection of TLS/FUS- EAT/mcl-1, a Bcl-2 related gene with anti-apoptotic functions. ERG chimeric transcripts in acute myeloid leukemia with Leuk Res. 2000 Jan;24(1):73-7 t(16;21)(p11;q22) and identification of a novel transcript. Blood. 1997 Aug 1;90(3):1192-9 Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Léonard C, Bilhou- Tamura S, Takemoto Y, Hashimoto-Tamaoki T, Mimura K, Nabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Sugahara Y, Senoh J, Furuyama JI, Kakishita E. Cytogenetic Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O, analysis of de novo acute myeloid leukemia with trilineage Duchayne E, Berger R. Cytogenetic profile of childhood and myelodysplasia in comparison with myelodysplastic syndrome adult megakaryoblastic leukemia (M7): a study of the Groupe evolving to acute myeloid leukemia. Int J Oncol. 1998 Français de Cytogénétique Hématologique (GFCH). Blood. Jun;12(6):1259-62 2002 Jul 15;100(2):618-26 Imashuku S, Hibi S, Kuriyama K, Todo S. Hemophagocytosis Shing DC, McMullan DJ, Roberts P, Smith K, Chin SF, by leukemic blasts in a case of acute megakaryoblastic Nicholson J, Tillman RM, Ramani P, Cullinane C, Coleman N. leukemia with t(16;21)(p11;q22). Int J Hematol. 1999 FUS/ERG gene fusions in Ewing's tumors. Cancer Res. 2003 Jul;70(1):36-9 Aug 1;63(15):4568-76 Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik Heller A, Loncarevic IF, Glaser M, Gebhart E, Trautmann U, MV, Steuber CP, Weinstein HJ, Carroll AJ. Chromosomal Claussen U, Liehr T. Breakpoint differentiation in chromosomal abnormalities in 478 children with acute myeloid leukemia: aberrations of hematological malignancies: Identification of 33 clinical characteristics and treatment outcome in a cooperative previously unrecorded breakpoints. Int J Oncol. 2004 pediatric oncology group study-POG 8821. Blood. 1999 Dec Jan;24(1):127-36 1;94(11):3707-16 This article should be referenced as such: Shikami M, Miwa H, Nishii K, Takahashi T, Shiku H, Tsutani H, Oka K, Hamaguchi H, Kyo T, Tanaka K, Kamada N, Kita K. Huret JL. t(16;21)(p11;q22). Atlas Genet Cytogenet Oncol Myeloid differentiation antigen and cytokine receptor Haematol. 2005; 9(1):34-36. expression on acute myelocytic leukaemia cells with

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in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Short Communication t(9;11)(q34;p15) Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F- 86021 Poitiers, France (JLH)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0911q34p15ID1380.html DOI: 10.4267/2042/38159 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Protein Class II homeobox gene. Disease NUP98 Acute myelomonocytic leukemia (M4 ANLL). Location Etiology 11p15.4 This leukemia case is likely to be treatment related (a Protein lymphoma was treated 4 years previously). Nucleoporin 98, a 98 kDa component of the nuclear Epidemiology pore complex implicated in nucleo-cytoplasmic Only one case to date: a 65-year-old female patient. transport. Prognosis Result of the chromosomal No data. anomaly Genes involved and proteins Hybrid gene PRRX2 Description Location 5'--> exon 11 of NUP98 is fused in frame with PRRX2 9q34 exon 2 to 3'.

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 37 t(9;11)(q34;p15) Huret JL

References This article should be referenced as such: Huret JL. t(9;11)(q34;p15). Atlas Genet Cytogenet Oncol Gervais C, Mauvieux L, Perrusson N, Hélias C, Struski S, Haematol. 2005; 9(1):37-38. Leymarie V, Lioure B, Lessard M. A new translocation t(9;11)(q34;p15) fuses NUP98 to a novel homeobox partner gene, PRRX2, in a therapy-related acute myeloid leukemia. Leukemia. 2005 Jan;19(1):145-8

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Leukaemia Section Mini Review

t(X;20)(q13;q13.3) Kavita S Reddy, Kathy E Richkind Genzyme Genetics, Orange, CA, USA (KSR); Genzyme Genetics, Santa Fe, NM, USA (KER)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0X20q13q13ID1381.html DOI: 10.4267/2042/38160 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 1‚4 (top to bottom; see case report section). Arrows indicate the derivatives 20 and X.

Clinics and pathology (AML)-M1; myelofibrosis --> acute leukemia. Epidemiology Disease Only 7 cases to date and they are exclusively female: 0 Myelodysplastic syndromes (MDS): refractory anaemia Male/7 Female; found in older patients (Median age 61 with excess of blasts (RAEB-RAEBt), refractory years; range: 57-86). anaemia (RA), MDS sideroblastic anemia and MDS pancytopenia and thrombocytopenia most often (5 Clinics cases); polycytemia vera --> acute myeloid leukemia Still poorly known.

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 39 t(X;20)(q13;q13.3) Reddy KS, Richkind KE

Fig 2: X-centromere probe DXZ1 (green) hybridized to the normal X and the derivative X (arrows). The androgen receptor (Xq12) AR (red) probe hybridized to derivative 20 and the normal X (arrows). The breakpoint on the X chromosome is proximal to AR. The karyotype is 46, X, t(X;20)(q13;q13.3).ish t(X;20)(q11.2q12;q13.3)(wcpX+,wcp20+,AR?;wcp20+, D20S180?,AR+,wcpX+). The revised breakpoints identified with FISH analysis are highlighted in bold.

Translocation (X;20)(q13;q13.3): a nonrandom Cytogenetics abnormality in four patients with myeloid disorders: Cytogenetics morphological case 4 Sole abnormality in 5 MDS cases and accompanying References changes +8, +9, del(13)(q21) and der(1;7)(q10;p10) in 2 cases that transformed to AML. Michaux L, Wlodarska I, Mecucci C, Hernandez JM, Van Orshoven A, Michaux JL, Van den Berghe H. Characterization Cytogenetics molecular by chromosome painting of balanced and unbalanced X By FISH the cytogenetic breakpoint was proximal to chromosome translocations in myelodysplastic syndromes. Cancer Genet Cytogenet 1995;82:17-22 AR gene and hence the breakpoint on X chromosome is t(X;20)(q11.2q12;q13.3). Gray BA, Cornfield D, Bent-Williams A and Zori RT. Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two patients with myelocytic disorders. Cancer Genet To be noted Cytogenet 2003;141:169-174 Case Report Reddy KS, Richkind K, Ross M, Seirra R. Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients Translocation (X;20)(q13;q13.3): a nonrandom with myeloid disorders. Cancer Genet Cytogenet. 2005 abnormality in four patients with myeloid disorders: Feb;157(1):70-3 case 1 Translocation (X;20)(q13;q13.3): a nonrandom This article should be referenced as such: abnormality in four patients with myeloid disorders: Reddy KS, Richkind KE. t(X;20)(q13;q13.3). Atlas Genet case 2 Cytogenet Oncol Haematol. 2005; 9(1):39-40. Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 3

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Solid Tumour Section Review

Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma Manuel Sánchez-Martín, Ines González-Herrero, Isidro Sánchez-García Laboratorio 13, Instituto de Biologia Molecular y Celular del Cancer (IBMCC), Centro de Investigacion del Cancer, Campus Unamuno, 37.007-Salamanca, Spain (MSM, IGH, ISG)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Tumors/MyxoidLipoSarcID5169.html DOI: 10.4267/2042/38162 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

displaying its own morphologic and clinical Identity characteristics. Alias Cytogenetic and molecular genetic analyses have Myxoid-round cell liposarcoma. shown that some of these STS are characterized by specific chromosomal translocations, whereas other Note STS show complex genetic aberrations. Sarcomas are relatively rare malignant tumours and Liposarcoma is the most common soft tissue comprise less than 10% of all cancers. Classical malignancy in adults accounting for at least 20% of all classifications of sarcomas are based on the site of sarcomas in this age group. Myxoid-round cell tumour (bone or soft tissue). Soft tissue sarcoma (STS) liposarcoma is a subtype of liposarcoma characterized is the collective term used for malignancies arising in by the presence of the reciprocal chromosomal muscles, fat, vessels, the peripheral nervous system and translocation t(12;16)(q13;p11). fibrous tissue. This translocation creates the FUS-DDIT3 chimeric Histopathologic examination of such tumours has gene. revealed a large number of distinct entities, each Clinics and pathology

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Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma Sánchez-Martín M, et al.

stimuli, and it is required for the maintenance of Classification genomic stability. The involvement of a nuclear Liposarcoma is a lipogenic tumour subclassified into riboprotein in these processes in vivo indicates that four main histologic groups, including well- FUS is important in genome maintenance. differentiated liposarcoma (lipoma-like and sclerosing Somatic mutations types), myxoid-round cell liposarcoma, pleomorphic Variants: FUS has been also shown a partner of gene liposarcoma, and dedifferentiated liposarcoma. The fusions linked in other malignances: fused to ERG in histologic group is predictive of both the clinical course acute myeloid leukaemia with t(16:21)(p11;q22), fused of the disease and the ultimate prognosis. to CREB3L2 in low-grade fibromyxoid .sarcoma (LGFMS) by a translocation between chromosome Cytogenetics bands 7q33-q34 (CREB3L2) and 16p11 (FUS) or fused Cytogenetics Morphological to ATF1 in histiocytoma. Cytogenetics analyses have shown that several DDIT3 (CHOP) lipogenic tumours are characterized by specific Location chromosomal abnormalities, the best known was the 12q13 reciprocal translocation t(12;16)(q13;p11) of myxoid- DNA / RNA round cell liposarcoma, described about twenty years ago.This translocation results in a fusion gene The DDIT3 gene was isolated from human cells and consisting of the 5' part of the FUS (TLS) gene and the has a high level of conservation with previously complete coding region of the CHOP gene (see fig.1). described hamster gene. Each is composed of 4 exons with intron/exon junctions maintained at identical Genes involved and proteins positions. They showed 91% identity in amino acid sequence and 78% identity in nucleotide sequence. The FUS (TLS) gene is located on chromosome 12 (12q13.1-q13.2). Location Protein 16p11 CHOP (C/EBP-homologous protein) is a nuclear DNA / RNA protein which was identified as a dominant-negative inhibitor of the transcription factors C/EBP and LAP. The FUS gene consists of 15 exons located within 11 The protein also was called DDIT3 for DNA damage- kb of genomic DNA, and the exon 1 contains a 72-bp inducible transcript 3' and GADD153 for 'growth untranslated region and the translation initiation codon. arrest- and DNA damage-inducible gene. The location of the FUS gene was identified as 16p11 DDIT3 is consistently rearranged in myxoid by the site of the breakpoint in the translocation. The liposarcomas in the characteristic chromosomal assignment was further narrowed to 16p11.2 by translocation t(12;16)(q13;p11). Its molecular cytogenetic studies. FUS is rearranged in myxoid characterization showed that the DDIT3 gene is fused liposarcomas in the characteristic chromosomal with a gene on chromosome 16 named FUS. translocation t(12;16)(q13;p11). Somatic mutations Protein Variants: An analysis of peripheral blood samples The FUS protein, provisionally designated TLS from 19 patients with myxoid liposarcoma linked to (translocated in liposarcoma), and then called FUS, t(12;16) and from 1 patient with myxoid liposarcoma contains an RNA-recognition motif and is a component associated to t(12;22;20) chromosomal translocation, of nuclear riboprotein complexes. resulting in the fusion of the DDIT3 and EWS genes, Lack of FUS in mice causes lethallity into neonatal found FUS-DDIT3 hybrid fragments in 3 patients with period, it influences lymphocyte development in a non- t(12;16) and the EWS-DDIT3 hybrid in the patient with cell-intrinsic manner, it has an intrinsic role in the the latter translocation. proliferative responses of B cells to specific mitogenic

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Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma Sánchez-Martín M et al.

Result of the chromosomal anomaly Hybrid Gene

The FUS-CHOP fusion genes consist of the 5’ promoter region and exons 1-5 or, more rarely, 1-7 or 1-8 of FUS gene fused to the complete coding region, including exons 1-4 or 2-4, of CHOP (DDIT3) gene.

Fusion Protein glycoprotein material within the terminally differentiated adipocytes, a characteristic figure of Oncogenesis liposarcomas associated with FUS-DDIT3. However, Oncogenic properties Transcriptional control of the transgenic mice expressing the altered form of DDIT3- fusion gene is dominated by the FUS housekeeping FUS (created by the in frame fusion of the FUS domain type of regulatory region, leading to stable expression to the carboxy end of DDIT3) developed liposarcomas. of the fusion protein in tumor cells. The transforming The characteristics of the liposarcomas arising in the properties of the FUS-DDIT3 fusion protein have been DDIT3-FUS mice were very similar to those previously demonstrated in NIH 3T3 cells and fibroblasts. In the observed in the FUS-DDIT3 transgenic mice indicating FUS-DDIT3 fusion, transcriptional activation is that the FUS domain is required not only for specifically conferred on the chimeric protein by the transformation but also influences the phenotype of the FUS segment after the translocation event. The portion tumor cells. These results provide evidence that the of FUS that is present in the FUS-DDIT3 and FUS- FUS domain of FUS-DDIT3 plays a specific and ERG fusion proteins is similar and this part has been critical role in the pathogenesis of liposarcoma. In this shown to be an autonomous transcriptional activation sense, when mice expressing the FUS domain are domain. The protein most likely functions as an crossed with DDIT3-transgenic mice to generate the abnormal transcription factor acting on a number of double-transgenic FUSxDDIT3, these animals develop downstream target genes. liposarcoma. These results provide genetic evidence Mouse models In vivo, mice expressing FUS-DDIT3 that FUS and DDIT3 domains function in trans for the develop liposarcomas. Overexpression of FUS-DDIT3 mutual restoration of liposarcoma, and identify a new transgene driven by the elongation factor 1alpha mechanism of tumour-associated fusion genes which (EF1alpha) promoter to all tissues, results in most of might have impact beyond myxoid liposarcoma. the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation References of intracellular lipid, induction of adipocyte-specific genes and a concordant block in the differentiation Thelin-Järnum S, Lassen C, Panagopoulos I, Mandahl N, Aman P. Identification of genes differentially expressed in TLS- program (see figure 2). No tumours of other tissues CHOP carrying myxoid liposarcomas. Int J Cancer. 1999 Sep were found in these transgenic mice despite widespread 24;83(1):30-3 activity of the EF1alpha promoter. This establishes Hicks GG, Singh N, Nashabi A, Mai S, Bozek G, Klewes L, FUS-DDIT3 overexpression as a key determinant of Arapovic D, White EK, Koury MJ, Oltz EM, Van Kaer L, Ruley human liposarcomas and provided the first in vivo HE. Fus deficiency in mice results in defective B-lymphocyte evidence for a link between a fusion gene created by a development and activation, high levels of chromosomal chromosomal translocation and a solid tumour. In instability and perinatal death. Nat Genet. 2000 Feb;24(2):175- 9 contrast, transgenic mice expressing high levels of DDIT3, which lacks the FUS domain, do not develop Pérez-Losada J, Pintado B, Gutiérrez-Adán A, Flores T, any tumour but consistently show the accumulation of a Bañares-González B, del Campo JC, Martín-Martín JF,

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Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma Sánchez-Martín M, et al.

Battaner E, Sánchez-García I. The chimeric FUS/TLS-CHOP Rabbitts TH, Forster A, Larson R, Nathan P. Fusion of the fusion protein specifically induces liposarcomas in transgenic dominant negative transcription regulator CHOP with a novel mice. Oncogene. 2000 May 11;19(20):2413-22 gene FUS by translocation t(12;16) in malignant liposarcoma. Nat Genet. 1993 Jun;4(2):175-80 Waters BL, Panagopoulos I, Allen EF. Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS Panagopoulos I, Aman P, Fioretos T, Höglund M, Johansson and ATF-1 genes induced by a chromosomal translocation B, Mandahl N, Heim S, Behrendtz M, Mitelman F. Fusion of the involving bands 12q13 and 16p11. Cancer Genet Cytogenet. FUS gene with ERG in acute myeloid leukemia with 2000 Sep;121(2):109-16 t(16;21)(p11;q22). Genes Chromosomes Cancer. 1994 Dec;11(4):256-62 Pérez-Losada J, Sánchez-Martín M, Rodríguez-García MA, Pérez-Mancera PA, Pintado B, Flores T, Battaner E, Sánchez- Panagopoulos I, Mandahl N, Mitelman F, Aman P. Two distinct Gar ćia I. Liposarcoma initiated by FUS/TLS-CHOP: the FUS breakpoint clusters in myxoid liposarcoma and acute FUS/TLS domain plays a critical role in the pathogenesis of myeloid leukemia with the translocations t(12;16) and t(16;21). liposarcoma. Oncogene. 2000 Dec 7;19(52):6015-22 Oncogene. 1995 Sep 21;11(6):1133-7 Pérez-Mancera PA, Pérez-Losada J, Sánchez-Martín M, Zinszner H, Albalat R, Ron D. A novel effector domain from the Rodríguez-García MA, Flores T, Battaner E, Gutiérrez-Adán A, RNA-binding protein TLS or EWS is required for oncogenic Pintado B, Sánchez-García I. Expression of the FUS domain transformation by CHOP. Genes Dev. 1994 Nov 1;8(21):2513- restores liposarcoma development in CHOP transgenic mice. 26 Oncogene. 2002 Mar 7;21(11):1679-84 Panagopoulos I, Mandahl N, Ron D, Höglund M, Nilbert M, Aman P, Ron D, Mandahl N, Fioretos T, Heim S, Arheden K, Mertens F, Mitelman F, Aman P. Characterization of the CHOP Willén H, Rydholm A, Mitelman F. Rearrangement of the breakpoints and fusion transcripts in myxoid liposarcomas with transcription factor gene CHOP in myxoid liposarcomas with the 12;16 translocation. Cancer Res. 1994 Dec t(12;16)(q13;p11). Genes Chromosomes Cancer. 1992 15;54(24):6500-3 Nov;5(4):278-85 Sánchez-García I, Rabbitts TH. Transcriptional activation by Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, TAL1 and FUS-CHOP proteins expressed in acute Brosjo O, Mandahl N, Panagopoulos I. Fusion of the FUS and malignancies as a result of chromosomal abnormalities. Proc BBF2H7 genes in low grade fibromyxoid sarcoma. Hum Mol Natl Acad Sci U S A. 1994 Aug 16;91(17):7869-73 Genet. 2003 Sep 15;12(18):2349-58 Ichikawa H, Shimizu K, Hayashi Y, Ohki M. An RNA-binding Park JS, Luethy JD, Wang MG, Fargnoli J, Fornace AJ Jr, protein gene, TLS/FUS, is fused to ERG in human myeloid McBride OW, Holbrook NJ. Isolation, characterization and leukemia with t(16;21) chromosomal translocation. Cancer chromosomal localization of the human GADD153 gene. Gene. Res. 1994 Jun 1;54(11):2865-8 1992 Jul 15;116(2):259-67 Crozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a Daugaard S. Current soft-tissue sarcoma classifications. Eur J novel RNA-binding protein in human myxoid liposarcoma. Cancer. 2004 Mar;40(4):543-8 Nature. 1993 Jun 17;363(6430):640-4 Ron D, Habener JF. CHOP, a novel developmentally regulated Panagopoulos I, Aman P, Mertens F, Mandahl N, Rydholm A, nuclear protein that dimerizes with transcription factors C/EBP Bauer HF, Mitelman F. Genomic PCR detects tumor cells in and LAP and functions as a dominant-negative inhibitor of peripheral blood from patients with myxoid liposarcoma. Genes gene transcription. Genes Dev. 1992 Mar;6(3):439-53 Chromosomes Cancer. 1996 Oct;17(2):102-7 Eneroth M, Mandahl N, Heim S, Willén H, Rydholm A, Alberts Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, KA, Mitelman F. Localization of the chromosomal breakpoints Toresson H, Höglund M, Forster A, Rabbitts TH, Ron D, of the t(12;16) in liposarcoma to subbands 12q13.3 and Mandahl N, Mitelman F. Expression patterns of the human 16p11.2. Cancer Genet Cytogenet. 1990 Aug 1;48(1):101-7 sarcoma-associated genes FUS and EWS and the genomic structure of FUS. Genomics. 1996 Oct 1;37(1):1-8 Turc-Carel C, Limon J, Dal Cin P, Rao U, Karakousis C, Sandberg AA. Cytogenetic studies of adipose tissue tumors. II. This article should be referenced as such: Recurrent reciprocal translocation t(12;16)(q13;p11) in myxoid liposarcomas. Cancer Genet Cytogenet. 1986 Dec;23(4):291-9 Sánchez-Martín M, González-Herrero I, Sánchez-García I. Soft Tissue Tumors: Liposarcoma: Myxoid liposarcoma. Atlas Kuroda M, Ishida T, Horiuchi H, Kida N, Uozaki H, Takeuchi H, Genet Cytogenet Oncol Haematol. 2005; 9(1):41-44. Tsuji K, Imamura T, Mori S, Machinami R. Chimeric TLS/FUS- CHOP gene expression and the heterogeneity of its junction in human myxoid and round cell liposarcoma. Am J Pathol. 1995 Nov;147(5):1221-7

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Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Solid Tumour Section Review

Uterus Tumours: an Overview Roberta Vanni, Giuseppina Parodo Dip. Scienze e Tecnologie Biomediche, Sezione di Biologia e Genetica, Università di Cagliari, Cittadella Universitaria, 09142 Monserrato (CA), Italy (RV, GP)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Tumors/UterusTumOverviewID5157.html DOI: 10.4267/2042/38163 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Clinics and pathology Note Note Anatomically, uterine neoplasms may be localized at Female pelvic gynaecological malignancies account for the corpus, isthmus (the transition between the almost 15% of all cancers in women. Uterine cancer is endocervix and uterine corpus) and cervix. The the most common, specifically endometrial cancer of fallopian tubes and uterine ligaments may also undergo the uterine corpus. tumour tranformation. This overview will focus on UTERINE CERVIX NEOPLASIA uterine cervix and corpus tumours, including benign, pre-malignant and malignant lesions. They may affect Note the endometrium, muscles or other supporting tissue. In countries that have well-developed screening Uterine tumours may be histologically typed according programs using the Papanicolaou smear test to detect to several classification systems. Those used most premalignant lesions, the incidence of invasive cervical frequently are based on the WHO (World Health cancer continues to decline. Age-standardised Organization) International Histological Classification incidence rates vary from about 10 per 100,000 in most of Tumours and on the ISGYP (International Society of developed countries to more than 40 (up to 100) per Gynecological Pathologists). The most widely-accepted 100,000 in many of the developing countries. staging system is the FIGO (International Federation of Worldwide, invasive cervical cancer is the second most Gynecology and Obstetrics) one. common female malignancy after breast cancer, with 500,000 new cases diagnosed each year. Among benign Classification lesions, endocervical polyps are the most common, while among malignant lesions, account for According to WHO recommendations, the main approximately 90%, and adenocarcinomas for UTERINE CERVIX categories are: approximately 10% of cervical cancers. Due to - Epithelial tumours, considerable ongoing evolution in understanding the - Mesemchymal tumours, pathobiology of cervix precursor lesions, there is a lack - Mixed epithelial and mesenchymal tumours, of uniform clinical, cytological and histological - Secondary tumours. terminology, the most widely accepted being the The main UTERINE CORPUS categories, once again modifications incorporated into the Bethesda System of according to WHO recommendations, are: cytological diagnosis. - Epithelial tumours, - Mesenchymal tumours, Etiology - Mixed epithelial and mesenchymal tumours, Carcinomas of the uterine cervix are thought to arise - Trophoblastic tumours, from precursor lesions, and different subtypes of - Secondary tumours. human papilloma virus (HPV) are major etiological factors in disease pathogenesis. Only certain types of

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HPV cause cervical cancer: HPV 16, 18, 33, 35, 45, 56, endocervical glandular atypia. 30-60% of AIS are called "high-risk" types, are associated with high-grade associated with SIL. 50-90% of cases are associated Squamous Intraepithelial Lesions (SIL) and invasive with HPV 16 or 18. carcinomas, whereas "low- risk" HPV 6, 11, 42, 44 are Squamous cell carcinoma (SCC) accounts for 80-90% associated with genital condyloma and low-grade SIL. of all cervical malignancies and for 60-80 % of 5% of cervical cancers are HPV DNA-negative. invasive carcinomas. There are two major forms: Epidemiology microinvasive and invasive SCC. Diagnosis of the former is based on the presence of microinvasion foci. Epidemiologic studies report that factors increasing the The invasive form may show heterogeneity at the likelihood of exposure to HPV, such as young age at microscopic level, and in most cases, infiltrating nests first intercourse, a large number of sexual partners, and clusters are characterised by an irregular, ragged race, high parity and low socioeconomic status, favour contour. cervical cancer development. Latin America, the Adenocarcinoma accounts for 5-20% of all cervical Caribbean, southern Asia, Southeast Asia, and sub- malignancies, and has increased during the past 20-30 Saharan Africa are areas with the highest incidence. years, particularly among women under 35. The tumour Clinics possibly originates from the pluripotential cells of the subcolumnar endocervical epithelium. It appears in a Early cervical cancer is usually asymptomatic. variety of histologic patterns, including mucinous, Approximately 80-90% of patients with cervical cancer endometrioid, clear cell, well- differentiated experience abnormal vaginal bleeding. HPV causes a villoglandular and serous adenocarcinoma. large spectrum of lesions ranging from relatively benign condyloma acuminatum to invasive squamous Mesenchymal neoplasia: Leiomyomas are rarer than those appearing in the cell carcinomas. uterine corpus and have a similar macroscopical and Pathology microscopical appearence. They account for Epithelial neoplasia: approximately 8% of all uterine smooth muscle tumors. Endocervical polyp is the most common benign lesion Leiomyosarcoma is very rare. found in the uterine cervix. It appears as a focal Mixed epithelial and mesenchymal neoplasia: hyperplastic protrusion of the endocervical folds, Adenomyoma and papillary adenofibromas are rare including the epithelium and the stroma. polyp-like lesions composed of an admixture of Microscopically, a variety of histologic patterns are fibroconnective tissue, smooth muscle and glandular observed, depending on the prevalence of the tissue elements. Adenomyomas may recur but behave type. In situ or invasive carcinomas do not usually arise benignly. from this lesion. Malignant Mullerian Mixed Tumour (MMMT) is Fibroepithelial polyp , or stromal polyp, is a benign rarely seen in the cervix, compared with its much more exophytic proliferation of the cervical stroma. It is common uterine counterpart. This lesion occurs in composed of stellate-shaped cells growing chaotically, postmenopausal women and typically forms polypoid covered by stratified squamous epithelium, and is often or peduncolated masses. Its histologic appearence seen in pregnant women. differs from that of its uterine counterpart. Microglandular hyperplasia is a common cervical Mullerian adenosarcoma is rare. It is microscopically lesion associated with oral contraception or with characterized by papillae covered by typical pregnancy in young women. endocervical epithelium and malignant mesenchymal Squamous intraepithelial lesion (SIL) is a precursor elements. of squamous cell carcinoma and usually remains Secondary tumours are uterine cervix tumours inactive for more than 20 years before it becomes originating outside the cervix. invasive. SIL usually affects the transformation zone Treatment near the endocervical epithelium. Precancerous changes in the cervix may be treated with Three different diagnostic systems are used: cryosurgery, cauterization or laser surgery. Cervical - CIN (Cervical Intraepithelial Neoplasia, CIN I, CIN conization may eventually prove to be therapeutic in II, CIN III), many patients. Depending on the stage of the disease, - SIL (Low grade SIL -LSIL - High grade SIL - HSIL), surgery (early invasive cancer), combined with - Mild, Moderate or Severe Dysplasia. radiation, thermotherapy or chemotherapy (more These systems correspond to: advanced cases), are treatments of choice. CIN I / LSIL / Mild dysplasia CIN II / Moderate dysplasia Prognosis CIN III / Severe dysplasia Early-stage cervical cancer and precancerous cervical CIN II and CIN III / HSIL conditions are almost 100% curable. The five-year Adenocarcinoma In Situ (AIS) is a precursor of relative survival rate for earliest-stage cervical cancer is invasive cervical adenocarcinoma, showing

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91%. Although death rates fell by 74% between 1955 both benign and malignant lesions, including and 1992 and continue to drop by about 2% a year, trophoblastic diseases. Early pathological proliferation invasive cervical cancer continues to register may sometimes be asymptomatic. Pain and pelvic significant morbidity and is a major cause of cancer pressure are usually manifestations of advanced deaths in women worldwide. Very recently, a disease. "predictive score" system that separates the Pathology thermoradiosensitive group from the thermoradioresistant group of advanced cervical cancer Epithelial neoplasia: has been developed on the basis of the expression Endometrial polyps are present in 24% of the general profiles of 35 genes, selected by cDNA microarray female population, mainly in women over 40 years of analysis. age. They may show morphologically diverse patterns, related to patient hormone status, and consist of UTERINE CORPUS NEOPLASIA hyperplastic, cystically dilated glands in a fibrous Note stroma with large, thick-walled blood vessels. Uterine cancer is the fourth most common malignancy Endometrial polyps originate from monoclonal in women, following breast cancer, lung and colorectal proliferation of mesenchyme and are not precancerous cancer. However, as it is usually detected in early lesions, but endometrial epithelial invasive cancer stages, it is not a common cause of cancer deaths. The (EIC) may be found in benign endometrial polyps, and most common corpus malignancy is the endometrial endometrial polypoid masses may be malignant carcinoma (approximately 95 %.); sarcomas represent (adenosarcoma, malignant Mullerian mixed - MMMT - only 4% and heterologous tumors such as , endometrial stromal tumor). They may be associated rhabdomyosarcomas, osteosarcomas and with long-term tamoxifen therapy. chondrosarcomas the remaining 1%. Endometrial hyperplasia (EH) is defined as a The most common corpus benign tumor is leiomyoma, proliferation of glands of irregular size and shape with a proliferation of mesenchymal origin, occurring in an increased gland/stroma ratio compared with approximately 77% of women of reproductive age, proliferative endometrium. Morphologic alterations according to a study on serial uterine sections. range from benign changes to premalignant disease. EH develops as a result of unopposed extrogenic Etiology stimulation. Association with polycystic ovarian The main risk factors for uterine corpus malignancy are disease has been described, but this entity is still a obesity, nulliparity, late menopause, diabetes, and subject of debate. The WHO classification (adopted in hypertension and radiation therapy. 10-25% of patients 1994 and currently in use) distinguishes: typical with mesenchymal malignancy report the (simple and complex) and atypical (simple and administration of pelvic radiation 5 to 25 years earlier. complex) hyperplasias. The latter confers signifcantly Benign endometrial neoplasia, such as endometrial higher risk of progression to arcinoma. polyps, hyperplasia and adenocarcinoma, may be Intraepithelial Carcinoma (EIC) is characterized by associated with tamoxifen therapy, possibly mediated markedly atypical nuclei, identical to those seen in through its agonistic estrogenic properties. As regards invasive serous carcinoma leiomyoma, evidence supports genetic susceptibility. Endometrial carcinoma is defined as an epithelial Concerning gestational trophoblastic diseases, tumor, usually with glandular differentiation, arising in hydatiform moles arise from abnormal conceptions and the endometrium and which has the potential to invade most choriocarcinoma and placental site trophoblastic the myometrium and spread to distant sites. Type-I tumours develop following complete moles. (related to estrogen) and Type-II (unrelated to estrogen) Epidemiology lesions are distinguished with respect to their biology and clinical course. Endometrioid carcinoma and The incidence of uterine malignancy varies widely serous carcinoma are the respective prototypes of the throughout the world, with lower rates occurring in two groups. Major genetic alterations (see genes) seem developing countries and higher rates in industrialized to distinguish the two types, and histological ones. classification of endometrial carcinoma may currently Benign neoplasia, specifically leiomyomas, most benefit from molecular analysis. commonly occurs in women aged 35-49 years, but can Endometrioid carcinoma is the most common be seen at any time between menarche and menopause. endometrial malignancy, accounting for more than 75% They are more common in black than in white women of all endometrial cancers, and is relatively rare in pre- (3-9:1). menopausal women. The histologic pattern resembles Clinics proliferative-phase endometrium and has less than 10% Onset is frequently accompanied by metrorrhagia, of squamous, serous, mucinous or clear differentiation. menometrorrhagia, spotting and irregular bleeding, for Both architectural and nuclear appearence are unavoidable criteria for grading lesions

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Serous carcinoma is a highly aggressive carcinoma, tumour (composed of an admixture of endometrial usually post-menopausal, accounting for 10% of stromal and smooth muscle cells), adenomatoid tumour endometrial carcinomas. Geographical distribution is (a benign lesion of the uterine serosa and myometrium worldwide, although a lower incidence is reported in originating from the mesothelium and forming gland- Norway and Australia. Papillary architecture with cells like structures), other rare mesenchymal tumours showing marked cytologic atypia is common. (benign and malignant, such as lipoma, haemangioma, Clear cell carcinoma comprises 1.6% of all uterine limphangioma, rhabdomyoma, rhabdomyosarcoma, carcinomas and may have different architectural liposarcoma, osteosarcoma, alveolar soft part sarcoma, patterns, such as solid, papillary tubular and cystic. etc) histologically identical to their counterparts arising Mucinous carcinoma is defined by the presence of in the usual sites. more then 50% of cells containing periodic acid-Shiff Mixed epithelial and mesenchymal neoplasia: positive, diastase-resistant intracytoplasmic mucin. It is Adenofibroma usually occurs in postmenopausal rare, and usually has a glandular architectural pattern. women and tends to recur. It presents an admixture of Squamous cell carcinoma is extremely rare and is epithelial and mesenchymal cells. microscopically similar to its cervix counterpart Carcinofibroma is a very rare lesion whose behaviour Mixed carcinoma is defined as an endometrial is not yet clear. It is composed of an admixture of carcinoma showing at least one other component malignant epithelial and benign mesenchymal cells. comprising at least 10% of the tumour. Adenosarcoma is a rare biphasic tumour which may Transitional cell carcinoma is very rare and is defined occur at any age. It is a low-grade neoplasm, with a by the presence of more than 90% of cells resembling potential for recurrence and metastasis. It is urothelial transitional cells. charaterized by benign epithelial and saromatous Small cell carcinoma is very uncommon and mesenchymal components. resembles small cell carcinoma of the lung. Carcinosarcoma (malignant mixed mesodermal Undifferentiated carcinoma includes approximately sarcoma - MMMT) , is still a debated entity: formerly 1-2% of tumours lacking either glandular or squamous classified among sarcomas, nowadays it is considered a differentiation. variant of carcinoma, on the basis of recent clinical, Mesenchymal neoplasia: histopathological, cytogenetic and molecular evidence. These tumours arise primarily from two distinct tissues: It accounts for 5% of all uterine corpus malignancies myometrial muscle (leiomyosarcoma) and endometrial and is found in postmenopausal women. stroma (mesodermal and stromal sarcomas). Microscopically it shows an admixture of Leiomyoma is a very common uterine smooth muscle carcinomatous and sarcoma-like elements, resulting in proliferation, usually detected in women over 30 years a characteristic biphasic appearance. It appears as a old. Its growth is hormone- dependent and typical large, soft, polypoid mass involving the endometrium nodules are composed of whorled, anastomosing and myometrium. The carcinomatous component may fascicles of smooth muscle cells. Less typical lesions be composed of papillary serous, endometrioid or clear are grouped into specific subtypes. cells, the stromal component of round or spindle cells. Endometrial stromal nodule is a rare lesion present in Gestational trophoblastic tumors: women aged 23-75 years. The lesion may protrude into Gestational trophoblastic tumors are neoplastic the uterine cavity or grow within the myometrium. disorders arising from placental trophoblastic tissue Microscopically, the cells resemble normal after abnormal fertilization. proliferative-phase endometrial stromal cells. The Partial hydatiform mole is an abnormal placenta lesion is benign, but a hysterectomy may be necessary grossly characterised by an admixture of normal and in order to evaluate the margin. hydropic chorionic villi. Leiomyosarcoma accounts for 1.3% of all uterine Complete hydatiform mole is an abnormal placenta malignancies. Most of them are intramural, and nuclear characterised by abnormal throphoblastic proliferation atypia, high mitotic index and cell necrosis are the main involving most chorionic villi. diagnostic criteria. Invasive hydatiform mole , usually subsequent to a Endometrial stromal sarcoma (ESS) is a rare tumor complete mole, is composed of hydatiform mole villi (0.2% of all uterine cancers) invading, by definition, within the myometrium. the miometrium. It is typically subdivided into low- Gestational choriocarcinoma is a highly malignant, grade (fewer than 5-10 mitoses per 10 HPF and often metastatizing neoplasm composed of a disordered minimal cellular atypia) and high-grade stromal array of syncytiotrophoblastic and cytotrophoblastic sarcoma, although this division has recently been elements, without chorionic villi. questioned. Placental site tumour is a rare neoplasm deriving from Miscellaneous mesenchymal tumors show no intermediate trophoblast cells in the placenta. predominant muscle smoot or stromal differentiation Secondary tumours are uterine corpus tumours and comprise: endometrial stromal and smooth muscle originating outside the uterus.

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Treatment cytogenetically-abnormal subgroups have been observed: (a) rearrangements in the 6p21-p22 region; The vast majority of uterine corpus malignant tumours (b) rearrangements in the 12q13-15 region; (c) are highly curable since they present early symptoms rearrangements in the 7q22 region. At least for the and may often be diagnosed precociously. Knowledge subgroup with 6p21 rearrangement, it has been of the surgicopathologic, as well as clinical, staging is demonstrated that karyotypically aberrant cells belong crucial in developing an appropriate management plan. to the stromal component of endometrial polyps. Surgical therapy is usually necessary for the majority of Endometrial carcinomas do not show specific endometrial malignancies. Other adjuvant/adjunctive chromosome changes. Most of them are characterized therapies such as radiation therapy, chemotherapy and by a hyperdiploid modal chromosome number. The hormonal therapy may be considered. majority show numerical chromosome changes, but Treatment for benign uterine corpus lesions depends on cases with both numerical and structural abnormalities the symptoms, tumor size and location and age of the have been observed in the context of complex patient. karyotypes. Non-random gains of 1q and 8q are Prognosis frequently found. Correlations between karyotypic Prognostic significance of hormone receptors in aberration patterns and histological differentiation have endometrial cancer has been reported; moreover, recently been reported, with the identification of immunohistochemistry for both estrogen and different copy number changes among the different progesterone receptors has been shown to correlate grades of type I carcinomas, between serous papillary with FIGO grade as well as survival. HER-2/neu and clear-cell carcinomas of type II, as well as between overexpression has been reported to be associated with homologous and heterologous carcinosarcomas. a poor prognosis. Endometrioid adenocarcinoma and Endometrial stromal tumours are cytogenetically adenosquamous carcinoma have the highest overall 5- heterogeneous. The most common karyotypic changes year survival rates. (respectively 76% and 68%), clear involve chromosomes 6, 7, and 17. A subgroup of cell and papillary serous carcinomas the lowest stromal lesions, including low-grade endometrial (respectively 51% and 46%). The evolution of sarcoma stromal sarcomas (more rarely in high-grade ESS) and depends primarily on the extent and stage of the disease endometrial stromal nodules are characterized by at diagnosis. Recurrences are very frequent. The overall t(7;17)(p15;q21) translocation, resulting in the fusion 5-year survival rate is 15-25%. of JAZF1 and JJAZ1 genes. Among benign neoplasias, endometrial polyps may In Endometrial Malignant Mullerian Mixed undergo malignant tranformation, while leiomyomas Tumours , chromosome 8 or 8q. gains have been usually do not. suggested to characterize a distinct cytogenetic subgroup. Cytogenetics Benign smooth muscle tumors are associated with abnormal karyotypes in almost 40-60% of cases. Note Different cytogenetically-abnormal subgroups have The vast majority of endometrial cancers are sporadic. been recognized. Chromosomal structural changes at However, hereditary predisposition to develop uterine the 6p21, 12q13-15; 7q22, and trisomy 12 define those carcinoma is associated with hereditary non-polyposis most frequently found; chromosome regions 1q42-44, colorectal carcinoma (HNPCC) and Cowden syndrome. 3q, and 10q are non-randomly involved in changes in a Germline mutations of the FH (fumarate hydratase) minority of cases. have been found to be involved in syndromes Uterine leiomyosarcomas have complex cytogenetic associated with uterine leiomyomas. Evidence supports karyotypes with numerical and structural aberrations the existence of genetic factors predisposing to non- and cytogenetic intratumoral heterogeneity. syndromic uterine leiomyoma, although susceptibility Hydatiform moles have peculiar karyotypes: complete genes have not yet been identifed. moles usually have a 46,XX karyotype of paternal Cytogenetics Morphological origin, arising from an anuclear oocyte fertilized by an haploid 23,X sperm which undergoes replication. More UTERINE CERVIX: rarely a 46,XY karyotype is found, arising from the Karyotypic analysis on uterine cervix lesions is limited. fertilizaion of an anuclear oocyte by two haploid No specific chromosome changes have been reported, sperm. Incomplete moles (more than 90%) have a although most lesions show cytogenetic abnormalities, triploid karyotype and the presence of both maternal including polyploidy. Chromosomes 5 and 17 are those and paternal chromosomal material, due to ferilization most frequently involved in changes in carcinomas. of an haploid oocyte by two haploid sperm. UTERINE CORPUS: Cytogenetics Molecular Endometrial polyps may show abnormal karyotypes, UTERINE CERVIX . A pronounced chromosomal usually with a single or few changes. Three main instability in advanced cervical carcinomas has been

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observed by comparative genomic hybridization uterine leiomyomas . Very recently, loss of the FH (CGH.). CGH profiles show 2q33-q37 deletions and 3q gene has been demonstrated in a subgroup of gains as characteristic changes. FISH analysis on nonsyndromic uterine leiomyoma characteried by 1q squamous cell carcinoma showed an increased DNA rearrangements. copy number in chromosomes 3 and X in the Dysregulation of the HMGA2 (12q15) and HMGA1 development and progression from HSIL to cervical (6p21.3) genes has been observed in uterine carcinoma. leiomyomas , as well as in endometrial polyps . UTERINE CORPUS . CGH data on endometrial cancer confirm G-banding results, pinpointing a References central role of 8q gains in the pathogenesis of Gurpide E. Endometrial cancer: biochemical and clinical carcinosarcomas and endometrial adenocarcinomas. correlates. 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in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Solid Tumour Section Mini Review

Soft Tissue Tumors: Low grade fibromyxoid sarcoma Ioannis Panagopoulos, Fredrik Mertens, Nils Mandahl, Clelia Tiziana Storlazzi Dept of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden (IP, FM, NM, CTS)

Published in Atlas Database: December 2004 Online updated version: http://AtlasGeneticsOncology.org/Tumors/LowGradFibromyxSarcID5185.html DOI: 10.4267/2042/38164 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Clinics Low grade fibromyxoid sarcoma usually presents as a Alias painless mass, typically in the proximal extremities. Hyalinizing spindle cell tumor with giant rosettes. Pathology Note Classical cases of LGFMS display a mixture of Low grade fibromyxoid sarcoma is a rare, low-grade hypocellular, collagen-rich areas and more cellular, malignant soft tissue neoplasm with a potential for myxoid areas. A characteristic feature is the whorling local recurrences as well as distant metastases. growth pattern, often seen at the transition from hypocellular to more cellular, myxoid areas. Mitotic Classification figures are rare. A subset of LGFMS shows focal Note collagen rosettes. Low grade fibromyxoid sarcoma belongs to the group Treatment of fibroblastic/myofibroblastic soft tissue tumors. Two The only consensus treatment for low grade main subtypes have been recognized: classical low fibromyxoid sarcoma is surgical excision. grade fibromyxoid sarcoma and low grade fibromyxoid sarcoma with giant collagen rosettes. Prognosis When radically excised, the prognosis is usually good. Clinics and pathology However, local recurrences have been reported in approximately 10% of the cases, and distant spreading Disease occurs in 5-10% of the cases. Low grade fibromyxoid sarcoma (LGFMS) Cytogenetics Embryonic origin Cellular origin unknown, but presumably of Note mesodermal derivation. Tumor cells show fibroblastic In the Mitelman Database of Chromosome Aberrations differentiation. in Cancer (2004), 16 cases with clonal aberrations are Etiology included. Unknown. No known risk factors. Cytogenetics Morphological The chromosomal translocation t(7;16)(q33;p11) is a Epidemiology characteristic feature. A few cases contain a Low grade fibromyxoid sarcoma is supposed to be rare, supernumerary ring as the sole chromosomal but as it is difficult to diagnose the true incidence is abnormality. Comparative genomic hybridization unknown. Patients of any age may be affected, and the allowed to assess the chromosomal origin of a male: female ratio is 1:1. supernumerary ring chromosome in one case. The

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analysis revealed gain of material from 7p14-pter, in placenta, lung, spleen and intestine, and the weakest 7q31-q33, and 16p. FISH experiments using contigs of in heart, brain, skeletal muscle, thymus, colon and BAC clones were performed in two cases of low grade leukocytes. In fetal tissues, the weakest expression was fibromyxoid sarcoma carrying a t(7;16) abnormality. detected in brain and heart. A splice variant, lacking The analysis revealed that the breakpoints were located exon 2, was found in placenta, spleen and fetal liver. within BAC clones RP11-388M20 (AC009088) in band Since northern blot analysis was not performed, the 16p11.2, and RP11- 29B3 (AC022173) and RP11- possibility of additional splice variants and the actual 377B19 (AC009263) in band 7q33; all the examined size of the normal CREB3L2 transcript is not clones gave split signals on the derivative determined yet. The cDNA clones with accession chromosomes 7 and 16. The FISH results for numbers BX649143 and BX648300 (5381 bp) indicate chromosome 7 identified a breakpoint region that the CREB3L2 mRNA might be longer than 7 kbp. containing a single gene (LOC155008), which is Protein homologous to Drosophila Bbf-2, encodes a B-ZIP The 1560 bp open reading frame is coding for a 519 transcription factor and named BBF2H7 (BBF2 human amino acid protein with an estimated molecular weight homolog on chromosome 7). The data for chromosome of 57 kDa. The amino acid sequence spanning residues 16 suggested FUS as the other candidate target gene. 291-356 of the predicted human CREB3L2 protein Probes contains a consensus B-ZIP domain highly similar to BAC clones RP11-388M20 (AC009088) and CTD- that in the CREB3L1 (OASIS), CREB3L3 (CREB-H), 2594M1 in band 16p11.2.BAC clones RP11- 29B3 CREB3L4 (CREB4 or AIBZIP), CREB3 (LUMAN) (AC022173), RP11-377B19 (AC009263) and CTD- and Drosophila Bbf-2 transcription factors with 80, 60, 2375H21 in band 7q33. 9, 56 and 71% identity, respectively. It also contains the amino acid sequence RRKKKEY that is exactly Genes involved and proteins conserved among CREB, CREM, ATF1, ATF6 and CREBL1. The leucine zipper motif of BBF2H7 is Note similar to that in CREB-H and CREB4 (pattern L-X6- The t(7;16)(q33;p11) in two cases of low grade C-X6-L-X6-L-X6-L-X6-L; Fig. 5). It contains six fibromyxoid sarcoma fuses the FUS gene to CREB3L2 repeats and consists of five leucines and one cysteine at (also named BBF2H7), a previously uncharacterized the second heptad position (amino acid 328) of the gene that is homologous to the Drosophila Bbf-2 gene. leucine zipper. Downstream of the B-ZIP domain, A further study of 59 low grade soft tissue tumors CREB3L2 also contains a hydrophobic region, which provided results indicating that this fusion gene is was predicted to be an a-helical transmembrane domain specific for LGFMS; all 12 fusion-positive cases in that (position 376-397; series fulfilled the morphologic criteria for LGFMS, GTCLMVVVLCFAVAFGSFFQGY). This structural suggesting that reverse transcriptase polymerase chain feature is also seen in the other members of the family, reaction (RT-PCR) analysis for the detection of a i.e. OASIS, CREB-H, CREB3 and CREB4. FUS/CREB3L2 chimeric transcript may be a valuable FUS tool in the differential diagnosis. Location CREB3L2 16p11 Location Note 7q34 Alternate symbols are: TLS, FUS1. The FUS gene is Note also rearranged in myxoid liposarcoma with Alternate symbols: BBF2H7, DKFZp586F2423, t(12;16)(q13;p11), which leads to its fusion with DKFZp686O19165. DDIT3. In acute myeloid leukaemia with DNA / RNA t(16;21)(p11;q22) and in Ewing sarcoma with The entire CREB3L2 gene spans more than 120 kb t(16;21)(p11;q22) as well, FUS is fused to the ERG genomic DNA and is composed of 12 exons. Exon 1, gene, and in angiomatoid fibrous histiocytoma FUS is containing the initiation codon ATG, is the largest (454 fused to ATF1. bp), and exon 7 the smallest (59 bp). Exon 12 includes the termination TAA codon. Introns 1 and 9 are the Result of the chromosomal largest (73132 bp) and smallest (281 bp), respectively. anomaly Using in silico analysis and RT-PCR methodology analysis, a 2400 bp cDNA was compiled containing a Hybrid Gene 1560 bp open reading frame by Storlazzi et al. (2003). Note RT-PCR analysis on cDNAs from 24 human tissues Up to now, FUS/CREB3L2 chimeric transcripts were showed that CREB3L2 is expressed in most of the identified in 14 cases. The fusion points varied within examined tissues. The strongest expression was found

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Soft Tissue Tumors: Low grade fibromyxoid sarcoma Panagopoulos I et al.

FUS, but clustered to exons 5, 6 and 7. Small intronic insertions were also seen at the junction. In CREB3L2, References all the fusion points have been found within exon 5. Bejarano PA, Padhya TA, Smith R, Blough R, Devitt JJ, Gluckman JL. Hyalinizing spindle cell tumor with giant rosettes- Detection -a soft tissue tumor with mesenchymal and neuroendocrine A detailed description of the RT-PCR protocols for features. An immunohistochemical, ultrastructural, and analysis of FUS/CREB3L2 transcripts has been cytogenetic analysis. Arch Pathol Lab Med. 2000 Aug;124(8):1179-84 reported. Mezzelani A, Sozzi G, Nessling M, Riva C, Della Torre G, Testi Fusion Protein MA, Azzarelli A, Pierotti MA, Lichter P, Pilotti S. Low grade Note fibromyxoid sarcoma. a further low-grade soft tissue malignancy characterized by a ring chromosome. Cancer The function of the FUS/CREB3L2 chimera is Genet Cytogenet. 2000 Oct 15;122(2):144-8 unknown but it is reasonable to assume that it will have Folpe A, van den Berg E, Molenaar WM. Low grade similar consequences as the other FUS chimeric fibromyxoid sarcoma WHO Classification of proteins in the cell. Thus, the B-ZIP-encoding domain Tumours.Pathology and Genetics of Soft Tissue and Bone of CREB3L2 comes under the control of the FUS Tumours.Editors: CDM Fletcher, KK Unni, F Mertens.IARC Press, Lyon 2002; pp: 104-105 promoter, which, in turn, may cause deregulation of genes normally controlled by CREB3L2. In addition, Reid R, de Silva MV, Paterson L, Ryan E, Fisher C. Low-grade by fusing the B-ZIP domain of CREB3L2 to the N fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;p11) translocation. terminal part of FUS, the ability to dimerize with other Am J Surg Pathol. 2003 Sep;27(9):1229-36 members of the OASIS family could be affected. The Storlazzi CT, Mertens F, Nascimento A, Isaksson M, Wejde J, FUS/CREB3L2 chimera might retain the ability, as do Brosjo O, Mandahl N, Panagopoulos I. Fusion of the FUS and FUS/DDIT3 and FUS/ERG, to bind to RNA BBF2H7 genes in low grade fibromyxoid sarcoma. Hum Mol polymerase II via the N-terminal part of FUS but would Genet. 2003 Sep 15;12(18):2349-58 lack the ability to recruit the transcription and translation factor Y-box binding protein-1 (YB-1) This article should be referenced as such: because of the replacement of the central and C- Panagopoulos I, Mertens F, Mandahl N, Storlazzi CT. Soft terminal parts of FUS by CREB3L2. Consequently, Tissue Tumors: Low grade fibromyxoid sarcoma. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):52-54. RNA splicing mediated by YB-1 also would be expected to be inhibited.

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Solid Tumour Section Mini Review

Soft Tissue Tumors: Soft Tissue Leiomyosarcoma Jian-Hua Luo Gene Array Laboratory, Univeristy of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA (JHL)

Published in Atlas Database: December 2004 Online updated version : http://AtlasGeneticsOncology.org/Tumors/SoftTisLeiomyoSarcID5122.html DOI: 10.4267/2042/38165 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Soft tissue leiomyosarcoma was classified based on Identity salient gene expression characteristics. Three types of Note leiomyosarcoma were proposed: 1) "Simplification" of Soft Tissue Leiomyosarcoma is a relatively rare gene expression in leiomyosarcoma, characterized by malignant tumor. It may be difficult to be distinguished dramatic down regulation of large number of genes; 2) from gastrointestinal stromal tumors and Schwann cell "Inflammation related" gene expression, characterized neoplasms. To make a correct identification of soft by the prominent presence of lymphocyte specific tissue leiomyosarcoma, immunostaining with several genes in the analysis; and 3) "neural" gene expression, smooth muscle differentiation markers (actin, calponin characterized by neuronal gene expression. Among and desmin), and negative staining results with S100 these subtypes, simplification gene expression is (to rule out Schwann cell neoplasm), c-kit and CD34 associated with the poorest prognosis, while (to rule out gastrointestinal stromal tumors) is needed. inflammation related one the best. Prognosis Clinics and pathology Local recurrent tumor, positive surgical margins, >50 years age, >20 mitoses per high power field are Clinics adversely associated with survival. The annual new cases in the U.S. are over 6,000. The five year survival rate after diagnosis is about 50%. Genes

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Soft Tissue Tumors: Soft Tissue Leiomyosarcoma Luo JH

Phylogenetic tree of leimyosarcomas and normal smooth muscle. Expression levels of 92 cDNA sequences from table III through V were analyzed for 11 leiomyosarcoma tissues. Experiment cluster analysis was performed using Michael Eisen's cluster tool and tree view. Data input and normalization of individual experiments were performed in GeneSpring TM 4.2 before imported into cluster tool. Red indicates high expression level, while green for low, black for no expression. The cutoff expression level for non-expressor was set at 200 arbitary units. Pathological grade (G) for each tumor is indicated, so is metastasis (r) if it is present.

Ren B, Yu YP, Jing L, Liu L, Michalopoulos GK, Luo JH, Rao References UN. Gene expression analysis of human soft tissue leiomyosarcomas. Hum Pathol. 2003 Jun;34(6):549-58 Jensen OM, Høgh J, Ostgaard SE, Nordentoft AM, Sneppen O. Histopathological grading of soft tissue tumours. Prognostic This article should be referenced as such: significance in a prospective study of 278 consecutive cases. J Pathol. 1991 Jan;163(1):19-24 Luo JH. Soft Tissue Tumors: Soft Tissue Leiomyosarcoma. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):55-56. Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996 May;14(5):1679-89

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Solid Tumour Section Mini Review

Soft tissue tumors: Lipoblastoma Cristina Morerio, Claudio Panarello Dipartimento di Ematologia ed Oncologia Pediatrica, IRCCS Istituto Giannina Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy (CM, CP)

Published in Atlas Database: January 2005 Online updated version: http://AtlasGeneticsOncology.org/Tumors/LipoblastomaID5155.html DOI: 10.4267/2042/38166 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

different stages of differentiation, ranging from Classification primitive, spindle-shaped cells to lipoblasts simulating Two forms of the tumor lesion have been described: mature fat cells. Differential diagnosis, particularly in encapsulated circumscribed type (lipoblastoma), and a older children or in diffuse lipoblastoma, includes noncapsulated diffuse infiltrative type myxoid liposarcoma and atypical lipoma and may be (lipoblastomatosis). based on distinct cytogenetic abnormalities. Clinics and pathology Treatment Surgical excision. Disease Prognosis Benign uncommon soft-tissue tumor of embryonal fat. These tumors have an excellent prognosis but local Embryonic origin recurrence is possible expecially in diffuse lesions. Develops from embryonic remnants of white fat tissue. Cytogenetics Epidemiology Primarily occurs in young children (<3 years) Cytogenetics Morphological prevalently male. Pseudodiploid karyotype with clonal chromosomal rearrangements involving the 8q11-13 region. Gain of Clinics chromosome 8 is reported. Presents in superficial tissues of arms and legs (deeper in lipoblastomatosis), though mediastinum, Cytogenetics Molecular retroperitoneum, trunk, head and neck may be affected. Detectable by metaphase and/or interphase FISH using Pathology specific PLAG1 probes. Lobulated tissue composed of immature fat cells Probes separated by fibro-vascular septa and areas with a RP11-140I16, BAC227k20, YAC164H5, RP11- myxoid matrix. The lobules contain lipoblasts in 299N14, YAC947h7.

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Soft tissue tumors: Lipoblastoma Morerio C, Panarello C

Dual-color FISH analysis in a case of lipoblastoma with complex structural rearrangement: RP11-140I16 (PLAG1) (red) was cohybrized with RP11-299N14 (HAS2) (green). Arrow indicates PLAG1-HAS2 fusion signal on the der(8), arrowhead indicates the normal chromosome 8. The BAC clones were provided by Prof. M.Rocchi.

is replaced by promoting regions from other genes, Genes involved and proteins notably hyaluronic acid synthase 2 (HAS2) or collagen PLAG1 1 a 2 (COL1A2). 5' HAS2 - 3' PLAG1 fused after an 8q Location intrachromosomal rearrangement that determined the 8q12.1 juxtaposition of band 8q12.1 to 8q24.1. The breakpoint DNA / RNA of HAS2 gene is in intron 1, whereas its coding 7313 bp mRNA sequence starts at the first codon of exon 2. 5' COL1A2 - 3' PLAG1 has been described in one case Protein of t(7;8)(p22;q13) PLAG1, (together with PLAGL1 and PLAGL2), Transcript belongs to a subfamily of C2H2 zinc finger transcription factors that activate transcription. Alternative splicing variants which included or lacked PLAG1 exon 2. HAS2 Fusion Protein Location Description 8q24.12 HAS2-PLAG1 and COL1A2-PLAG1 both encode a COL1A2 full-lenght PLAG1 protein. Location 7q22.1 References Chung EB, Enzinger FM. Benign lipoblastomatosis. An Result of the chromosomal analysis of 35 cases. Cancer. 1973 Aug;32(2):482-92 Sandberg AA, Gibas Z, Saren E, Li FP, Limon J, Tebbi CK. anomaly Chromosome abnormalities in two benign adipose tumors. Hybrid Gene Cancer Genet Cytogenet. 1986 May;22(1):55-61 Panarello C, Rosanda C, Morerio C, Russo I, Dallorso S, Note Gambini C, Ricco AS, Storlazzi T, Archidiacono N, Rocchi M. HAS2-PLAG1, COL1A2-PLAG1 Chromosomal Lipoblastoma: a case with t(7;8)(q31;q13). Cancer Genet rearrangements in tumor tissue determines PLAG1 Cytogenet. 1998 Apr 1;102(1):12-4 transcriptional up-regulation. Astrom A, D'Amore ES, Sainati L, Panarello C, Morerio C, Mark J, Stenman G. Evidence of involvement of the PLAG1 Description gene in lipoblastomas. Int J Oncol. 2000 Jun;16(6):1107-10 The 8q12 rearrangement results in a promoter- Chen Z, Coffin CM, Scott S, Meloni-Ehrig A, Shepard R, Issa swapping event, whereby the PLAG1 promoter element B, Forsyth DR, Sandberg AA, Brothman AR, Lowichik A.

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Soft tissue tumors: Lipoblastoma Morerio C, Panarello C

Evidence by spectral karyotyping that 8q11.2 is nonrandomly distinction from lipoblastoma using FISH analysis. Virchows involved in lipoblastoma. J Mol Diagn. 2000 May;2(2):73-7 Arch. 2002 Sep;441(3):299-302 Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao Sandberg AA. Updates on the cytogenetics and molecular S, Fletcher JA. PLAG1 fusion oncogenes in lipoblastoma. genetics of bone and soft tissue tumors: lipoma. Cancer Genet Cancer Res. 2000 Sep 1;60(17):4869-72 Cytogenet. 2004 Apr 15;150(2):93-115 Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL, Morerio C, Rapella A, Rosanda C, Tassano E, Gambini C, Kozakewich HP, Fletcher JA. PLAG1 alterations in Romagnoli G, Panarello C. PLAG1-HAS2 fusion in lipoblastoma: involvement in varied mesenchymal cell types lipoblastoma with masked 8q intrachromosomal and evidence for alternative oncogenic mechanisms. Am J rearrangement. Cancer Genet Cytogenet. 2005 Jan Pathol. 2001 Sep;159(3):955-62 15;156(2):183-4

Harrer J, Hammon G, Wagner T, Bolkenius M. Lipoblastoma This article should be referenced as such: and lipoblastomatosis: a report of two cases and review of the literature. Eur J Pediatr Surg. 2001 Oct;11(5):342-9 Morerio C, Panarello C. Soft tissue tumors: Lipoblastoma. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):57-59. Kuhnen C, Mentzel T, Fisseler-Eckhoff A, Debiec-Rychter M, Sciot R. Atypical lipomatous tumor in a 14-year-old patient:

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Solid Tumour Section Mini Review t(16;21)(p11;q22) Jean Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F- 86021 Poitiers, France (JLH)

Published in Atlas Database: January 2005 Online updated version: http://AtlasGeneticsOncology.org/Tumors/t1621p11q22EwingID5329.html DOI: 10.4267/2042/38167 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Epidemiology About 40 reported cases, mainly found in young adults; Disease children cases are described; median age is about 30 Ewing tumours yrs; balanced sex ratio. Note Clinics t(16;21)(p11;q22) has been found in rare cases of Blood data: anemia, thrombocytopenia, mild Ewing tumours, a paediatric neoplasm with small hyperleucocytosis; with high monocytic cell count at round-cells derived from neural crests cells usually times. associated with translocations involving EWSR1. Cytology Cytogenetics Myelocytic and monocytoid features are often present; Ewing tumours are usually associated with a eosinophils in the bone marrow are sometimes t(11;22)(q24;q12) with 5' EWSR1 - 3' FLI1 abnormal and/or elevated; erythrophagocytosis may be involvement, less often associated with found. t(21;22)(q22;q12) with 5' EWSR1 - 3' ERG Prognosis involvement, rarely associated with t(2;22)(q36; q12) (5' EWSR1 - 3' FEV) or with t(17;22)(q21;q12) (5' Seems poor: complete remission may not be achieved; EWSR1-3' ETV4). there is high incidence of relapse within a year and a median of survival is about 22 months (cases herein Prognosis reviewed). Recent treatments have improved the prognosis of Ewing's tumours. The prognosis is mainly determined Cytogenetics by the presence of metastases at the time of diagnosis. Additional anomalies Disease ANLL cases: found solely in about 60% of cases in at least a subclone; associated with +10, +8, or de(9q)/-9 de novo acute non lymphocytic leukemia (ANLL); to in about 10% of cases each. be noted is one case of chronic myelogenous leukemia (CML) -blast crisis. Genes involved and proteins Phenotype / cell stem origin ANLL cases: mainly M1, M2, M4, M5a, M5b, or M7 FUS ANLL; may be preceded by a myelodysplastic Location syndrome (MDS). 16p11

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 60 t(16;21)(p11;q22) Huret JL

Protein myeloid leukemia is always detectable by molecular analysis using AML1. Blood. 1993 Mar 15;81(6):1573-9 RNA binding protein; member of the TET family, like EWSR1. Nobbs MC, Chan-Lam D, Howell RT, Kitchen C, Copplestone JA. Acute non-lymphocytic leukemia with t(16;21). Cancer ERG Genet Cytogenet. 1993 Oct 15;70(2):144-5 Location Okada K, Takeichi M, Uchida H, Shirota T, Sakai N, Ito H. Translocation (16;21)(p11;q22) in acute nonlymphocytic 21q22 leukemia. Cancer Genet Cytogenet. 1994 Jul 1;75(1):60-3 Protein Panagopoulos I, Aman P, Fioretos T, Höglund M, Johansson ETS transcription factor. B, Mandahl N, Heim S, Behrendtz M, Mitelman F. Fusion of the FUS gene with ERG in acute myeloid leukemia with t(16;21)(p11;q22). Genes Chromosomes Cancer. 1994 Result of the chromosomal Dec;11(4):256-62 anomaly Satoh K, Miura I, Chubachi A, Ohtani H, Hirokawa M, Niitsu H, Miura AB. [Acute monoblastic leukemia (M5a) with Hybrid Gene dysmegakaryocytopoiesis associated with t(16;21) (p11;q22)]. Rinsho Ketsueki. 1994 Feb;35(2):160-4 Description Scott AA, Head DR, Kopecky KJ, Appelbaum FR, Theil KS, 5' FUS including exons 1 to 6, 7 or 8 - 3' ERG from Grever MR, Chen IM, Whittaker MH, Griffith BB, Licht JD. HLA- exon 7, 8 or 9 to C-term. DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia Fusion Protein potentially misdiagnosed as French-American-British acute Description myeloid leukemia-M3. Blood. 1994 Jul 1;84(1):244-55 N-term FUS transactivation domain fused to the C-term Hiyoshi M, Koh KR, Yamane T, Tatsumi N. Acute nonlymphoblastic leukaemia with t(16;21): case report with a DNA binding ETS domain of ERG. review of the literature. Clin Lab Haematol. 1995 Oncogenesis Sep;17(3):243-6 Seems to act as a transcriptional activator. Hiyoshi M, Yamane T, Hirai M, Tagawa S, Hattori H, Nakao Y, Yasui Y, Koh KR, Hino M, Tatsumi N. Establishment and characterization of IRTA17 and IRTA21, two novel acute nonlymphocytic leukaemia cell lines with t(16;21) translocation. Br References J Haematol. 1995 Jun;90(2):417-24 Mecucci C, Bosly A, Michaux JL, Broeckaert-Van Orshoven A, Harigae H, Kobayashi M, Mihara A, Watanabe N. Detection of Van den Berghe H. Acute nonlymphoblastic leukemia with minimal residual disease in cerebro-spinal fluid of a patient bone marrow eosinophilia and structural anomaly of with acute myelogenous leukemia with t(16;21)(p11;q22) chromosome 16. Cancer Genet Cytogenet. 1985 translocation by reverse transcriptase-polymerase chain Aug;17(4):359-63 reaction. Tohoku J Exp Med. 1997 Dec;183(4):297-302 Minamihisamatsu M, Ishihara T. Translocation (8;21) and its Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, variants in acute nonlymphocytic leukemia. The relative Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, importance of chromosomes 8 and 21 to the genesis of the Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, disease. Cancer Genet Cytogenet. 1988 Jul 15;33(2):161-73 Yanagisawa M, Hayashi Y. Consistent detection of TLS/FUS- ERG chimeric transcripts in acute myeloid leukemia with Berkowicz M, Rosner E, Resnitzky P, Mamon Z, Ben-Bassat I, t(16;21)(p11;q22) and identification of a novel transcript. Blood. Ramot B. Acute nonlymphocytic leukemia with t(16;21) Cancer 1997 Aug 1;90(3):1192-9 Genet Cytogenet. 1990 Jul 1;47(1):139-40 Tamura S, Takemoto Y, Hashimoto-Tamaoki T, Mimura K, Sadamori N, Yao E, Tagawa M, Nakamura H, Sasagawa I, Sugahara Y, Senoh J, Furuyama JI, Kakishita E. Cytogenetic Itoyama T, Tokunaga S, Ichimaru M, Nakamura I, Kamei T. analysis of de novo acute myeloid leukemia with trilineage 16;21 translocation in acute nonlymphocytic leukemia with myelodysplasia in comparison with myelodysplastic syndrome abnormal eosinophils: a unique subtype. Acta Haematol. evolving to acute myeloid leukemia. Int J Oncol. 1998 1990;84(4):212-6 Jun;12(6):1259-62 Marosi C, Bettelheim P, Geissler K, Lechner K, Köller U, Haas Imashuku S, Hibi S, Kuriyama K, Todo S. Hemophagocytosis OA, Chott A, Hagemeijer A. Translocation (16;21)(p11;q22) in by leukemic blasts in a case of acute megakaryoblastic acute monoblastic leukemia with erythrophagocytosis. Cancer leukemia with t(16;21)(p11;q22). Int J Hematol. 1999 Genet Cytogenet. 1991 Jul 1;54(1):61-6 Jul;70(1):36-9 Morgan R, Riske CB, Meloni A, Ries CA, Johnson CH, Lemons Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik RS, Sandberg AA. t(16;21)(p11.2;q22): a recurrent primary MV, Steuber CP, Weinstein HJ, Carroll AJ. Chromosomal rearrangement in ANLL. Cancer Genet Cytogenet. 1991 abnormalities in 478 children with acute myeloid leukemia: May;53(1):83-90 clinical characteristics and treatment outcome in a cooperative Ferro MR, Cabello P, Garcia-Sagredo JM, Resino M, San pediatric oncology group study-POG 8821. Blood. 1999 Dec Roman C, Larana JG. t(16;21) in a Ph positive CML. Cancer 1;94(11):3707-16 Genet Cytogenet. 1992 Jun;60(2):210-1 Shikami M, Miwa H, Nishii K, Takahashi T, Shiku H, Tsutani H, Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai Oka K, Hamaguchi H, Kyo T, Tanaka K, Kamada N, Kita K. M, Kaneko Y. The 8;21 chromosome translocation in acute Myeloid differentiation antigen and cytokine receptor expression on acute myelocytic leukaemia cells with

Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 61 t(16;21)(p11;q22) Huret JL

t(16;21)(p11;q22): frequent expression of CD56 and Shing DC, McMullan DJ, Roberts P, Smith K, Chin SF, interleukin-2 receptor alpha chain. Br J Haematol. 1999 Nicholson J, Tillman RM, Ramani P, Cullinane C, Coleman N. Jun;105(3):711-9 FUS/ERG gene fusions in Ewing's tumors. Cancer Res. 2003 Aug 1;63(15):4568-76 Okita H, Umezawa A, Fukuma M, Ando T, Urano F, Sano M, Nakata Y, Mori T, Hata J. Acute myeloid leukemia possessing Heller A, Loncarevic IF, Glaser M, Gebhart E, Trautmann U, jumping translocation is related to highly elevated levels of Claussen U, Liehr T. Breakpoint differentiation in chromosomal EAT/mcl-1, a Bcl-2 related gene with anti-apoptotic functions. aberrations of hematological malignancies: Identification of 33 Leuk Res. 2000 Jan;24(1):73-7 previously unrecorded breakpoints. Int J Oncol. 2004 Jan;24(1):127-36 Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Léonard C, Bilhou- This article should be referenced as such: Nabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O, Huret JL. t(16;21)(p11;q22). Atlas Genet Cytogenet Oncol Duchayne E, Berger R. Cytogenetic profile of childhood and Haematol. 2005; 9(1):60-62. adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood. 2002 Jul 15;100(2):618-26

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Cancer Prone Disease Section Mini Review

LEOPARD syndrome Maria Cristina Digilio Medical Genetics, Bambino Gesù Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy (MCD)

Published in Atlas Database: December 2004 Online updated version: http://AtlasGeneticsOncology.org/Kprones/LeopardID10084.html DOI: 10.4267/2042/38168 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

on the upper part of the trunk and neck, although they Identity can also be present on the face, limbs, palms, soles and Alias genitalia. The mucosae are characteristically spared. Multiple-lentigines syndrome. Lentigines are rarely present at birth and, classically, Generalized lentiginosis. develop during childhood, increasing in number until Cardiocutaneous syndrome. puberty and darkening with age. Cafe-au lait patches as Progressive cardiomyopathic lentiginosis. well as axillary freckling have also been described. Structural cardiac defects can be detected in 70% of the Note patients. Hypertrophic cardiomyopathy is the most LEOPARD syndrome is characterized by multiple common defect. It is progressive and commonly lentigines, cardiac anomalies, facial dysmorphisms, involves the intraventricular septum. Pulmonary valve abnormalities of the genitalia in males, retardation of stenosis with valve leaflet dysplasia, partial growth, and deafness. LEOPARD syndrome shares atrioventricular canal and mitral valve anomalies can many features with Noonan syndrome, in which also be present. Arrhythmias include heart block, lentigines and deafness usually are not present. bundle branch block, and hemiblock. Molecular studies have demonstrated that LEOPARD Deafness is generally sensorineural, may be unilateral, and Noonan syndromes are allelic conditions. but can be profound. Most cases have deafness Inheritance diagnosed in childhood, but some are reported to have LEOPARD syndrome is an autosomal dominant developed it in adult life. multiple congenital anomaly syndrome, with high Facial anomalies include hypertelorism, palpebral penetrance and markedly variable expression. ptosis, and large low-set ears. They occur in 90% of the patients. Clinics A high prevalence of genitourinary abnormalities has been reported especially in male patients. These include Phenotype and clinics cryptorchidism, hypospadias, as well as malformations of the kidneys and collecting systems. The main clinical features of LEOPARD syndrome are Pectus carinatum or excavatum are detectable. In old multiple lentigines, congenital heart defect or age, there is a tendency to develop thoracic kyphosis. electrocardiographic abnormalities, deafness, facial Growth retardation is frequent. The adult height is anomalies, urogenital malformations, skeletal generally below the 25th centile. anomalies, retardation of growth, and learning Mild mental retardation and learning difficulties, so as difficulties. language defects related to deafness, can occur in Diffuse lentiginosis is a characteristic of LEOPARD patients with LEOPARD syndrome. syndrome. Lentigines are brown macules, usually 2 to 8 mm in diameter, generally most heavily concentrated

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LEOPARD syndrome Digilio MC

Legend: Typical multiple lentigines in a patient with LEOPARD syndrome.

Neoplastic risk Prognosis A distinct class of somatic mutations of PTPN11, The prognosis is mainly determined by the nature and appearing to have high gain-of-function levels, severity of cardiac lesions. In fact, the major concern is contributes to leukemogenesis. The identification of that of hypertrophic cardiomyopathy, because of its these mutations at a germinal level explains the higher association with arrhythmia and sudden death. prevalence of myeloproliferative disorders and acute leukemia among children with Noonan or LEOPARD Cytogenetics syndrome. The RAS/MAPK pathway is deregulated in juvenile myelomonocytic leukemia due to mutations in Note NRAS, KRAS2 or NF1. It has be hypothesized that Chromosome analysis is normal in patients with germline or somatic mutations in PTPN11 could also LEOPARD syndrome. interfere with RAS/MAPK pathway. Multiple granular cell myoblastomas, a tumor believed Genes involved and proteins to arise from Schwann cells, have been reported in one patient. PTPN11 Central giant cell granulomas presenting as cyst-like Alias lesions in the mandible have also been described in Protein-tyrosine phosphatase, nonreceptor-type, 11 LEOPARD syndrome. Location Choristoma, a congenital corneal tumor containing cellular elements of ectodermal derivatives, may 12q24.1 occasionally coexist with LEOPARD syndrome. DNA/RNA Treatment Description: It contains two Srd homology 2 (SH2) Beta-blockade or calcium channel blockers are most domains and a protein tyrosine phosphatase domain frequently used in treatment of obstructive (PTP); 15 exons. cardiomyopathy. If there is no response to drug Protein therapy, surgery for left ventricular outflow obstruction Description: 593 amino acids, 68 kD. or transplantation can be indicated. Expression: Highly expressed in human tissues, The use of lasers has been shown to be effective in the particularly abundant in heart, brain, and skeletal treatment of lentigines. Noninvasive agents such as muscle. tretinoin cream and hydroquinone cream used in Function: The protein-tyrosine phosphatases are a combination have been shown to lighten lentigines highly polymorphic set of molecules having a role in after several months of application. regulating the responses of eukaryotic cells to

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LEOPARD syndrome Digilio MC

extracellular signals. They achieve this by regulating Choi WW, Yoo JY, Park KC, Kim KH. LEOPARD syndrome the phosphotyrosine content of specific intracellular with a new association of congenital corneal tumor, choristoma. Pediatr Dermatol. 2003 Mar-Apr;20(2):158-60 proteins. The pathogenetic mechanism that causes PTPN11 mutations to specifically exhibit a Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio VM, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B. dermatological phenotype and preferentially cardiac Correlation between PTPN11 gene mutations and congenital expresssion in hypertrophic cardiomyopathy is at heart defects in Noonan and LEOPARD syndromes. J Med present unclear. Genet. 2003 Sep;40(9):704-8 Mutations Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD, Gelb BD. Somatic Germinal: LEOPARD syndrome has proved to be mutations in PTPN11 in juvenile myelomonocytic leukemia, allelic to Noonan syndrome, with two recurrent myelodysplastic syndromes and acute myeloid leukemia. Nat PTPN11 mutations in exons 7 (Tyr279Cys) and 12 Genet. 2003 Jun;34(2):148-50 (Thr468Met). Additional mutations in exons 7, 12, and Digilio MC, Pacileo G, Sarkozy A, Limongelli G, Conti E, 13, different from the two common mutation hot spots, Cerrato F, Marino B, Pizzuti A, Calabrò R, Dallapiccola B. have been reported as a rare occurrence in the Familial aggregation of genetically heterogeneous hypertrophic syndrome. All the mutations occur in exons that code cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking for the protein tyrosine phosphatase (PTP) domain. PTPN11 mutations. Birth Defects Res A Clin Mol Teratol. 2004 Molecular and biochemical studies have shown that the Feb;70(2):95-8 mutations destabilize the catalytically inactive Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, conformation of the protein, resulting in a gain of Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, function. PTPN11 mutations are detectable in about Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cavé 90% of patients with LEOPARD syndrome. H. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004 References Nov;41(11):e117 Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Gorlin RJ, Anderson RC, Blaw M. Multiple lentigenes Wilson M, Calabrò R, Pizzuti A, Dallapiccola B. Clinical and syndrome. Am J Dis Child. 1969 Jun;117(6):652-62 molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68 Selmanowitz VJ, Orentreich N, Felsenstein JM. Lentiginosis profusa syndrome (multiple lentigines syndrome). Arch Sarkozy A, Obregon MG, Conti E, Esposito G, Mingarelli R, Dermatol. 1971 Oct;104(4):393-401 Pizzuti A, Dallapiccola B. A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD Somerville J, Bonham-Carter RE. The heart in lentiginosis. Br syndrome and Noonan-like/multiple giant cell lesion syndrome. Heart J. 1972 Jan;34(1):58-66 Eur J Hum Genet. 2004 Dec;12(12):1069-72 Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone syndrome. Case report and review of the literature. Am J Med. I, Spinelli M, Palmi C, Carta C, Pession A, Aricò M, Masera G, 1976 Mar;60(3):447-56 Basso G, Sorcini M, Gelb BD, Biondi A. Genetic evidence for Coppin BD, Temple IK. Multiple lentigines syndrome lineage-related and differentiation stage-related contribution of (LEOPARD syndrome or progressive cardiomyopathic somatic PTPN11 mutations to leukemogenesis in childhood lentiginosis). J Med Genet. 1997 Jul;34(7):582-6 acute leukemia. Blood. 2004 Jul 15;104(2):307-13

Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, This article should be referenced as such: Marino B, Pizzuti A, Dallapiccola B. Grouping of multiple- lentigines/LEOPARD and Noonan syndromes on the PTPN11 Digilio MC. LEOPARD syndrome. Atlas Genet Cytogenet gene. Am J Hum Genet. 2002 Aug;71(2):389-94 Oncol Haematol. 2005; 9(1):63-65. Legius E, Schrander-Stumpel C, Schollen E, Pulles- Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002 Aug;39(8):571-4

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Deep Insight Section

The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Eric Engel Department of Medical Genetics and Development, University of Geneva, Geneva, Switzerland (EE)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Deep/UniparentDisomy2005ID20049.html DOI: 10.4267/2042/38169 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

A situation of Non-Traditional Mendelian Inheritance What is Uniparental Disomy (UPD)? is achieved whenever an exceptional mode of recessive UPD is the occult presence of a chromosome pair transmission, distinctly alien to the usual pattern, leads inherited from only the mother or father in a diploid paradoxically to a similar phenotype. conceptus (or cell-line). How does UPD come about? A two-step twist of chromosomal inheritance (usually one step occurring at meiosis, the other at mitosis) leads to a diploid state with one pair issued from one parent only. What is the meiotic error leading to UPD? Laws and Out-Laws in Mendelian Recessive The usual meiotic process entails the same one that Inheritance leads to zygotic trisomy or monosomy (i.e. MeI or Two basic traditional tenets of the Mendelian Laws of MEII non-segregation). Inheritance are the segregation (separation) and the What is the mitotic step superseding the meiotic one independent assortment of alleles. and resulting in UPD? In the Non-Traditional Mode of Mendelian Inheritance, An early somatic error, namely a mitotic non- the non-congruent path of transmission usually resorts disjunction or a chromosome lag restoring diploidy. to a stratagem, the meiotic mis-segregation of alleles What is the end-result of the two-step process followed by a revised assortment at mitosis. Both steps leading to UPD? may end-up in the uniparental transmission of allele pairs while euploidy is maintained, a situation referred - Trisomy rescue by loss of one or the other member of to as Uniparental Disomy. the uniparental pair, (thus restoring the biparental parity) or by the loss of the normaly inherited Exemples of Non-Traditional Mendelian chromosome (leaving in place the monoparental pair). Inheritance causing genetic harm through UPD - Monosomy duplication (always resulting in a 1) duplication of a same dominant mutant (must often monoparental pair). be lethal) What may be the broad genetic make-up of the 2) duplication of the same recessive mutant uniparental pair? 3) overdose of the duplicated active domain of a parentally imprinted area The overall content of the pair be one of isodisomy (i.e. 4) loss of a singly active domain of a parentally both members are a carbon copy of one over the other) imprinted area with complete allelic sameness as seen in the process 5) combination of 3) and 4) resulting of mitotic monosomy duplication... 6) combination of 2) with 3) or 4) or 5) - quite rare

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

...or one of heterodisomy (non-identical allelism Reduction to homozygosity by isodisomy formation between homologous members) as may occur for the Depending on the dual meiotic-mitotic comedy of complete lack of crossing-over of two homologues errors, an F1 individual can become homozygous for a failing MeI segregation. Aside from these extreme recessive allele, if this allele gets duplicated in a examples, the UPD content resulting from meiotic non- uniparental pair. Thus, the singly heterozygous partner segregation is often a mix-pot of iso- and of a couple (Aa)* can sire a homozygous child (aa)** heterodisomy. by "reduction to homozygosity" as shown below: Definition of isodisomy The homoallelic duplication of a chromosome or a chromosome segment in one pair of a diploid individual or in a 2n cell-line or a 2n cell is called isodisomy. NOn-TRAditional Mendelian Inheritance (NOTRAMI)! Conditions for the occurrence of an isodisomic recessive trait: 1) Inheritance of a UPD pair showing duplication of a same chromosome or duplication of chromosome segments shared by homologues as a result of crossing over. 2) Presence of a locus with a recessive mutant on that chromosome or segment. What can bring about duplication of a same segment (isodisomy) in a uniparentally inherited pair: 1) Transmission at normal MeII of a pair including the two same crossed-over segments derived from a tetravalent, which failed MeI segregation. Specific factors potentially favoring complementation 2) Transmission of the non-crossed-over segment of the of aneuploid gametes * chromatids of a reduplicated chromosome, which failed a) A high frequency of germ cell aneuploidy targeting a MeII segregation. same homologous member chromosome in both sexes 3) The mitotic non-disjunction of a reduplicated causing a number of gametes to be either disomic or monosomic member. nullisomic for that chromosome (scarce evidence). Note: the centromeric and juxta-centromeric areas of a b) Presence in both parents of a balanced translocation tetravalent do not cross-over and stay heterodisomic. involving a same homologous member favoring As a result, the above areas of a MeII reduplicated unbalanced segregation of the translocated partner in chromosome remain isodisomic. The typing of these the germ cells in a complementary pattern (some very areas with appropriate polymorphisms allows to suggestive evidence). distinguish between MeI and MeII non-disjunction but (*Probably the least common pathway to UPD) not between MeII and mitotic non disjunction.

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

Sometime the UPD does not involve the whole of a two homologous non-sister chromatids. When chromosome and remains confined to a segment of a interstitial, the segmental UPD results from two pair as it arises from a somatic crossing over between symmetrical breaks, which are shown below as the

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

result of an "interchromatid kiss"! Mitotic segregation of the duplicated chromosomes, thereafter leads to mosaicism with one native and one reshuffled balanced cell line.

On the slide below are presented examples of both types of segmental UPD, terminal or interstitial, as found for various chromosomes, 4, 6, 7, 11, 14 and 20. Some were discovered because of reduction to homozygosity causing recessive traits, while others involved imprinted domains and disrupted them.

In other instances the segmental UPD is terminal and results from a single symmetrical break in each of two homologous non-sister chromatids, as seen below. Mosaicism involving two somatic cell types also results from this.

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

Uniparental disomies for chromosome 1 as a cause of recessive phenotypes.

Aneuploid mode and mood of chromosomes: called the aneuploid mode and mood of that particular chromosome. The results for chromosome 1 UPD's emphasize the - Recombination which may stay normal or be major role of maternal meioses errors causing gamete perturbed in the process. nullisomy and disomy in cases of either maternal or parental UPD1 (8 cases). Paternal meioses errors also account for 4 cases. The variable aneuploid mode and mood at the origin of numerical abnormalities of different The perfect culprit for Non-Traditional Mendelian chromosome numbers of the set Inheritance in UPD - Great difference in the incidence of trisomy for -A chromosome from a disomic or nullisonic ovum different chromosomes * responsible after fertilization for trisomies or - Variable association with increased parental monosomies respectively liable to rescue by mitotic (maternal) age * deletion or duplication. - Absence of all monosomies except for the X -A large member of the set. chromosome * -A member carrying a locus with a common mutation - Differential selection and survival at different stages or an imprinted domain. of pregnancy * Factors influencing the chance occurrence of - Different frequencies of non-disjunction among trisomy rescue different chromosomes * a) The relatively large pool size of the trisomy liable to And, consequently, great differences in the chances of rescue (i.e. 16, 15, 21, 22, X). UPD formation and isodisomy for individual numbers. b) The factors modulating the size and nature of such a (*Jacobs PA, Hassold TJ. Adv Genet. 1995;33:101-33.) pool: Aneuploid mode and mood of some clinically - the aneuploid mode and mood of specific significant chromosomes chromosome members - maternal age - abnormal segregation of common centric fusions - etc... At meiosis, what affects the occurrence and genetic content of the non-disjoined pair? - Some ill-understood specific factors of the chromosome member implicated which I have just

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

Possible end-points of the various factors affecting transition to isodisomy in the formation of uniparental pairs 1) Some mechanisms rule out or lower the chances of a transition from hetero- to isodisomy and minimize the risks of transmission of a recessive allele. 2) Other mechanisms carry-out a higher to much higher risk of isodisomy along with an increased chance of homozygosity for a recessive allele.

NOTRAMI What suppresses or lowers the risk of isodisomy as a cause of reduction to homozygosity in UPD? 1) an MeI nulli-chiasmate or pauci-chiasmate synapsis (i.e. an absolute or relative recombination failure of Conclusion : homologues) followed by MeI non-segregation and normal MeII separation. Except for the 45,X, most cases are of maternal origin, 2) an MeI failure of synapsis (i.e. the lack of the meiotic stage of non-disjunction is variable for homologous pairing) followed by the same pole different numbers (from 100% MeI to 66% MeII) and migration of the two resulting univalent an normal the lethality rate quite disparate. MeII separation.

On the following few slides, we show some specific examples of the role of the aneuploid mechanisms on the production of UPD for chromosomes 21, 1, 7 and 15:

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

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The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa ! Engel E

Summary process, the meiotic disjunctional pattern and the post- zygotic mitotic adjustment of the chromosomes which 1) Presence of a uniparental pair in a diploid genome all concur in shaping the end-product of the uniparental (UPD) results from an aberrant mode of transmission pair and its genetic impact. separate from Traditional Mendelian Inheritance. 5) To this day, some thirty different recessive Instead of the classic tenets of allele segregation and phenotypes have been traced once or a few times to the independent assortment, an abnormal and complex presence of uniparental pairs. The good thing about the pattern of segregation leads to this unusual unilateral uniparental inheritance of recessive traits is that their assortment of alleles in the offspring. risk of recurrence is almost nil. 2) The phenotype effect of this odd transmission then depends on the character -normal, mutant or imprinted- Illustrations by Mr Jean-Claude Malgouyres of the mis-assorted gene(s). 3) In the case of recessive inheritance, a singly This article should be referenced as such: heterozygous parent may sire a homozygous affected child. This will occur when the uniparental pair is Engel E. The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa homoallelic (isodisomy). !. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):66- 4) Isodisomy in uniparental pairs depends on various 74. factors such as the aneuploid ways and means of the chromosome number involved, the recombination

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Case Report Section Paper co-edited with the European LeukemiaNet

A new case of t(1;11)(q21;q23) in a child with M1 ANLL Katell Le Du, Eric Jeandidier, Francine Garnache, Pierre Rohrlich, Jean-Luc Bresson, Marie- Agnès Collonge-Rame Service d'Hématologie, CHU-Hôpital J. Minjoz. Bld Flemming, 25030 Besançon Cedex, France (KLD, PR); Laboratoire de Biochimie-Unité de Génétique, CH-Hôpital E. Muller, BP 1370, 68070 Mulhouse Cedex, France (EJ); Etablissement Français du Sang- Bourgogne/Franche-Comté, BP 1937, 25020 Besançon Cedex, France (FG); Service de Génétique, Histologie, Biologie du Développement et de la Reproduction, CHU, Place St Jacques, 25030 Besançon Cedex, France (JLB, MACR)

Published in Atlas Database: January 2005 Online updated version: http://AtlasGeneticsOncology.org/Reports/0111CollongeID100008.html DOI: 10.4267/2042/38170 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Immunophenotype CD13+,CD15+,CD65+,CD33+,CD117+, MPO+, Age and sex MDR-, CD34-, CD36-, CD14-, CD4+, lineage B-, 21 months old male patient. lineage T-. Previous history Diagnosis No preleukemia. No previous solid tumors. Inborn AML1 (FAB classification), LAM with 11q23 condition of note: Prematurity (borth at 33 weeks of abnormalities (WHO classification). gestation). Organomegaly Survival No hepatomegaly, no splenomegaly, no enlarged lymph Date of diagnosis: 04-2004 nodes. Treatment: Induction treatment including cytosine- arabinoside (200 mg/m_ D+1 to D+8) and Blood mitoxantrone (12 mg /m_ D+1, D+2, D+3). One WBC: 10.6X 10 9/l intrathecal injection (including methotrexate, steroids, HB: 7.1g/dl and cytosine-arabinoside). Platelets: 71X 10 9/l Complete remission: Yes Blasts: 8% Relapse: no Survival: 8 +months Cyto-Pathology Classification Karyotype Sample: Bone marrow Cytology Culture time: 24/72 h Bone marrow: 84 % of blastic cells. Cytochemestry: peroxydase: 100% of positive blasts; butyrate esterase: Banding: G and R banding positive in 11% of blasts. Results 46,XY,t(1;11)(q21;q23)[6]

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A new case of t(1;11)(q21;q23) in a child with M1 ANLL Le Du K et al.

Other molecular cytogenetics technics Other Molecular Studies Fluorescence in Situ Hybridization was performed using a MLL dual color, break apart rearrangement Results: probe and a chromosome 1 specific labeled spectrum MLL multiplex PCR [t(4;11), t(6;11), t(9;11), t(10;11), green painting probe (ABBOTT). t(11;19)]: negative. ETO/AML1: negative. Other molecular cytogenetics results MYH11/CBFB: negative. FLT3 mutations research: Confirmation of MLL rearrangement by the negative. t(1;11)(q21;q23).

Bone marrow (MGG staining).

Partial karyotype showing the t(1;11)(q21;q23)(R bands).

FISH results.

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A new case of t(1;11)(q21;q23) in a child with M1 ANLL Le Du K et al.

Other Findings References Note: Mitelman F, Johansson B, Mertens F. Mitelman Database of Chromosome Aberrations in Cancer. Meningeal punction: no blastic cells infiltration. http://cgap.nci.nih.gov/Chromosomes/Mitelman Busson-Le Coniat M, Salomon-Nguyen F, Hillion J, Bernard Comments OA, Berger R. MLL-AF1q fusion resulting from t(1;11) in acute leukemia. Leukemia. 1999 Feb;13(2):302-6 To our knowledge, 26 cases of translocation t(1;11)(q21;q23) (involved the genes AF1q (1q21) and Meloni-Balliet AM, Morgan R, Piatt J, Sandberg AA. Translocation t(1;11)(q21;q23), a new subgroup within M4 MLL(11q23) have already been described in the acute nonlymphocytic leukemia. Cancer Genet Cytogenet. literature. All cases were acute leukemia except for one 1989 Feb;37(2):269-71 secondary myelodysplastic syndrome. In 14 cases (57 Tse W, Zhu W, Chen HS, Cohen A. A novel gene, AF1q, fused %), the translocation was the sole abnormality. The to MLL in t(1;11) (q21;q23), is specifically expressed in other 12 cases showed additional chromosomal leukemic and immature hematopoietic cells. Blood. 1995 Feb abnormalities. This rare translocation is preferentially 1;85(3):650-6 associated with AML4, AML5, or biphenotypic Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage- leukemia of infants or children. Only one case of AML Pochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM. M1/M2 in a 3-year-old female was reported with Ten novel 11q23 chromosomal partner sites. European 11q23 t(1;11)(q21;q23) as the sole karyotypic change. We Workshop participants. Leukemia. 1998 May;12(5):811-22 present here the second case of AML1 with This article should be referenced as such: t(1;11)(q21;q23). The chid is in complete remission at Le Du K, Jeandidier E, Garnache F, Rohrlich P, Bresson JL, 6 months after diagnosis. Collonge-Rame MA. A new case of t(1;11)(q21;q23) in a child with M1 ANLL. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):75-77.

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Translocation (X; 20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 1 Kavita S. Reddy, Kathy E Richkind Genzyme Genetics, Orange, CA, USA (KSR); Genzyme Genetics, Santa Fe, NM, USA (KER)

Published in Atlas Database: January 2005 Online updated version: http://AtlasGeneticsOncology.org/Reports/0X20ReddyID100009.html DOI: 10.4267/2042/38171 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Karyotype Age and sex Sample: BM 57 years old female patient. Culture time: 24/48h unstimulated cultures. Previous history Banding: G-banding. No preleukemia. Previous malignancy: Breast Results: 46,X,t(X;20)(q13;q13.3)[5]/46,XX[15]. infiltrating ductal carcinoma treated with radiation and tamoxifen. Organomegaly No hepatomegaly, no splenomegaly, no enlarged lymph nodes, no central nervous system involvement. Blood WBC: 3.8X 10 9/l HB: 11.4g/dl Platelets: 160X 10 9/l Cyto-Pathology Classification Diagnosis Myelodysplastic syndrome (MDS): refractory anaemia. Survival Treatment Maintenance therapy for MDS patient declined bone marrow transplantation (BMT). Relapse: no

Status: Alive Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) Survival: 42 months for cases 1•4 (top to bottom). Arrows indicate the derivatives 20 and X.

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Michaux L, Wlodarska I, Mecucci C, Hernandez JM, Van References Orshoven A, Michaux JL, Van den Berghe H. Characterization by chromosome painting of balanced and unbalanced X Gray BA, Cornfield D, Bent-Williams A, Zori RT. Translocation chromosome translocations in myelodysplastic syndromes. (X;20)(q13.1;q13.3) as a primary chromosomal finding in two Cancer Genet Cytogenet. 1995 Jul 1;82(1):17-22 patients with myelocytic disorders. Cancer Genet Cytogenet. 2003 Mar;141(2):169-74 This article should be referenced as such: Reddy KS, Richkind K, Ross M, Seirra R. Translocation Reddy KS, Richkind KE. Translocation (X;20)(q13;q13.3): a (X;20)(q13;q13.3): a nonrandom abnormality in four patients nonrandom abnormality in four patients with myeloid disorders: with myeloid disorders. Cancer Genet Cytogenet. 2005 case 1. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):78- Feb;157(1):70-3 79.

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Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 2 Kavita S Reddy, Kathy Richkind Genzyme Genetics, Orange, CA, USA (KSR); Genzyme Genetics, Santa Fe, NM, USA (KER)

Published in Atlas Database: January 2005 Online updated version: http://AtlasGeneticsOncology.org/Reports/0X20ReddyID100010.html DOI: 10.4267/2042/38172 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Karyotype Age and sex Sample: PB 61 years old female patient. Culture time: 24/48h unstimulated cultures. Previous history Banding: G-banding. Preleukemia: Myelofibrosis. Previous malignancy: A Results: low-grade lobular and ductal carcinoma with a small 46,X,t(X;20)(q13;q13.3),der(1;7)(q10;p10)[20]/46,XX[ percentage of intraductal breast disease treated with 1]. tamoxifen. Organomegaly No hepatomegaly, no splenomegaly, no enlarged lymph nodes, no central nervous system involvement. Blood WBC: 3.05X 10 9/l HB: 8.1g/dl Platelets: 62X 10 9/l Cyto-Pathology Classification Diagnosis Myelofibrosis -> acute leukemia. Survival Treatment: Induction treatment: topotecan and cytarabine. Relapse: no Status: Alive Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 1•4 (top to bottom). Arrows indicate the derivatives 20 Survival: 55 months. and X.

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Wong KF, Kwong YL, Tang KC. Biclonal acute monoblastic References leukemia showing del(7q) and trisomies 9 and 22. Cancer Genet Cytogenet. 1995 Jul 1;82(1):70-2 Gray BA, Cornfield D, Bent-Williams A, Zori RT. Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two This article should be referenced as such: patients with myelocytic disorders. Cancer Genet Cytogenet. 2003 Mar;141(2):169-74 Reddy KS, Richkind KE. Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: Reddy KS, Richkind K, Ross M, Seirra R. Translocation case 2. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):80- (X;20)(q13;q13.3): a nonrandom abnormality in four patients 81. with myeloid disorders. Cancer Genet Cytogenet. 2005 Feb;157(1):70-3

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Translocation (X; 20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 3 Kavita S Reddy, Kathy E Richkind Genzyme Genetics, Orange, CA, USA (KSR); Genzyme Genetics, Santa Fe, NM, USA (KER)

Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Reports/0X20ReddyID100011.html DOI: 10.4267/2042/38173 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Age and sex 77 years old female patient. Previous history No preleukemia. Previous malignancy: No clinical information. Cyto-Pathology Classification Diagnosis Myelodysplastic syndrome (MDS): sideroblastic anemia. Survival Relapse: no. Status: No clinical information. Karyotype Sample: BM Culture time: 24/48h unstimulated cultures Banding: G-banding Results: 46,X,t(X;20)(q13;q13.3)[10]/46,XX[10]

Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 1•4 (top to bottom). Arrows indicate the derivatives 20 and X.

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Wong KF, Kwong YL, Tang KC. Biclonal acute monoblastic References leukemia showing del(7q) and trisomies 9 and 22. Cancer Genet Cytogenet. 1995 Jul 1;82(1):70-2 Gray BA, Cornfield D, Bent-Williams A, Zori RT. Translocation (X;20)(q13.1;q13.3) as a primary This article should be referenced as such: chromosomal finding in two patients with myelocytic disorders. Reddy KS, Richkind KE. Translocation (X;20)(q13;q13.3): a Cancer Genet Cytogenet. 2003 Mar;141(2):169-74 nonrandom abnormality in four patients with myeloid disorders: Reddy KS, Richkind K, Ross M, Seirra R. Translocation case 3. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):82- (X;20)(q13;q13.3): a nonrandom abnormality in four patients 83. with myeloid disorders. Cancer Genet Cytogenet. 2005 Feb;157(1):70-3

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Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders: case 4 Kavita S Reddy, Kathy E Richkind Genzyme Genetics, Orange, CA, USA (KSR); Genzyme Genetics, Santa Fe, NM, USA (KER) Published in Atlas Database: January 2005 Online updated version : http://AtlasGeneticsOncology.org/Reports/0X20ReddyID100012.html DOI: 10.4267/2042/38174 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics Results 46,X,t(X;20)(q13;q13.3)[3].ish t(X;20)(q11.2- Age and sex 12;q13.3) (wcpX+, wcp20+, AR_; wcp20+, D20S108+, 66 years old female patient. AR+, wcpX+)/46,XX[18] Previous history Other molecular cytogenetics results No preleukemia. Previous malignancy: No clinical 46,X,t(X;20)(q13;q13.3)[3].ish t(X;20)(q11.2- information. 12;q13.3) (wcpX+,wcp20+,AR_;wcp20+,D20S108+,AR+,wcpX Blood +)/46,XX[18] WBC : 4.16X 10 9/l HB : 13.5g/dl Platelets : 103X 10 9/l Cyto-Pathology Classification Diagnosis Myelodysplastic syndrome (MDS): pancytopenia and thrombocytopenia Survival Relapse: no Status: No clinical information Survival: 1 month Karyotype Sample: BM Culture time: 24/48h unstimulated cultures

Banding: G-banding Fig. 1. Partial karyotypes of the translocation t(X;20)(q13;q13.3) for cases 1•4 (top to bottom). Arrows indicate the derivatives 20 and X.

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Fig 2: Case 4: X-centromere probe DXZ1 (green) hybridized to the normal X and the derivative X (arrows). The androgen receptor (Xq12) AR (red) probe hybridized to derivative 20 and the normal X (arrows). The breakpoint on the X chromosome is proximal to AR. The karyotype is 46,X,t(X;20)(q13;q13.3).ish t(X;20)( q11.2q12 ;q13.3)(wcpX+, wcp20+, AR_; wcp20+, D20S180_, AR+, wcpX+). The revised breakpoints identified with FISH analysis are highlighted in bold.

Reddy KS, Richkind K, Ross M, Seirra R. Translocation Other Findings (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders. Cancer Genet Cytogenet. 2005 Note: Feb;157(1):70-3 In case 4, the breakpoint on X-chromosome was found Wong KF, Kwong YL, Tang KC. Biclonal acute monoblastic to be more proximal between Xq11.2q-12 by FISH leukemia showing del(7q) and trisomies 9 and 22. Cancer using androgen receptor probe. Genet Cytogenet. 1995 Jul 1;82(1):70-2 References This article should be referenced as such: Reddy KS, Richkind KE. Translocation (X;20)(q13;q13.3): a Gray BA, Cornfield D, Bent-Williams A, Zori RT. Translocation nonrandom abnormality in four patients with myeloid disorders: (X;20)(q13.1;q13.3) as a primary chromosomal finding in two case 4. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):84- patients with myelocytic disorders. Cancer Genet Cytogenet. 85. 2003 Mar;141(2):169-74

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Educational Items Section Short Communication

Genetics and Public Health Anne-Marie Laberge Institute for Public Health Genetics, University of Washington, Box 357236, Seattle, WA 98195, USA (AML)

Published in Atlas Database: November 2004 Online updated version: http://AtlasGeneticsOncology.org/Educ/GenetPublicHealthID30053ES.html DOI: 10.4267/2042/38175 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

I - Introduction II - Populations targeted by public health genetics interventions III - Ethical, legal, and social implications of public health genetic interventions III - 1. Use of genetic information: confidentiality and discrimination III - 2. DNA banks III - 3. Prenatal diagnosis, assisted reproduction and embryo selection IV - Examples of the role of public health in genetics IV - 1. Folic acid and neural tube defects IV - 2. Newborn screening IV - 3. Carrier screening in the context of reproductive decisions IV - 4. Prenatal screening for aneuploidy and neural tube defects IV - 5. Screening for genetic susceptibilities in adults IV - 6. Pharmacogenetics and ecogenetics IV - 7. Personalized Health Care and Genetic Information Conclusion

I - Introduction Advances in genetic knowledge and technology could be used to try to prevent disease and improve The role of public health is to ensure that the basic population health. conditions required for people to be healthy are present. The perceived role of genetics in public health is Until recently, public health focused mostly on changing, as is the definition of what is a genetic environmental causes and risk factors for disease, such disease. The role of genetics in public health is as infections, cigarette smoking, diet, etc. Since the broadened if we consider all the diseases for which sequencing of the human genome has been completed, genetics might play a role, either by the presence of a high hopes rest on the potential to prevent the impact of genetic susceptibility for the development of this genetic risk factors or susceptibilities to disease. disease or for response to treatment, or by the presence

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of protective genetic factors, such as in resistance to Sachs disease. In programs targeted at specific infection. communities, it is important to ensure that the One day, it might be possible to determine for each community is in favor of screening and that it does not individual which genetic susceptibilities and protective become a source of stigmatization for the community. factors each individual possesses, and act accordingly III - Ethical, legal, and social to prevent the occurrence of disease. In the meantime, the role of genetics in public health is mostly limited to implications of public health genetic monogenic diseases. interventions II - Populations targeted by public III - 1. Use of genetic information: confidentiality health genetics interventions and discrimination The issue of confidentiality of genetic information is Public health considers the overall health of the frequently raised. Genetic information is different from population as a group, and not the health of each other types of personal information found in a medical individual. Since resources for public health chart. First, genetic information does not change over interventions are limited, priorities need to be time: the presence of a mutation or a polymorphism in established to determine which interventions will be an individual is immutable. Second, genetic most beneficial to the population as a whole. These information about one individual has implications not priorities will be based on the characteristics of the only for the individual in question, but also for his/her disease, such as its prevalence, its severity, and family members, since the genetic abnormalities are treatment availability, as well as the amount of heritable in most cases. In some cases, genetic resources needed for the intervention. information is used to confirm a clinical diagnosis, but Monogenic diseases are rare. Is it justifiable to it is increasingly used to confer a level of risk or implement population-based interventions to identify a susceptibility for the development a specific condition. few rare cases of a particular genetic disease? There is In that context, it is not surprising that some are no single right answer to this question. It depends on worried that information about a specific genetic the burden these rare cases represent for society, on our susceptibility might be used by insurers or employers ability to act to attenuate this burden, and on the value as a source of discrimination. we place on obtaining an early diagnosis, compared to the complexity of detecting these cases and the amount III - 2. DNA banks of resources needed to detect them. For example, Genetic research often requires the collection of DNA newborn screening for phenylketonuria is considered samples. Many DNA banks were formed from DNA beneficial because it makes it possible for the children samples collected for specific research projects or from identified through screening, who would otherwise blood samples collected for newborn screening. Once have developed severe mental retardation, to develop they have served their intended use, what should now normally by following a special diet. In the majority of be done with these samples? Who do they belong to? developed countries, all newborns are screened for Can the researcher use them for other purposes without phenylketonuria to detect a handful of cases, because the consent of those who gave these samples? Can he the impact of treatment on these children’s potential only do it if he anonymizes the samples first? Or does ability to contribute to society is so great. On the other the researcher need to contact each individual to renew hand, similar newborn screening for Huntington his/her consent? To respect the autonomy of disease is not being considered, because it is a late- individuals who participated in previous research onset disease for which there is no treatment and no projects, it would be necessary to contact them again to clear benefit to an early diagnosis. Screening would not obtain renewed consent before using their samples for change the impact of the disease on the affected other research projects. On the other hand, these individuals or its burden on society. samples are easily accessible and could be used to To improve the yield of a screening program for a further scientific knowledge for the benefit of society genetic disease, one option is to target a population at without major negative impact on the individual who higher risk of disease, often the families of affected provided the sample, especially if the samples are cases. This approach limits the amount of resources anonymized. In some cases, the nature of the needed for screening and increases the yield of prospective research will also influence the decision to screening. It unfortunately is limited by the fact that use or not use samples from a DNA bank. Researchers many new cases of genetic disease occur in individuals and ethicists all over the world are faced with these with no family history who would not be identified by issues. Institutional review boards are assessing each family-based screening. In some cases, ethnic groups research project based on its specific context, because can be the target population of screening programs, no consensus has been reached for now on procedures when prevalence of the disease in questions is for the use of DNA banks in research. particularly high in that ethnic group. For example, III - 3. Prenatal diagnosis, assisted reproduction and Ashkenaze Jewish populations are screened for Tay- embryo selection

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Assisted reproduction has made it necessary to redefine born with NTD in women who took folic acid fundamental concepts, such as paternity and maternity. supplements. Even though the way in which folic acid We now use the terms biological mother, gestational acts to prevent NTD has not been elucidated, these mother (or surrogate mother), and social mother. We observed findings have led to the hypothesis that folic also differentiate between biological father and social acid supplementation would be beneficial to all women father. Before DNA tests, paternity was always planning a pregnancy, to prevent the birth of a child assumed, but it is now possible to determine with with a NTD. strong certainty whether an individual is or isn’t a Because the neural tube closes during the fourth week given child’s biological father. In the past, maternity of gestation, it is recommended to start folic acid was simply attributed to the woman who had given supplementation before conception. The minimal dose birth to the child. But these days, it is possible for a needed to obtain an effect has not been established, but woman to have an embryo conceived with her own the usually recommended daily dose is 400 micrograms eggs carried to term by another woman. The first in women with no specific risk factor, and should be woman is then the biological mother, and the second started at least 3 months before conception. However, the gestational mother. The social mother will be the supplementation often does not occur, either because one acting as a parent to the child in question. women are not aware of the benefits of folic acid Assisted reproduction is not reserved for infertile supplementation or because pregnancy was not couples anymore, but is also used by couple who want planned. to ensure that their child will be born without a specific To address this problem, some countries have decided hereditary disease, or even to make sure that their child to add folic acid to the food supply, most often in flour. will be a matched donor for an older sibling in need of This type of public health intervention has occurred in a bone marrow transplant. Genetic tests performed on the past to prevent other diseases: iodized salt to embryos make it possible to select only embryos that fit prevent goiter, and vitamin D in milk to prevent rickets. certain criteria. For now, this technology is mostly used Folic acid fortification of flour has not been done to avoid the birth of children with severe hereditary without controversy. Some fear that folic acid childhood diseases, but it is feared that it opens the fortification will mask vitamin B12 deficiency and door to embryo selection based on other criteria, such delay its diagnosis. Others worry about long-term as physical appearance or intellectual ability. effects of a folic acid-fortified diet or about potential When a pregnant woman is offered the possibility of interactions between folic acid and prescribed drugs. undergoing prenatal diagnosis for genetic diseases No study has shown that this fortification strategy through amniocentesis or chorionic villous sampling, it would be sufficient to reduce the incidence of NTD in implies that selective abortion is an option they will the population. In spite of all that, many professional consider if the fetus is indeed affected with a genetic organizations have declared themselves in favor of disease. For some, this option is unacceptable for fortification. Folic acid fortification has been ethical, moral, and/or religious reasons. It raises the established at the end of the 1990s in many developed question of the legal status of the embryo, the definition countries, most often in flour. Studies done since of human life and of a human being. fortification seem to show a significant reduction in the IV - Examples of the role of public incidence of NTD in the population, even when accounting for the secular trend. health in genetics IV - 2. Newborn screening There are already many examples of the role of public health in genetics. Better known examples deal with Phenylketonuria (PKU) is the first example of reproductive technologies (prenatal screening, carrier population-based genetic screening. It was put in place screening) and newborn screening. More recent in the U.S.A. in the early 1960s, thanks to the examples in the adult setting concern genetic development by Dr Robert Guthrie of a technique susceptibility screening and pharmacogenetics. allowing the measurement of blood phenylalanine levels using blood samples collected on filter paper. IV - 1. Folic acid and neural tube defects Samples collected in this way are easy to store and Neural tube defects (NTD) account for an important ship, and can be preserved for extended periods of part of birth defect-related infantile mortality and time. The technique itself is cheap and easy to perform. morbidity. Their incidence tends to be decreasing over These characteristics have made it possible to develop time (secular trend). During the 1980s, studies have large-scale screening programs. Newborn screening for shown a decrease in the recurrence of NTD in PKU is now performed by the state in most developed subsequent pregnancies with the use of folic acid for countries. women having already had a child with a NTD. Since In the wake of newborn screening tests, a screening then, studies done in women with no family history of “system” was developed. Today, a newborn screening NTD have also shown lower incidence rates of children system includes sample collection and shipment to

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screening facilities, performance of the screening test in World Health Organization, state that an effective the laboratory, diffusion of test results to parents and treatment must be available and that the early referring physicians, and, for newborns with abnormal application of that treatment must improve the health results, rapid access to specialized evaluation and outcome of the child. Even though long term impact of appropriate care. In parallel, severe quality control early diagnosis of cystic fibrosis on the evolution of criteria have been established and voluntary laboratory disease has not been irrevocably established, some quality control programs are managed by government argue that early diagnosis is of benefit to parents agencies, such as the Center for Disease Control in the because it avoids unnecessary anxiety related to U.S.A. delayed diagnosis in a symptomatic child, and enables Since the 1960s, other diseases have been added to them to make informed reproductive decisions for newborn screening panels. The list varies by region, but future pregnancies. The benefit is not for the child it almost always includes congenital hypothyroidism, itself, but for parents, and it is not related to the early and often includes galactosemia, tyrosinemia, sickle onset of effective treatment. According to this cell anemia, and/or congenital adrenal hyperplasia. For argument, it would be justifiable to screen for genetic all these diseases, a dietary-based or drug-based conditions with no known effective treatment but treatment is available to prevent the effects of the whose early diagnosis would be of value to the parents. disease or attempt to control their progression, and it In the case of cystic fibrosis, early diagnosis can seems preferable to start these treatments as early as possibly be of value to the child, but this would not be possible. the case for other diseases for which newborn screening In the last few years, a new technology, tandem mass has been advocated, such as Duchenne muscular spectrometry (MS/MS), makes it possible to detect over dystrophy and Fragile X syndrome. 30 metabolic diseases during the newborn period, such IV - 3. Carrier screening in the context of as aminoacidemias, organic acidurias, and urea cycle reproductive decisions defects, to name a few. The use of this technology for The first carrier-screening program for recessive newborn screening is controversial for several reasons. diseases was developed in the Ashkenazi Jewish Among the diseases that can be detected with MS/MS, communities in New York and Washington, D.C., in some have a poorly defined natural history. In those the U.S.A. With the support of the community and cases, it is difficult to predict what will happen to the religious officials, a carrier-screening program for Tay- affected newborn and the impact that early diagnosis Sachs disease was established in the early 1970s, and treatment could have. It is not clear whether dietary shortly after the discovery of the enzyme whose treatment will be as effective in all cases. However, deficiency is the cause of the disease. Tay-Sachs newborn screening using MS/MS would make it disease then had a relatively high prevalence in the possible to learn more about these diseases, which Ashkenazi Jewish community. This disease causes might otherwise go undetected (even if symptomatic). progressive neurodegeneration starting in the first year In the U.S.A., advocacy groups formed by parents of of life and inevitably leading to the child’s death, children with diseases detectable with MS/MS are usually by four years of age. Both the community lobbying for the addition of this technology to state-run members and the health professionals involved agreed newborn screening programs. Those opposed to using that this disease is so severe that it would be preferable MS/MS for newborn screening argue that there is no to take measures to avoid the birth of affected children. evidence that early diagnosis and treatment of these The screening strategy has been adapted to the needs diseases will improve their natural course, which goes and realities of the different communities: in orthodox against the criteria largely used to decide whether or communities where selective abortion was not not to add new diseases to newborn screening acceptable, premarital screening is performed and programs. They stress that the availability of the results are taken into account in the rabbi’s decision to technology and its capacity to detect disease does not bless the marriage or not, which has been deemed mean that the information it provides is valuable for acceptable by the community. Carrier screening newborns. programs for Tay-Sachs disease now exist in Newborn screening for cystic fibrosis is also currently Ashkenazi Jewish communities around the world. debated. Newborn screening programs for cystic Thanks to these programs, the incidence of the disease fibrosis already exist in many regions of the world: in has decreased by over 90% in these communities. In Wisconsin and Colorado (USA), in Brittany (France), the wake of this success, other diseases with relatively and some regions of the United Kingdom and high prevalence in Ashkenazi Jewish communities have Australia. Some studies have shown that children been added to carrier screening panels, such as identified through newborn screening achieve better Canavan disease and Gaucher disease, to name a few. nutritional status and/or better respiratory function than In response to the success of Tay-Sachs carrier those diagnosed through symptoms, but these screening in Ashkenazi Jewish communities, similar differences are mild and tend to disappear over time. programs have been developed in other communities The main newborn screening criteria, as defined by the

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where an autosomal recessive disease was highly affected. In general, this option is considered prevalent in children, such as carrier screening for beta- acceptable because most people consider these thalassemia in Cyprus and Sardinia. These programs conditions to be severe enough and prevalent enough to have also led to drastic reductions in disease prevalence justify a population-based screening program. Those in these communities. Carrier screening programs for who consider termination to be unacceptable can select sickle cell anemia in African Americans in the U.S.A. out of the screening process. in the 1970s have not had the same success, partly IV - 5. Screening for genetic susceptibilities in adults because the distinction between being a healthy carrier Since the sequencing of the human genome, advances and having the disease was not made clear. This had in genetic knowledge has led us to consider the led to discrimination against carriers. potential use of genetic information to assess individual Recently, the American College of Obstetrics and susceptibilty to disease. Although this is not widely Gynecology has recommended that all pregnant women possible yet, there are some examples of the use of be offered carrier screening for cystic fibrosis. This genetic tests for that purpose. These examples raise recommendation has been questioned by some, because questions about the real clinical utility of that type of screening is routinely offered when pregnancy is information at the individual level. already ongoing and because cystic fibrosis is not Hereditary hemochromatosis is an autosomal recessive considered as severe as Tay-Sachs disease. disease. Individuals who suffer from this disease can IV - 4. Prenatal screening for aneuploidy and neural develop cirrhosis of the liver, diabetes, and tube defects cardiomyopathy. Symptoms are caused by a defect in For a detailed discussion of what is available in iron metabolism, which leads to iron deposition in prenatal diagnosis, see “Prenatal Diagnosis” section. tissues. Two main mutations in the hemochromatosis In terms of population health, it is of note that prenatal gene have been identified, C282Y and H63D. Most screening for chromosomal abnormalities and neural cases are C282Y homozygotes. Regular phlebotomies tube defects is offered to pregnant women in many reduce iron deposition and can help prevent or reduce countries. These screening programs may be targeted at symptoms. For that reason, hemochromatosis is women with specific risk factors (i.e. according to considered an ideal target for population-based maternal age), or to all pregnant women. In most cases, screening. The use of a genetic test as a screening test newborns with chromosomal abnormalities or neural for hereditary hemochromatosis is justified if we tube defect are born of mothers with no specific risk assume that penetrance of the disease is high, i.e. that factors. A screening test done during pregnancy can most C282Y homozygotes will develop symptoms of identify those women at higher risk of carrying a fetus hemochromatosis in their lifetime if untreated, and that with one of these conditions. This blood test, which they would benefit from early diagnosis and preventive measures a combination of serum and/or ultrasound treatment. Unfortunately, penetrance seems lower than markers, is not a diagnostic test: like all screening tests, previously thought: it seems that only a minority of it tends to be highly sensitive, but not necessarily very C282Y homozygotes actually develop symptoms of specific. The role of a screening test is to detect all hemochromatosis in their lifetime. The value of cases of the targeted condition, at the expense of a population-based genetic screening for certain amount of false positive results. For prenatal hemochromatosis is being questioned. It is currently screening, the test result is usually given as the recommended to use transferrin saturation level as a probability that the fetus is affected, and the result is screening test for hemochromatosis. This is a considered “positive” when this probability is higher biochemical index of iron overload, and is closer to the than a specific threshold, usually between 1/400 and phenotype of hemochromatosis than the genetic test. 1/200. Since this threshold is relatively low, there is Factor V Leiden (FVL) is a variant of factor V, a inevitably a high proportion of false positive results, coagulation factor. This variant is associated with an i.e. pregnancies with test results above the threshold increased risk of thrombosis. Even though the presence and considered at high risk of having an affected fetus, of FVL in an individual with a history of thrombosis but whose fetus is actually not affected. In a screening can help explain the cause of the thrombosis, it does context, we tolerate a certain amount of false positive not usually change immediate treatment or long-term results that will have to undergo definitive diagnostic management of that individual, who will be treated as testing through amniocentesis and incur the associated any other individual with a personal history of risk of miscarriage. It is the price to pay to reduce as thrombosis. On the other hand, not all individuals who much as possible the rate of false negative results, i.e. a have FVL will develop thrombosis. It is difficult to result placing the risk below the threshold when the justify population-based screening for FVL, and fetus is actually affected. These screening programs especially to submit them to long-term prophylactic have been developed to give women the possibility of anticoagulation treatment, which is associated with terminating the pregnancy if the fetus is found to be significant risks of bleeding. Other factors also

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influence the risk of thrombosis in these individuals, agent in question if it gives them a false sense of such as smoking and hormonal therapy, and make it security and protective measures are lessened, which difficult to predict risk of thrombosis on an individual would paradoxically put them at higher risk of actually basis. developing complications. As our knowledge of gene-environment interactions IV - 7. Personalized Health Care and Genetic increases, it might be possible to improve our Information assessment of individual disease susceptibility by using Some hope that a better understanding of genetic predictive models based on combinations of genetic variability will help adapt treatments on the basis of an and environmental risk factors. For now, the impact of individual’s genetic characteristics and the risks and genetic susceptibility is difficult to assess, especially on benefits of the many treatment options available for an individual basis. that individual. This will depend on how fast IV - 6. Pharmacogenetics and ecogenetics knowledge will grow in pharmacogenetics and Pharmacogenetics is a field of genetics focusing on the ecogenetics. In some cases, the treatment will be the role of genetics in individual variability of drug same, but the dose, duration or timing of treatment will response and side effect occurrence. If we can predict be different according to the individual’s genotype. In the pharmacologic response of a given individual to a other cases, treatment itself will be tailored for specific specific drug based on the presence or absence of a individual genotypes, targeting specific genetic given genetic polymorphism, we could adjust dosage differences. Over time, a better understanding of accordingly. Most genetic polymorphism studied until genetic susceptibilities might help target preventive now have been in genes involved in the metabolism or measures to individuals who can potentially benefit elimination of drugs. It is thought that these from them the most. But, in the context of increasing polymorphisms might accelerate or slow drug health care costs, the use of resources to personalize metabolism or drug elimination. health care based on genetic characteristics will have to Ecogenetics is similar to pharmacogenetics, but focuses be balanced against its benefits. on the role of genetics in explaining the individual Conclusion variability of response to environmental factors (carcinogens, pesticides, food products, industria The impact of genetics in public health is still limited, pollutants, etc.), instead of response to drugs. This but is expected to grow in the near future, as genetic information could be used in the workplace to identify knowledge rapidly increases. Current examples of the individual workers at risk of developing complications use of genetics in public health can serve as lessons for related to occupational exposure to specifc agents. the future. There is the danger that this might be used to discriminate against those with genetic susceptibility to This article should be referenced as such: develop complications, who might be refused Laberge AM. Genetics and Public Health. Atlas Genet employment. On the other hand, workers at low-risk of Cytogenet Oncol Haematol. 2005; 9(1):86-91. complications might be exposed to higher levels of the

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in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Educational Items Section Short Communication

Glossary of Medical and Molecular Genetics Louis Dallaire Centre de Recherche, Hôpital Ste-Justine, Montréal, Canada (LD)

Published in Atlas Database: November 2004 Online updated version : http://AtlasGeneticsOncology.org/Educ/GlossaryID30028ES.html DOI: 10.4267/2042/38176 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology

This French / English glossary of medical and molecular genetics is intended for students in human and biological sciences as well as medical and para-medical personnel. It is mainly a tool for teaching and research. This glossary contains terminology frequently used in clinics and the laboratory. Within all areas of genetics the utilisation of terms in the glossary may also evolve with time or develop specific conations in different areas of study. There is no direct correspondence between the French and English terms defined in these glossaries. Certain terms exist in only one of these languages. Also the utilisation of a given term may differ to some extent between French and English. The definitions of terms common to both glossaries are not necessarily literal translations of one another. Suggestions, corrections as well as the addition of new terms are welcomed. We are grateful to the authors of those references who have contributed to the preparation of this glossary.

membrane filters for detection of specific base A sequences by radio-labelled complementary probes. Acardia (French: acardia) Congenital absence of the Advanced maternal age, AMA (French: âge maternel heart. avancé, AMA) In most prenatal diagnostic clinics 35 Acellular system , see: system acellular. years of age and more is considered as advanced Acentric (French: acentrique) Absence of centromere maternal age due to the increased risk of chromosomal in a chromosome structure. non disjunction in the foetus. Achondrogenesis (French: achondrogénèse) Affinity chromatography (French: chromatographie Example of bone dysplasia due to a mutation in a d’affinité) Any form of chromatography in which the collagen gene, COL2A1. Skeletal malformations are components of the sample are separated on the basis of seen at ultrasound during the second trimester of chemical affinity for a substance such as a binding pregnancy. protein or an immunoglobulin. Acrocentric (French: acrocentrique) Position of the AFP, alpha foetoprotein (French: AFP, centromere near the end of a chromosome. alphafoetoprotéine) Specific foetoglobulin synthesized Chromosomes 13-15 and 21,22 in man are acrocentric. by the liver and secreted in foetal serum during the Adaptor (French: adapteur) Short nucleotidic foetal life and the neonatal period. An open spinal sequence that has the property to link two DNA defect in the fetus is usually accompaniedby an fragments that hat have no terminal complementary increase in AFP in the amniotic fluid and a transudation sequences. towards the maternal circulation. AFP measurements in amniotic fluid and maternal serum are used in prenatal Adenine (French: adénine) A nitrogenous base, one diagnosis of genetic diseases. member of the base pair A-T, adenine- thymine. Agenesis (French: agénésie) Absence of an organ or ADN transfer, Southern blotting (French: structure. marquage Southern) Transfer by absorption of DNA fragments separated in electrophoretic gels to

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(French: allèle) Alternative forms of a genetic locus; a normal modal number, is considered a deviation from single allele for each locus is inherited separately from the 2n ratio. each parent. Example: at a locus for eye colour the Angelman syndrome (French: Angelman, syndrome allele might result in blue or brown eyes. de) Angelman and Prader Willi syndromes are Allelic frequencies (French: fréquences alléliques) examples of syndromes related to parental imprinting. Frequencies of allelic genes. Both syndromes include mental retardation and clinical anomalies. They are due to the loss of a segment of Allelomorph gene , see: alleles. chromosome 15 located in the proximal region of the Allotransplant (French: allotransplant) Organ or long arm, 15q11q13. Depending on the parental origin tissue transplant between two individuals. of chromosome 15 and the exact location of the Alpha foetoprotein , see AFP. chromosomal anomaly, two different syndromes are Alu sequences (French: séquences ALU) DNA identified. segments of approximately 300 base pairs with similar Annealing (French: annelage) Hybridization of a sequences. There are 50,000 copies in the human synthetic oligonucleotide to a single strand nucleic genome. They have a reconnaissance site for the ALU acid. It is how a specific nucleotide sequence can be restriction enzyme. identified. AMA , see advanced maternal age. Anophtalmia (French: anophtalmie) Congenital Amino acid (French: acide aminé) Any of a class of absence of eye. 20 molecules that are combined to form proteins in Anthelix (French: anthélix) Proximal fold of the living things. The sequence of amino acids in a protein external ear. and hence protein function are determined by the Antibody (French: anticorps) A specific substance genetic code. produced by man, and animal, as a reaction to the Amniocentesis (French: amniocentèse) presence of an antigen. Transabdominal or transuterine aspiration of amniotic Anticipation (French: anticipation) Phenomenon in fluid usually performed during the second trimester of which the severity of the condition seems to increase or pregnancy, for instance in the process of prenatal occur at an earlier age in subsequent generations. diagnosis of a genetic disease. Anticodon (French: anticodon) Group of three Amplifiable plasmid (French: plasmide amplifiable) nucleotides located at one end of the transfer tRNA and Plasmid that continues to replicate even when host cell by which it adapts, to the corresponding codon of the multiplication is blocked. messenger mRNA, to fix the amino acid it carries. Amplification (French: amplification) An increase in Antigen (French: antigène) A substance which has the the number of copies of a specific DNA fragment; can power of inducing, in man or in an animal, the take place in vivo or in vitro. See cloning, polymerase formation of antibodies. chain reaction. Antisense strand (French: brin anti-sens) Nucleic Amplification, DNA (French: amplification d’ADN) acid that has a sequence exactly opposite to a mRNA In vivo or in vitro increase in the number of a specific molecule made by the body; it binds to the mRNA DNA fragments. molecule to prevent a protein from being made. Amplification gene (French: amplification de gène) Apoptosis (French: apoptose) Programmed cell The increase in number of those genes needed for death. specialized functions in certain differentiated cells. Arachnodactyly (French: arachnodactylie) Long and Analogue base (French: base analogue) Molecule thin finger(s). which can replace a structure similar to nitrogenous Arhinencephaly (French: arhinencéphalie) Absence DNA or RNA bases. Example : 5-bromo-uracil is a of mid-brain structure. mutagenic analogue. Arrayed library (French: banque de gènes) Individual Anaphase (French: anaphase) Stage in and the first primary recombinant clones (hosted in phage, cosmid, and second following the metaphase, during which the YAC, or other vector) that are placed in two- centromere splits and the chromatids which were lined dimensional arrays inmicrotiter dishes. Each primary up on the spindle begin to move apart towards opposite clone can be identified by the identity of the plate and poles of the spindle. the clone location (row and column) on that plate. Anencephaly (French: anencéphalie) Absence of Arrayed libraries of clones can be used for many cranial bone structure usually accompanied by a severe applications, including screening for a specific gene or brain defect. genomic region of interest as well as for physical Aneuploidy (French: aneuploïdie) Situation when one mapping. Information gathered on individual clones or more chromosomes, missing or in excess of the from various genetic linkage and physical map analyses

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is entered into a relational database and used to construct physical and genetic linkage maps B simultaneously; clone identifiers serve to interrelate the BAC, bacterial artificial chromosome (French: multilevel maps. chromosome bactérien artificiel, BAC) A vector used Artificial gene (French: gène artificiel) A double- to clone DNA fragments of 100 to 300 kb insert size, stranded DNA molecule, carrying a specific sequence, average of 150 kb in Escherichia coli cells. Based on that will code for a specific amino acid sequence and the naturally occurring F-factor plasmid found in the that has been produced in vitro. bacterium Escherichia coli. Ascites (French: ascite) Accumulation of fluid in the Back mutation (French: réversion vraie). abdominal cavity. Bacteriophage (French: bactériophage), see phage. Asymmetrical division (French: division Balanced translocation (French: translocation asymétrique) Unequal segregation of chromosomes in équilibrée) transposisiton of chromosomal segments mitosis. It leads to two daughter cells that have a without modification of the quantity of genetic different and abnormal number of chromosomes. material. Example: 46,XX leading to 47,XXX / 45,X. Banding , see chromosome banding. A-T, see base pair. Barr body (French: corpuscule de Barr), see sex AT , see ataxia telangiectasia. chromatin. Ataxia telangiectasia, AT (French: Ataxie Base pair (French: paire de bases) Two nitrogenous télangiectasique, AT) Ataxia telangiectasia is an bases, adenine and thymine or guanine and cytosine, autosomal recessive disease characterized by a held together by weak bonds. Two strands of DNA are neurological and immunological symptomatology. held together in the shape of a double helix by the Lymphoma and leukemia are often observed as bonds between base pairs. complications of this syndrome. Cellular clones are Base pairing (French: appariement de bases) The identified that have chromosomal anomalies involving pairing of nitrogenous bases in the polynucleotide chromosomes 7 and 14. There is deficiency in repair of chains by nitrogen bonds in a specific manner. The lesions induced by ionizing radiations. pairing occurs between a purine base of one strain and Attenuator (French: atténuateur) A sequence of bases a pyrimidine of another strain in DNA, RNA or hybrid that occurs in the leader sequence of some operons and DNA/RNA molecules. In DNA the complementary controls transcription. Synthesis of RNA may be bases pairs are Adenine and Thymine and Guanine and terminated at this site. Cytosine. In RNA the base pairs are Adenine with Autogen regulation (French: régulation autogène) Uracil and Guanine with Cytosine. Regulation system where a gene product controls its Base pair substitution (French: substitution d’une own expression. paire de bases) A class of lesions in DNA molecules Autogenic recombination (French: rebombinaison which can give rise to gene mutations. They consist of autogène) Regulation system where a gene product transitions which preserve the purine-pyrimidine axis, controls its own expression. and of transversions which reverse it. Autolog graft (French: autogreffe) Cell or tissue graft Base ratio AT / GC (French: rapport de bases AT / derived from it own body. GC) The amount of A equals the amount of T and the amount of G equals the amount of C but he amount of Autoradiography (French: autoradiographie) A A+T does not equals the amount of G + C. This ratio is technique that uses X- ray film to visualize constant within a species but varies between species. radioactively labelled molecules or fragments of molecules; used in analyzing length and number of Base sequence (French: séquence de bases) The DNA fragments after they are separated by gel order of nucleotide bases in a DNA molecule. electrophoresis. Base sequence analysis (French: analyse d'une Autosome (French: autosome) A chromosome not séquence de bases) A method, sometimes automated, involved in sex determination. The diploid human for determining the base sequence. genome consists of 46 chromosomes, 22 pairs of Base triplets, triplet code, codon (French: triplets autosomes, and 1 pair of sex chromosomes : the X and de bases) A sequence of 3 nucleotides comprising a Y chromosomes. codon of a nucleic acid and representing the code for an Auxotrophic (French: auxotrophie) Requiring a amino acid. growth factor that is not required by the parental or Bayesian analysis (French: analyse bayésienne) prototype strain; may refer to microorganisms. Mathematical method for calculating probality of the

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carrier state in mendelian disorders combining several Cell colony (French: colonie cellulaire) Group of independent likelihoods. cells derived from the same initial cell. Beckwith Wiedeman, syndrome (French: Cell free system (French: système acellulaire) a syndrome de Beckwith Wiedeman) Malformation preparation obtained from a broken cell preparation by syndrome characterized by a macroglossia, differential centrifugation. A system composed of omphalocele and macrosomia. This is an example of a subcellular fractions and cell-free extracts, but devoid syndrome due to the phenomenon of parental of intact cells. imprinting. The gene is localized at 11p15.5. Cell line (French: lignée cellulaire) A cultured cell Biotechnology (French: biotechnologie) A set of type that can be reproduced indefinitely, or is biological techniques developed through basic research immortalized. and now applied to research and product development. Cell sorter (French: trieur de cellules) Apparatus that In particular, the use by industry of recombinant DNA, allows to sort different cell types or particles. cell fusion, and new bioprocessing techniques. Cell strain (French: souche cellulaire) A population of Bivalent (French: bivalent) A part of homologous animal cells that develops from a primary culture by chromosomes in association as seen at metaphase of the reseeding serially; the characteristics of the parent cell first meiotic division. are retained in culture. bp , see base pair. Cell cycle (French: cycle cellulaire) One can Brachydactyly (French: brachydactylie) Short finger. distinguish 4 successive phases in a somatic cell life: Brachyphalangy (French: brachyphalangie) Short mitosis, G1 phase, S phase of DNA replication and phalanx. phase G2. Phases G1, S and G2 are found in interphase. BRCA1 / BRCA2 The first breast cancer genes to be Centimorgan, cM (French: cM centimorgan) A unit identified. Mutated forms of these genes are believed to of measure of recombination frequency. One be responsible for about half the cases of inherited centimorgan is equal to a 1% chance that a marker at breast cancer, especially those that occur in younger one genetic locus will be separated from a marker at a women. Both are tumour suppressor genes. second locus due to crossing over in a single generation. In human beings, 1 centimorgan is Breakage syndrome (French: maladie cassante, equivalent, on average, to 1 million base pairs. syndrome d’instabilité chromosomique) Syndrome manifested by chromosomal anomalies, mainly Centric fusion (French: fusion centrique) Fusion of chromosomal breakage and chromatid exchange. chromosomes at the level of the centromere. Brushfield spots (French: taches de Brushfield) Centromere, kinetochore (French: centromère) A Presence of white speckles on the iris, a phenomenon specialized chromosome region to which spindle fibres commonly seen in Down syndrome. attach during cell division. Cephalometry (French: céphalométrie) Measurement C of the head. CAAT sequence (French: CAAT, séquence) Chiasma (French: chiasma) Exchange sites between Sequence that has been conserved in some eukaryotic chromatids observed in prophase of meiosis 1 promoters. It lies about 40 base pairs upstream from the subsequent to crossing over. TATA box. This region controls the frequency of Chimera (French: chimera) An organism that contains initiation by RNA polymerase. cells or tissues with a different phenotype. These can be Candidate gene (French: gène candidat) Gene mutated cells of the host organism or cells from a suspected to be involved in the etiology of a disease. different organism or species. Canthus (French: canthus) Inner and outer corners of Chimeric gene, hybrid gene (French: gène the eyes. chimérique) Gene made of DNA fragments of different CAP, catabolite activator protein (French: origins. protéine CAP) The CAP is a positive regulatory Chorionic villus sampling, chorionic villi protein, activated by cyclic AMP needed for RNA (French: villosités choriales, prélèvement de) A polymerase to initiate transcription of certain operons procedure used for prenatal diagnosis at the end of the of E. coli. The CAP protein can bind at different sites first trimester around the 12th to the 14th week of relative to RNA polymerase. pregnancy. Fetal tissue is withdrawn from the villus Caruncle , see: canthus. area of the chorion either trans uterine cervix or trans CAT assay (French: CAT, essai) Reporter gene assay abdominal under ultrasonic guidance. used to measure activity of a promoter under different Chromatid (French: chromatide) A duplicated conditions, such as to define elements of a promoter or chromosome is formed by two longitudinal units or to study signals that activates an intact promoter. chromatids joined at the centromeric region. A CDNA , see: complementary DNA. chromosome is formed by two sister chromatids. Each Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 95

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chromatid is made of a long DNA strand unique and position on homologue chromosomes in double identical to the sister chromatid but different from the heterozygote individuals. When two alleles are located homologue chromosome originating from the other near each other on the same chromosome,they are in cis parent. position. When they are located on different homologue Chromatid exchange , see: crossing over. chromosomes they are in trans position. Cis and trans are analogue to coupling and repulsion. Chromatin (French: chromatine) Constitutive structure of chromosomes made of DNA, basic Cistron (French: cistron) Genetic function unit chromosomal proteins and small RNA quantities. defined by the cis-trans test. The smallest unit of Chromatin is visible during interphase. genetic material that must be intact to function as a transmitter of genetic information. Chromonema (French: chromonéma, chromonème) The thin, threadlike form of an uncoiled chromosome Cleavage site (French: site de coupure)The cleavages seen in interphase, early prophase, and late telophase, generated by restriction endonucleases can be within or as opposed to the tightly coiled metaphase immediately adjacent to the recognition sequence but in chromosome. some cases the cleavages are displaced from the recognition sequence by a specific number of Chromosomal anomaly (French: anomalie nucleotides. chromosomique) A chromosome anomaly can be constitutional, acquired, homogenous, mosaic, Cleft palate (French: fente palatine) Fissure of the numerical, structural. mucous membrane and / or the bone structure of the palate. Chromosomal condensation (French: condensation chromosomique) Induction of Clinical heterogeneity (French: hétérogénéité chromosomal condensation in an interphase nucleus by clinique) Different phenotypes due to mutations in the fusion with a cell in mitosis. Condense chromosomes in same gene. S phase appear pulverized. Clinodactyly (French: clinodactylie) Incurved finger. Chromosome (French: chromosome) The self- Clone (French: clone) A group of cells derived from a replicating genetic structures of cells containing the single ancestor. cellular DNA that bears in its nucleotide sequence the Clone bank (French: banque de clones) See genomic linear array of genes. In prokaryotes, chromosomal library. DNA is circular, and the entire genome is carried on Clone sorting (French: criblage) Operation of one chromosome. Eukaryotic genomes consist of a identification and sorting of clones. number of chromosomes whose DNA is associated with different kinds of proteins. Cloning (French: clonage) The process of asexually producing a group of cells (clones), all genetically Chromosome banding (French: bande identical, from a single ancestor. In recombinant DNA chromosomique) Chromosome regions identified by technology, the use of DNA manipulation procedures specific stains. to produce multiple copies of a single gene or segment Chromosome instability syndrome (French: of DNA is referred to as cloning DNA. syndrome d’instabilité chromosomique) Genetic Cloning vector (French: vecteur de clonage) DNA disease characterized by an increase rate of molecule originating from a virus, a plasmid, or the cell chromosomal breaks, exchange between sister of a higher organism into which another DNA fragment chromatids and spontaneous structural anomalies. of appropriate size can be integrated without loss of the Chromosome jumping (French: saut vectors capacity for self-replication; vectors introduce chromosomique) Methods for obtaining at a foreign DNA into host cells, where it can be considerable distance from an initial cloned fragment reproduced in large quantities. Examples are plasmids, without the need for overlapping clones of DNA cosmids, and yeast artificial chromosomes; vectors are regions between the two sites. often recombinant molecules containing DNA Chromosome puff (French: puff chromosomique) sequences from several sources. An enlarged region along a polytene chromosome, the Club foot (French: pied bot) Congenital deformation site of active transcription. of the foot. Chromosome set (French: haplome) See genome. cM , see centimorgan. Chromosome walking (French: marche le long d'un Coarctation of aorta (French: coarctation de l’aorte) chromosome) Sequential isolation of molecular clones Congenital cardiac anomaly manifested by a in order to span large intervals on the chromosome. constriction of the aorta isthmus. Cis control (French: contrôle en cis). Code , see : genetic code. Cis-trans position effect (French: effet de position Coding sequence , see: sequence, coding. cis-trans) Terms cis and trans describe the gene

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Codominant (French: codominant) Two alleles that Constriction (French: constriction) Reduced are expressed simultaneously in the heterozygote state. thickness in a chromosomal region. The centromere is Example the ABO blood group. the primary constriction. Chromosome 1,9,16 have a Codon , see: genetic code. secondary constriction. Coefficient of inbreeding , see: parental coefficient. Contact inhibition (French: inhibition de contact) The inhibition of cell division and cell motility in Coloboma (French: colobome) Congenital defect normal animal cells when in close contact with each seen as a fissure. Examples: coloboma of the eyelid, other. iris, retina… Contig map (French: carte de contig) A map Compatibility (French: compatibilité) Tissular depicting the relative order of a linked library of small compatibility or histocompatibility allows successful overlapping clones representing a complete grafts; histocompatibility of the donor and recipient are chromosomal segment. identical or very close. Contigs (French: contigs) Group of clones Complementary DNA, cDNA (French: ADN representing overlapping regions of a genome used to complémentaire, ADNc) DNA that is synthesized from determine the physical map of a chromosome region. a messenger RNA template; the single-stranded form is Contig is the abbreviation for contiguous. often used as a probe in physical mapping. Copy error (French: erreur de copie) an error that Complementary sequences (French: séquences arises during DNA replication from a failure to insert complémentaires) Nucleic acid base sequences that can nucleotides complementary to those in the parent DNA form a double- stranded structure by matching base chain. pairs; the complementary sequence to G- T- A- C is C- A- T- G. Corepressor (French: corépresseur) Affector molecule that modifies a regulatory protein Complementation (French: complementation) (activation), allowing it to bind to an operator to Complementary effect of a double mutation on inactivate transcription. different genes. The two mutant genes may reconstitute a normal phenotype. Xeroderma pigmentosum is an Cosmid (French: cosmide) Artificially constructed example of complementation. cloning vector containing the cos gene of phage lambda. Cosmids can be packaged in lambda phage Compound heterozygote , see heterozygote particles for infection into E. coli; this permits cloning composite. of larger DNA fragments (up to 45 kb) than can be Conditional mutation (French: mutation introduced into bacterial hosts in plasmid vectors. conditionnelle) Mutation expressed only under certain Coupling (French: couplage) The occurrence on the conditions. Lethal mutations exist in a cell but in the same chromosome in a double heterozygote of the two homozygote state under conditional forms, like for mutant genes of interest, the normal alleles being on the instance if they are expressed at certain temperatures. homologous chromosome. The genes are said to be Confined placental mosaicism (French: mosaïque linked in coupling. placentaire) Chromosomal mosaicism limited to Craniolacuna (French: craniolacunie) Circumscribed placental tissues. deficient cranial bone defect. Congenital (French: congénital) Presence at birth of a Craniosynostosis (French: craniosynostose) Fusion trait or defect. of cranial sutures. Conjugation, mating (French: conjugaison) Natural Crossing over (French: enjambement) The breaking transfer of plasmidic or chromosomal DNA from a during meiosis of one maternal and one paternal bacterial cell to another via a cytoplasmic bridge. chromosomes, the exchange of corresponding sections Consanguinity coefficient (French: coefficient de of DNA, and the rejoining of the chromosomes. This consanguinité) Probality for an individual to carry two process can result in an exchange of alleles between copies of the same gene transmitted by his parents who chromosomes. have a common ancestor. Cybrid (French: cybride) Cytoplasmic hybrid resulting Conserved sequence (French: séquence conservée) from the fusion of protoplasts. A hybrid contains the A base sequence in a DNA molecule (or an amino acid cytoplasmic and nuclear genetic information from the sequence in a protein) that has remained essentially two parental cells. unchanged throughout evolution. Cycline (French: cycline) Protein family that plays an Constitutive gene (French: gene constitutive) Gene important role in the regulation of cell division. expressed without particular regulation. Cyst (French: kyste) Abnormal closed cavity, of Constitutive mutation (French: mutation various sizes in which there is a liquid collection of constitutive) Mutation that inhibits the normal gene infectious or embryological origin. regulation; its expression becomes independent of environmental factors. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 97

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Cystic fibrosis, mucoviscidosis (French: fibrose Diakinesis (French: diacinèse) Terminal phase of the kystique, mucoviscidose) A disease affecting the first meiotic division during which the chromosomes pancreas, gastro intestinal and pulmonary functions and are tightly bond and strongly coloured by the staining due to several different mutations in the CFTR gene solutions. located on chromosome 7 at the 7q31.2 locus. Dicentric (French: dicentrique) An aberrant Cytoplasmic gene (French: gène chromosome that contains two centromeres. extrachromosomique) Any gene that ordinarily exists Differentiation (French: différenciation) The act or on nucleic acid in the cytoplasm, especially on process of acquiring completely individual characters, mitochondrial or chloroplast chromosomes. such as occurs in the progressive diversification of cells Cytoplasmic inheritance (French: hérédité and tissues of the embryo. cytoplasmique, maternelle, extranucléaire) The DiGeorge, Velo Cardio Facial, CATCH 22, inheritance of traits controlled by genes located on the syndrome (French: DiGeorge, VeloCardio Facial, DNA of mitochondria. CATCH 22, syndrome) Syndrome due to a deletion at Cytosine-C (French: cytosine-C) A nitrogenous base, the 22q11.2 locus, involving several genes one member of the base pair G- C (guanine and accompanied by, in VCF, facial dysmorphism, palatal cytosine). insufficiency, heart defect or, in Di George syndrome, parathyroid hypoplasia, thymus hypoplasia, and D outflow of the heart defect. Dalton atomic mass unit (French: Dalton, unité de Diploid (French: diploïde) A full set of genetic masse) Atomic mass unit. One Dalton corresponds to material, consisting of paired chromosomes one one hydrogen atom (1,657 x 10 –24). chromosome from each parental set. Most animal cells DAPI (French: DAPI) Chromosome stain derived from except the gametes have a diploid set of chromosomes. fluorescent stain <4’,6-diamidino-2-phenylindole> that The diploid human genome has 46 chromosomes. stains preferentially heterochromatin of chromosomes Diplotene (French: diplotène) One prophase stage of 9,15 and Y. the first meiotic division. Defective prophage , see prophage, defective. Discordant (French: discordant) A twin pair (or set of Deformation (French: déformation) Malformation individuals) in which one member exhibits a certain due to an abnormal position of a limb or an abnormal trait and the other does not. pressure. Disomy uniparental, UPD , see uniparental disomy. Dehiscence (French: déhiscence) The formation of a Dispermia (French: diandrie) Presence of two fissure. spermatozoid during the fertilization likely to lead to a Deletion (French: délétion) Loss of part of a whole triploidy. chromosome or loss of DNA nucleotide bases. Disruption (French: disruption) In the disruption Denaturation (French: dénaturation) Formation of a sequence the fetus is subject to a destructive problem. It single DNA strand from a double strain under heating may be a vascular, infectious or mechanical problem of chemical bonds responsible for base pairing. leading to a malformation. One example is the effect of Denaturation mapping (French: cartographie par an amniotic band. dénaturation partielle) A method employing electron Dizygote (French: dizygotie) The product of microscopy of DNA partially denaturated which fertilization of two separate eggs by two separate permits the decision as to whether the gene sequence in sperms; non identical twin pair. a viral genome is linear or circularly permuted. DNA, deoxyribonucleic acid (French: ADN, acide De novo mutation (French: mutation de novo, néo- désoxyribonucléique) The molecule that encodes mutation) Spontaneously occurring mutation. genetic information. DNA is a double- base pairs of Deoxyribonucleotide , see nucleotide. nucleotides. The four nucleotides in DNA contain the bases stranded molecule held together by weak bonds Derepression (French: dérépression) An increase in between base pairs of nucleotides. The four nucleotides the synthesis of the product of a regulated gene by in DNA contain the bases: adenine (A), guanine (G), interference with the action of a repressor. It can be cytosine (C), and thymine (T). In nature, base pairs produced by the mutation of the repressor gene or of the operator gene or by an inducer that binds to the form only between A and T and between G and C; thus repressor, releasing it from the operator. the base sequence of each single strand can be deduced from that of its partner. Dermatoglyphics (French: dermatoglyphes) The study of the surface markings of the skin. DNA probes , see: probe. Dermatoglyphic studies are used in a number of DNA repair (French: réparation de l’ADN) Genes malformation syndromes due to a chromosomal encoding proteins that correct errors in DNA aberration as in trisomy 21 or Down syndrome. sequencing.

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DNA replication (French: replication d'ADN) The use of existing DNA as a template for the synthesis of E new DNA strands. In humans and other eukaryotes, E. coli (French: E coli) Escherichia colli is a common replication occurs in the cell nucleus. bacterium that has been studied intensively by DNA-RNA hybrid (French: hybride ADN-ARN) A geneticists because of its small genome size, normal double helix consisting of one chain of DNA hydrogen lack of pathogenicity, and ease of growth in the bonded to a complementary chain of RNA. laboratory. DNA sequence (French: séquence d'ADN) The Ectoderm (French: ectoderme) The outer of three relative order of base pairs, whether in a fragment of layers of cells comprising the early embryo. Gives rise DNA, a gene, a chromosome, or an entire genome. See: to skin and neural tissue. base sequence analysis. Effusion (French: épanchement) Abnormal presence DNA synthetizer (French: synthétiseur d’ADN) An of fluid in a tissue or cavity. automated machine design to synthesize short Electrofocusing, electro focalisation , see polynucleotide chains -oligonucleotides- similar in isoelectric focusing. structure to DNA. Electrophoresis (French: électrophorèse) A method DNA transfer , see: Southern blotting. of separating large molecules (such as DNA fragments Domain (French: domaine) Discrete portion of a or proteins) from a mixture of similar molecules. An protein with its own function. The combination of electric current is passed through a medium containing domains in a single protein determines its overall the mixture, and each kind of molecule travels through function. the medium at a different rate, depending on its electrical charge and size. Separation is based on these Dominant (French: dominant) An allele that is almost differences. Agarose and acrylamide gels are the media always expressed, even if only one copy is present. commonly used for electrophoresis of proteins and Double helix (French: double hélice) The shape that nucleic acids. two linear strands of DNA assume when bonded Electroporation (French: électroporation) Technique together. used to facilitate the penetration of DNA in cells based Double heterozygote , see: composite, compound on the use of electric pulsions to increase the heterozygote. membrane permeability. Double minute chromosomes (French: Embryo (French: embryon) fetus before the end of the chromosome minuscule double) Fragment of unstable third month. extrachromosomic DNA without a centromere. Minute Embryonic biopsy (French: biopsie embryonnaire) chromosomes are small spherical structures, observed Biopsy of embryonic tissues usually performed on in pairs in varying number from cell to cell. They stain spontaneous miscarriage material. homogeneously. They are duplicated once in mitosis and are lost in cellular division. Embryonic stem cell , see: stem cell. Ductus arteriosus, patent (French: persistance du Encephalocele (French: encéphalocèle) Cranial canal artériel) Persistence of the arterial canal after defect of the midline with hernia of the meningeal birth. membrane containing spinal fluid and abnormal brain tissue. Duplicate (French: dupliquer) Make a copy. 3’ End, terminus (French: extrémité 3’) The end of a Dysgenic (French: dysgénique) Detrimental to the polynucleotide chain terminating with a 3’ carbon hereditary qualities of man or tending to counteract atom. The 5’ position of one pentose ring is connected racial improvement through an influence bearing on to the 3’ position of the next pentose ring via a reproduction. Refers to a genetic anomaly. phosphate group. All RNA chains, as well as DNA Dysmorphism (French: dysmorphisme) chains, grow in the 5’ to 3’ direction. Developmental anomaliy seen in a variety of 5’ End, terminus (French: extrémité 5’) The syndromes with a genetic or environmental origin. beginning of a polynucleotide chain terminating which Dysostosis (French: dysostose) Defective has a free 5’ group. The 5’ position of one pentose ring ossification. is connected to the 3’ position of the next pentose ring Dysplasia (French: dysplasia) Abnormality of via a phosphate group. All RNA chains, as well as development. DNA chains, grow in the 5’ to 3’ direction. Dysraphia (French: dysraphie) Developmental defect Endoderm (French: endoderme) One of three layers of the median raphe. Examples: spina bifida, cleft lip. of cells comprising the early embryo It gives rise to the lining of the gut and cells of the pancreas and liver. Dysraphism (French: dysraphisme) Term used to describe a neural tube or spine anomaly. Endonuclease (French: endonucléase) An enzyme that cleaves its nucleic acid substrate at internal sites in

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Endoreduplication (French: endoreduplication) Presence of duplicated chromosomes in metaphase with F four chromatids and two centromeres.This duplication Fallot tetralogy (French: tétralogie de Fallot) is total if all chromosomes are concerned and selective Congenital heart defect manifested by an inversion of if only one chromosome or part of it is duplicated. the great vessels, and a ventricular septal defect. Enhancer (French: amplificateur) Element that Familial (French: familial) Relevant to a trait that is increases the utilization of (some) eucaryotic promoters more frequent in members of an affected individual in cis configuration, but that can function in any family than in the general population. This may be 1ocation, upstream or downstream, relative to the caused by genetic or environmental factors, or both. promoter. Family history (French: histoire familiale) Family Enzyme (French: enzyme) A protein that acts as a history based on genealogy to identify individuals catalyst, speeding the rate at which a biochemical carriers of or affected with a trait or genetic disease reaction proceeds but not altering the direction or similar to the propositus genotype or phenotype. nature of the reaction. Family tree (French: pedigree, histoire familiale) Epicanthus (French: épicanthus) A fold of skin Ancestral information in relation to an individual or projected over the inner canthus. family. Epidemiology (French: épidémiologie) Study of the Fibroblast (French: fibroblaste) Young conjonctive different factors that intervene in the onset and cell. evolution of diseases. Filling in (French: remplissage) Insertion of Epigenetic (French: épigénétique) The term that nucleotides in a single DNA strand to make it entirely refers to any factor that can affect the phenotype double stranded. without change in the genotype. Finger loop (French: boucle digitale) Image formed Equatorial plane (French: plan équatorial) by the epidermal ridges on finger tips. Radial and Alignment of chromosomes at metaphase in a ring cubital loops are found as well as whorls and arches. formation at the nuclear circumference. One notes an excess of arches on the fingertips in EST, Expressed sequence tag , see sequence trisomy 18. tagged site. Finger printing (French: cartographie peptidique) Euchromatin (French: euchromatine) Region of Analytical method that supplies an exact identity card chromosomes that have a normal cycle of spiralisation- of a protein molecule containing electrophoretic and despiralisation by opposition to heterochromatin. chromatographic properties of various polypeptide segments of the molecule. Eukaryote (French: eucaryote) Cell or organism with membrane-bound, structurally discrete nucleus and FISH Fluorescent in situ hybrization (French: other well- developed subcellular compartments. hybridation in situ en fluorescence) A physical Eukaryotes include all organisms except viruses, mapping approach that uses fluorescein tags to detect bacteria, and blue- green algae. hybridization of probes with metaphase chromosomes and with the less- condensed somatic interphase Euploidy (French: euploïdie) Normal number of chromatin. chromosomes. Flow cytometry (French: cytométrie de flux)Analysis Evolutionarily conserved , see: conserved of biological material by detection of the light- sequence. absorbing or fluorescing properties of cells or Exogenous DNA (French: ADN exogène) DNA subcellular fractions (i.e., chromosomes) passing in a originating outside an organism. narrow stream through a laser beam. An absorbance or Exons (French: exon) The protein-coding DNA fluorescence profile of the sample is produced. sequences of a gene. Automated sorting devices, used to fractionate samples, Exonuclease (French: exonucléase) An enzyme that sort successive droplets of the analyzed stream into cleaves nucleotides sequentially from free ends of a different fractions depending on the fluorescence linear nucleic acid substrate. emitted by each droplet. Expressed gene , see gene expression. Flow karyotyping (French: caryotypage de flux) Use of flow cytometry to analyze and/or separate Expressivity (French: expressivité) Intensity of gene chromosomes on the basis of their DNA content. expression from mild to severe. Fondamental research (French: recherche Extremity 3’ , see: 3’ end terminus. fondamentale) Research that studies normal and Extremity 5’ , see: 5’ end terminus. abnormal physiological processes, while clinical

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research is applied to prevention, diagnostic and cure of Gene cluster (French: groupe de gènes) Any group disease. of two or more closely linked genes on a chromosome Founder effect (French: effet fondateur) The high that are related functionally. frequency of a mutant gene in a rapidly expanding Gene construction (French: Construction génique) population founded by a small ancestral group when Portion of DNA involved in the transfer into a cell one or more of the founders were, by chance, carriers containing an interest gene and the promoter and of the mutant gene. regulator sequences essential to its expression and Fragile site (French: site fragile) Non-staining gaps, regulation in the receptor cell. known as fragile sites, are occasionally observed in Gene conversion (French: conversion de gène) characteristic sites on several chromosomes. Unequal recovery of genetic markers or alleles in the Fragile X (French: X-fragile) Common form of X region of the exchange during genetic recombination. linked mental retardation associated with a fragile site Processes analogous to meiotic gene conversion in on X chromosome. The genetic defect has been eukaryotes. Changes from heterozygosity to identified as an abnormal amplification or more than 60 homozygosity by mechanism other than segregation. times of triple CGG at the Xq27.3 locus. If the child Gene expression (French: expression génique) The has the disease the mother can have a pre-mutation process by which a gene coded information is with an abnormal amplification between 60-200 repeats converted into the structures present and operating in of the CGG triplet. The amplification hampers the the cell. Expressed genes include those that are expression of gene FMR-1. FRAXA site is not far from transcribed into mRNA and then translated into protein FRAXE site, a variant of the syndrome. and those that are transcribed into RNA but not Fragment (French: fragment) Part of a chromosome translated into protein. detached by breakage : if there is a centromere we refer Gene families (French: familles de gènes) Groups of to a centric fragment and if not it is called acentric. closely related genes that make similar products. Frameshift (French: décalage du cadre de lecture) A Gene flow (French: flux génétique) The spread of shift in the reading frame used to translate the base genes from one breeding population to others owing to sequence of mRNA. It is caused by the addition or the dispersal of gametes or zygotes. deletion of one or more bases, resulting in an Gene fusion (French: fusion de gènes) Association of alternative peptide being formed. gene fragments leading to the formation of a chimera. Frameshift mutation (French: mutation de Gene library , see genomic library. changement de phase) Change resulting from addition Gene mapping (French: cartographie génique) or deletion of nucleotides, in numbers other than three Determination of the relative positions of genes on a (French : triplets; codons), which moves the translation DNA molecule, chromosome or plasmid, and of the ‘reading frame’ so that a new set of codons, beyond the distance, in linkage units or physical units, between point of abnormality in the messenger RNA, is read. them. FRAXA, FRAXE , see: fragile X Gene product (French: produit génique) The G biochemical material, either RNA or protein, resulting from expression of a gene. The amount of gene product Gamete (French: gamète) Mature male or female is used to measure how active a gene is; abnormal reproductive cell, sperm or ovum, with a haploid set of amounts can be correlated with disease- causing alleles. chromosomes or 23 for humans. Gene rearrangement (French: réarrangement G-C, see: base pair. génétique) Collection of several pieces of DNA Gemellity, twinning (French: gémellité) initially not contiguous. Simultaneous development of two embryos. It is Gene tagging (French: étiquetage génétique) univitelline if originating from an egg subdivision or Insertion of a genetic marker in or close to a gene. bivitelline if several eggs were fertilized at the same time. Gene therapy (French: thérapie génique) Insertion of normal DNA directly into cells to correct a genetic Gene (French: gène) The fundamental physical and defect. functional unit of heredity. A gene is an ordered sequence of nucleotides located in a particular position Gene transfer (French: transfert de gène) Transfer of on a particular chromosome that encodes a specific genetic material from one cell to another or from one functional product: a protein or RNA molecule. organism to another. Gene amplification , see amplification gene. Genetic code (French: code génétique) The sequence of nucleotides, coded in triplets (codons) along the Gene candidate (French: gène candidat) Gene mRNA, that determines the sequence of amino acids in suspected to be responsible for the occurrence of a protein synthesis. The DNA sequence of a gene can be genetic disease. used to predict the mRNA sequence, and the genetic

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code can in turn be used to predict the amino acid Genetic polymorphism (French: polymorphisme sequence. génétique) The regular and simultaneous occurrence in Genetic competence (French: compétence the same population of two or more alleles at a genetic génétique) Cellular state that allows penetration of a locus, with at least one minor allele having a frequency foreign nucleic acid. greater than 1%. Genetic complementation , see complementation. Genetically modified organism, GMO (French: organisme génétiquement modifié, OGM) Organism of Genetic consensus (French: consensus génétique) which the genome has been modified. If the Short DNA sequence found in a number of genes and reproductive cells carry the modification they will living organisms. transmit it to the descents. Genetic construction (French: construction Genetics (French: génétique) The study of the génique) Portion of DNA needed for the transfer in a patterns of inheritance of specific traits. cell of a gene of interest including the promoter and regulators essential to its expression and regulation in Genic conversion , see: genetic conversion. the receiving cell. Genocopy (French: génocopie) The production of the Genetic conversion, gene conversion (French: same phenotype by different genes also called "mimetic conversion génique) Non reciprocal genetic genes". recombination. Interaction between allelic sequences Genome (French: génome) All the genetic material in during meiosis leading to an unequal exchange of the chromosomes of a particular organism; its size is genetic information. generally given as its total number of base pairs. Genetic diagnosis (French: diagnostic génétique) Genome map (French: carte génomique) Research Detection of genes of an organism by hybridization of and technology development efforts aimed at mapping its genome with specific molecular probes. Diagnosis and sequencing some or all of the genome of human of a genetic disease. beings and other organisms. Genetic disease (French: maladie génétique) Genome sequencing (French: séquençage du Disease due to the mutation of one or several genes. génome) Determination of the order in which the bases When only one gene is involved, we refer to a are arranged within a length of DNA or RNA or, the monogenic disease. sequence of amino acids that make up a protein. Genetic disruption (French: disruption génique) Genomic library, gene bank (French: banque de Interruption of the coding sequence of a gene due to the gènes) A collection of clones made from a set of introduction of another DNA sequence. randomly generated overlapping DNA fragments Genetic distance (French: distance génétique) representing the entire genome of an organism. Degree of filiation between different genomes. In Genotype, haplome (French: génotype) The sum of molecular genetics the genetic distance is measured by genetic information or gene contained in the the percentage of structural homology between two chromosomes of the individual as distinguished from sequences by molecular hybridization or by comparing their phenotype. It determines not a unique phenotype nucleotide sequences. but a range of phenotype capacities referred to as an Genetic drift (French: dérive génétique) Any change individual’s “norm of reaction” to the environment. either directed or undirected in gene frequency in a Germinal stem cell , see stem cell. population. Glabella (French: glabelle) Region of the face Genetic engineering (French: génie génétique) between eyebrows. Manipulations by which an individual having a new GMO , see: modified organism. combination of inherited properties is established. Guanine-G (French: guanine-G) A nitrogenous base, Genetic footprint (French: empreinte génétique) one member of the base pair G-C or guanine and Fine structural characteristic of a specific DNA region cytosine). allowing to identify a specific cell and its association. Genetic heterogeneity (French: Hétérogénéité H génétique) Presence of similar phenotypes due to Haploid (French: haploïde) A single set of different genetic mechanisms. chromosomes: half the full set of genetic material Genetic load (French: fardeau génétique) In humans present in the egg and sperm cells of animals and in the we refer to hereditary defects which lower life egg and pollen cells of plants. Human beings have 23 expectancy or reduce reproduction capacity. chromosomes in their reproductive cells. Genetic map , see linkage map. Haplome , see: genotype. Genetic material (French: matériel génétique) See : Haplotype (French: haplotype) Genetic material genome. carried by only one of two chromosomes and corresponding to a specific character. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 102

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Harelip (French: fente labiale) Uni or bilateral closure Heterozygosity (French: hétérozygosité) The defect of the upper lip. presence of different alleles at one or more loci on Hare lip and cleft palate (French: gueule de loup, homologous chromosomes. fente labio-palatine) Hare lip and cleft palate frequently Heterozygote composite, compound (French: observed in holoprosencephaly or a chromosomal hétérozygote composite) Individual who is defect like the trisomy 13. heterozygote at two different loci. HAT culture medium (French: milieu de culture Hexadactylia (French: hexadactylie) Autosomal HAT) A tissue culture medium containing dominant malformation characterized by the presence hypoxanthine, aminopterin anbd thymidine, used in of a sixth digit on hands and or feet. somatic cells fusion experiments. Histone (French : histone) Basic chromosomal HDL, high density cholesterol (French: cholestérol proteins present in eukaryotes believed to be involved de haute densité, HDL) Cholesterol transported by high in the coiling and condensation of chromosomes. density lipoproteins. Holandric (French: holandrique) Hereditary trait due Helix (French: helix) The margin of the external ear. to the presence of a gene on Y chromosome. Very few Hematopoietic (French: hématopoïétique) Related to characters are linked to the Y chromosome. The the formation of blood cells, a process that occurs transmission of the trait is exclusively from father to mainly in the bone marrow. son. Hemizygosity (French: hémizygotie) Presence of a Homeobox (French: homéobox) A short stretch of single gene copy in a diploid cell, example : X and Y in nucleotides whose base sequence is virtually identical the male. In abnormal situations there may be a in all the genes that contain it. It has been found in deletion on a chromosome or entire loss of that many organisms from fruit flies to human beings. In the chromosome leading to a partial or complete deletion, fruit fly, a homeobox appears to determine when ex Turner 45X syndrome or the Cri du Chat 5p- particular groups of genes are expressed during anomaly. development. Heritability (French: héritabilité) That portion of the Homoduplex (French: homoduplex) A DNA character variance due to hereditary factors as distinct molecule with completely complementary base from factors of environment. sequences. Heterochromatin (French: hétérochromatine) A Homologies (French: homologies) Similarities in fraction of chromatin that has characteristics distinct DNA or protein sequences between individuals of the from the bulk of the chromosomal material, the same species or among different species. euchromatin. Homologous chromosomes (French: Heteroduplex (French: hétéroduplex) A DNA double chromosomes homologues) A pair of chromosomes helix in which the complementary strands are derived containing the same linear gene sequences, each from different molecules, so that there may be small derived from one parent. regions of mismatching. Homologous recombination , see: recombination Heteroduplex technique, mapping (French: homologous. technique d’hétéroduplex) Technique that allows to Homoplasmy (French: homoplasmie) The presence visualize in electron microscopy non homologous of a single population of mt DNA in the cells of a segments of a mutant from the normal type. single individual. This is normal. Heterokaryon (French: hétérocaryon) A cell in which Homozygous (French: homozygote) Designating a genetically different haploid nuclei may co-exist and diploid nucleus, cell or organism that contains two multiply. identical alleles for any one gene. Heteromorphism (French: hétéromorphisme) Host cell (French: cellule hôte) Cell carrying foreign Normal morphological variation in chromosome genetic material brought by a virus, a plasmid, a staining. recombine DNA in vitro or an entire cell. Heteroplasmy (French: hétéroplasmie) Presence of Housekeeping gene (French: gène domestique) more than one type of mitochondria in cells of an Gene that regulates vital functions of all cell types. individual : simultaneous presence of normal DNA and HPLC, high pressure liquid chromatography mutant mtDNA. (French: HPLC, chromatographie liquide à haute Heteroploidy (French: hétéroploïdie) Any different performance) Chromatographic technology used to chromosome number from normal. separate and quantitate mixtures of substances in Heterosis (French: hétérosis) Advantage of solution. The high pressure technique allows a rapid heterozygote genotypes over homozygote genotypes of analysis of complex mixtures. their parents.

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Human gene therapy (French: thérapie génique tissue is exposed to the specific antibody or antigen humaine) Insertion of normal DNA directly into cells to labelled with a fluorochrome. correct a genetic defect. Immunosuppression (French: immunosuppression) Human Genome Initiative (French: initiative en The artificial prevention or diminution of the immune génome humain) Collective name for several projects response, as by irradiation or by administration of anti- begun in 1986 by DOE to (1) create an ordered set of metabolites, anti-lymphocyte serum, or specific DNA segments from known chromosomal locations, antibody. (2) develop new computational methods for analyzing Imprinting, parental see: parental imprinting. genetic map and DNA sequence data, and (3) develop Inborn error of metabolism (French: erreur innée new techniques and instruments for detecting and du métabolisme) Genetic metabolic disorder in which a analyzing DNA. This DOE initiative supported by the protein defect produces a metabolic block which may NIH is now known as the Human Genome Program. have a deleterious effect. Hybrid DNA-RNA (French: hybride ADN-ARN) Incidence (French: incidence) Number of new Double stranded molecule made of a DNA and a RNA patients or individuals who acquired the disease during complementary chains. a certain period of time in a specific population. Hybrid gene, chimeric gene (French: gene Individual primary recombinant clones (French: hybride) Gene made of DNA fragments of various recombinant individuel primaire) Recombinant clones origins. (hosted in phage, cosmid, YAC or other vector that are Hybrid selection (French: sélection d’hybride) placed in two-dimensional arrays in microtiter dishes. Selection of a double-stranded DNA molecule with Each primary clone can be identified by the identity of heteroduplex regions. the plate and the clone location (row and column) on Hybridization (French: hybridation) The process of that plate. Arrayed libraries of clones can be used for joining two complementary strands of DNA or one many applications, including screening for a specific each of DNA and RNA to form a double-stranded gene or genomic region of interest as well as for molecule. physical mapping. Information gathered on individual Hybridization, in situ (French: hybridation in situ) clones from physical map analyses is entered into a Hybridization of a specific DNA or RNA probe, relational database and used to construct physical and marked with cellular DNA or RNA, on a tissue or fixed genetic linkage map simultaneously; clone identifiers cells. serve to interrelate the multilevel maps. Hybridization on colony (French: hybridation sur Induction (French: induction) The starting or colonie) Hybridization in situ allowing to identify enhancement of synthesis of an enzyme by a cell, bacteria with a specific DNA sequence. taking place upon the provision of the substrate for the enzyme. Hydrocephaly (French: hydrocéphalie) Fluid invasion within the cranium. Abnormal enlargement of Informatics (French: informatique) The study of the cerebral ventricles. application of computer and statistical techniques to the management of information. In genome projects, Hydrops, anasarca (French: hydrops) Fetus informatics includes the development of methods to showing ascites and abnormal tissue oedema. search databases quickly, to analyze DNA sequence Hyperdiploidy (French: hyperdiploïdie) The state of information, and to predict protein sequence and being hyperploid, or having more than the typical structure from DNA sequence data. number of chromosomes in unbalanced sets, as in Informativity (French: informativité) Possibility to Down's syndrome. identify two chromosomes of the same pair in Hypertelorism (French: hypertélorisme) Abnormal particular in the region that carries the mutant gene. distance between the two eyes measured at the pupil Initiation factor (French: facteur d’initiation) Any level. class of protein factors which are requisite for the Hypoploidy (French: hypoploïdie) State of having formation of the initiation complex and the initiation of lost one or more chromosomes. mRNA translation. Hypothenar (French: hypothenar) The ridge on the Insert (French: insert) Sequence of foreign DNA palm along the basis of the fingers and the ulnar region. introduced in a specific DNA molecule. I Insertion (French: insertion) The acquisition of extra nucleotides within a DNA sequence. They may affect Immunofluorescence technique, method only one nucleotide, a point mutation, but they usually (French : immunofluorescence, méthode) A method affect several nucleotides in the sequence. determining the location of antigen or antibody in tissue by the pattern of fluorescence resulting when the Insertion mutation, mutagenesis (French: mutagénèse par insertion) A mutation that results from

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an insertion of one or more nucleotides into the DNA charged molecules on the basis of their isoelectric chain. They can revert to the wild-type state by removal point. of the extra sequences. They may change the triplet IVF, in vitro fertilization (French: fécondation in code reading of genetic information. vitro, FIV) Fertilization of the ovum by a sperm outside Insertion sequence , see : sequence, insertion. of the living organism. In situ hybridization (French: hybridation in situ) IVM, maturation in vitro (French: IVM, maturation Use of a DNA or RNA probe to detect the presence of in vitro) see maturation in vitro. the complementary DNA sequence in cloned bacterial or cultured eukaryote cells. K Integration (French: intégration) Recombination Karyotype (French: caryotype) A photomicrograph of process that inserts a small DNA molecule into a larger individual chromosomes arranged in a standard format one. showing the number, size, and shape of each Intercalary (French: intercalaire) Loss of a portion of chromosome type; used in low- resolution physical a chromosome between two breaks. mapping to correlate gross chromosomal abnormalities with the characteristics of specific diseases. Interest gene (French: gène d’intérêt) Gene made of DNA fragments of various origins. Kilobase, kb (French: kilobase, kb) Unit of length for DNA fragments equal to 1000 nucleotides. Interferon (French: interferon) A protein that is synthesized by animal cells in response to viral Kinetochore , see: centromere. infection and non specifically inhibits replication of the L viruses. It is found in serum almost at the onset of the infection and long before the production of antibody. LDL, low density cholesterol (French: cholesterol de basse densité, LDL) Cholesterol transported by low Interphase (French: interphase) The period in the cell density lipoproteins. cycle when DNA is replicated in the nucleus; it is followed by mitosis. Leaky (French: partiellement fonctionnel) Said of a gene mutation which allows some residual level of Interrupted gene (French: gène discontinu) Gene gene expression. made of several alternate series of exons and introns RNA introns are eliminated during splicing. Leptonema (French: leptonème) First stage of the Differential splicing of introns of an interrupted gene first meiotic division. can give rise to several proteins; one then speaks of Lethal factor (French: facteur létal) An abnormality mosaic gene. of the genome that leads to death in utero, ex Intragenic recombination (French: recombinaison :chromosomal anomaly, mutation. intragénique) The process by which progeny derive a Library (French: banque) An unordered collection of combination of genes different from that of either DNA clones from a particular organism whose parent. In higher organisms, this can occur by crossing relationship to each other can be established by over. physical mapping. Introns, intervening sequence (French: intron) Ligand (French: ligand) A molecule that can bind to a The DNA base sequences interrupting the protein- receptor and thereby induce a signal in the cell, coding sequences of a gene; these sequences are example: a hormone. transcribed into RNA but are cut out of the message Ligase, DNA (French: ligase, ADN) An enzyme that before it is translated into protein. creates a phosphodiester bond between the 3’ end of Inversion (French: inversion) An abnormality in one DNA segment and the 5’. chromosome structure that results from a portion of the Ligation (French: ligature) Covalent linkage of a chromosome becoming detached, rotating through 180o DNA molecule extremities allowing to reunite by a and then becoming attached again. bridge two DNA molecules in one single unit. In vitro (French: in vitro) Occurring outside a living Linkage (French: liaison, groupe de liaison) The organism. proximity of two or more markers, genes or RFLP In vivo (French: in vivo) Taking place in the living markers on a chromosome; the closer together the body. markers are, the lower the probability that they will be Isochromosome -i (French: isochromosome, -i) separated during DNA repair or replication processes Abnormal chromosome formed by the duplication of (binary fission in prokaryotes, mitosis or meiosis in two short arms -ip- or long arms -iq- of equal length eukaryotes), and hence the greater the probability that and with identical loci. The other arm is lost. they will be inherited together. Isoelectric focusing (French: électrofocalisation) Linkage desequilibrium (French: déséquilibre de An analytical separation procedure similar to gel liaison) Situation where two genes or alleles are more electrophoresis. It is used to separate proteins and other often or less associated in cis in a given population and Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 105

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for which the frequency departs from expected value Marker gene (French: gène marqueur) Gene according to the Hardy Weinberg law. expression that allows sorting of cells where it is found. Linkage group (French: groupe de liaison) Group of Maternal inheritance , see: cytoplasmic inheritance. genes that seem to be close together according to their Maturase (French: maturase) Enzyme that intervenes hereditary transmission. They are generally neighbour in the maturation of pre-m-RNA. on the same chromosome. Maturation (French: maturation) Modifications of Linkage map (French: carte de liaison) A map of the messengerRNA made of additions and deletions at the relative positions of genetic loci on a chromosome, time of, or after the transcription. determined on the basis of how often the loci are Maturation in vitro, IVM (French: maturation in inherited together. Distance is measured in vitro) To describe the maturation of ova in vitro. centimorgans (cM). Mb , see: megabase. Linker (French: lieur) Synthetic bicatenary olinucleotide added in vitro to a DNA sequence that Megabase, Mb (French: mégabase, Mb) Unit of brings a new restriction site. length for DNA fragments equal to 1 million nucleotides and roughly equal to 1 cM. Localize (French: localiser) Determination of the location of a gene or other marker on a chromosome. Meiosis (French: méiose) The process of two consecutive cell divisions in the diploid progenitors of Localized mutagenesis , see mutagenesis. sex cells. Meiosis results in four rather than two Locus (French: locus) The position on a chromosome daughter cells, each with a haploid set of chromosomes. of a gene or other chromosome marker; also means the Mendelian inheritance (French: hérédité DNA at that position. The use of locus is sometimes mendélienne) Classical heredity as described by restricted to mean regions of DNA that are expressed. Gregory Mendel in 1866. Lod score (French: lod score) The abbreviation for Mesoderm (French: mésoderme) One of the three logarithm of the odds. A measure of the odds ratio layers of cells comprising the early embryo. Gives rise obtained by dividing the likelihood that two loci are to muscle, bone, connective tissues and blood as well linked at a specific recombination fraction by the as the vascular and the uro-genital systems. likelihood that they are unlinked. (French : ARN messager, ARNm) RNA that serves as a Lymphedema (French: lymphoédème) Congenital or template for protein synthesis. Also see: genetic code. acquired oedema due to an obstruction of lymphatic vessels. Metacentric (French: métacentrique) Chromosome with a more or less central centromere and arms of Lymphocyte (French: lymphocyte) Leukocyte which approximately equal length. arises in the lymph glands and the lymph nodes. It has a single nucleus and non-granular protoplasm. Metaphase (French: métaphase) A stage in mitosis or meiosis during which the chromosomes are aligned Lyon hypothesis , see sex chromatin. along the equatorial plane of the cell. Lytic phage (French: phage de lyse) Any phage that Methylation (French: méthylation) Chemical reaction causes host cells to lyse. adding a methyl group to a compound. Note the M hypermethylation in the FRA X syndrome leading to FMR1 gene inactivation. May be involved in the Macrocephaly (French: macrocéphalie) Excessive regulation of gene expression. size of the head. Microsatellite, minisatellite (French: microsatellite) Macrorestriction map (French: carte de Highly polymorphic DNA marker comprised of macrorestriction) Map depicting the order of, and mononucleotides, dinucleotides, trinucleotides or tetra- distance between sites at which restriction enzymes nucleotides that are repeated in tandem arrays and cleave chromosomes. distributed throughout the genome. The best studied are Malformation (French: malformation) Any the CA dinucleotide repeats. They morphological defect present at birth, being apparent or are used for genetic mapping. not. Microcephaly (French: microcéphalie) Head Mapping (French: cartographier) See gene mapping, circumference < 2nd percentile at birth. The other linkage map, physical map. parameters can be normal. Marker (French: marqueur) An identifiable physical Micrognathia (French: micrognathie) Congenital or location on a chromosome : restriction enzyme cutting acquired insufficient development of the mandible. site, gene whose inheritance can be monitored. Markers Midface (French: étage moyen de la face) Median can be expressed regions of DNA (genes) or some region of the face. segment of DNA with no known coding function but whose pattern of inheritance can be determined. Also Minicell (French: minicellule) Bacterial cell of see RFLP, restriction fragment length polymorphism. reduced sized that has lost its chromosomal DNA. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 106

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Minichromosome (French: minichromosome) Monosomy (French: monosomie) Presence of only Unidentified small chromosome that replicates one copy of a pair or segment of a chromosome. according to the mitotic cell cycle. Generally there is Monozygocity (French: monozygotie) Twins only one copy of this chromosome. originating from the same egg. Minigene (French: minigène) Gene, reconstructed for Morgan , see: centimorgan. experimental means, from regulating sequences and Morphogenesis (French: morphonogénèse) double strand cDNA and the corresponding mRNA. A Development of forms and structures of the organism. minigene codes directly for mature mRNA. Morula (French: morule) Name given to the human Miniphage (French: miniphage) Phage, reconstructed fertilized egg after the first divisions or blastomere for experimental needs, that has kept part of its segmentation. At this stage the egg is still in the genital functions. tract. Nidation takes place at the blastocyst stage. Miniplasmid (French: miniplasmide) Plasmid Mosaic (French: mosaïque, myxoploïdie) Presence of reconstructed for experimental needs with remaining two or more distinct cells in an individual. part of its functions. mRNA , see messenger RNA. Misense mutation (French: mutation non-sens) mutation that replaces an amino acid codon by a Mucolipidosis (French: mucopolidose) Group of nonsense codon. hereditry metabolic defects due to the deficiency of enzymes essential for the degradation of Mismatch, misparing (French: mésappariement) oligosaccharides; unlike mucopolysaccharidoses they Non pairing of a zone in a fragment of nucleic acid do not excrete abnormal amounts of glysaminoglycans double strand. in urine. Skeletal, cardiac, ocular and systemic Mitogen (French: mitogène) Agent inducing mitoses. deleterious effects are observed in the affected Mitosis (French: mitose, caryocinèse) The process of individuals. nuclear division in cells that produces daughter cells Multifactorial or multigenic disorders (French: genetically identical to each other and to the parent cell. maladies multifactorielles, multigéniques) See Mitotic index (French: index mitotique) Proportion of polygenic disorders. dividing cells in relation to all cells analyzed. Multigeny (French: multigénie) Genetic property that Modification, nucleic acid (French: modification presents a phenotype character that is dependant of d’un acide nucléique) Any transformation observed in several genes. nucleotides after their assembling into a Multiple allelomorphs (French: alleles multiples) polynucleotide. Relative to various possible forms of a gene. Mixoploidy , see: mosaicism. Multiplexing (French: multiplexe) A sequencing Modal number (French: nombre modal) Normal approach that uses several pooled samples number of chromosomes. simultaneously, greatly increasing sequencing speed. Molecular biology (French: biologie moléculaire) Mutagen (French: mutagène) Any physical or Study of molecules carrying the hereditary message, chemical agent significantly increasing mutational DNA,RNA structure, synthesis, modifications or events and thus mutation rates above the spontaneous transformations. background level. Those are induced mutations as Molecular genetics (French: génétique moléculaire) opposed to the normally occurring spontaneous Branch of genetics concerned with the molecular mutations. structure and activities of the genetic material, Mutagenic (French: mutagène) Capable of inducing including the replication of DNA, the transcription into stable, heritable changes in the genetic information of a RNA and the translation of RNA to form proteins. cell. Molecular hybridization , see : hybridization. Mutagenic agent , see mutagen. Monocistronic (French: monocistronique) Mutant (French: mutant) Gene that has undergone a Descriptive of messenger RNA molecules that code for mutation or an individual who carries this mutant gene. one polypeptide chain. Mutation (French: mutation) Any heritable change in Monoclonal antibodies (French: anticorps DNA sequence. Compare polymorphism. monoclonaux) Homogeneous antibodies produced by a clone of B lymphocytes originating from a unique N mother cell that will generally detect only one genetic NAIP , see: neuronal apoptosis inhibitory protein. determinant. Nearest neighbor sequence analysis (French: A Monolayer (French: monocouche) Tissue culture in biochemical technique for estimating the frequencies monocellular layers. that pairs are next to one another.

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Neuronal apoptosis inhibitory protein, NAIP Nucleus (French: noyau) The cellular organelle in (French: Protéine inhibitrice de la mort neuronale eukaryotes that contains the genetic material. programmée) Protein that inhibits the programmed Null mutation (French: mutation nulle) An allele that neuronal death. results in either the absence of the gene product or the Neurotropic factors (French: facteurs absence of any function at the phenotypic level. neurotropiques) Factors that have some affinity for the nervous tissues. Nick (French: cassure monocaténaire) Breakage O affecting only one of two strands of a nucleotide double Oligogenic diseases (French: maladies helix. oligogéniques) Diseases or traits that result from the Nick translation (French: marquage par déplacement effects of relatively few genes some of which have de l’encoche) Replaces part of a preexisting strand of relatively large effects. duplex DNA with newly synthesized material. Omphalocele (French: omphalocèle) Umbilical Nitrogen base (French: base nitrogénique) A hernia. nitrogen-containing molecule having the chemical Oncogene (French: oncogène) A gene, one or more properties of a base. forms of which is associated with cancer. Many Non disjunction (French: non disjonction) Failure of oncogenes are involved, directly or indirectly, in separation of homologue chromatids at the mitotic controlling the rate of cell growth. anaphase as well as the second meiotic division. There Oocyte (French: ovocyte, oocyte) An immature or is desequilibrium of the two sister alleles or unfertilized ovum, also called the egg. chromosomes. Open reading frame (French: cadre de lecture Nonsense codon (French: codon nonsens) Codon ouvert, ORF) The sequence of DNA or RNA located that does not specify an amino acid but indicates the between the start-code sequence, or initiation codon termination of a polypeptide chain. These codons and the stop-code sequence, or termination codon. interrupt the reading of the messenger RNA (mRNA) Operator (French: opérateur) DNA site to which a strand and also cause release of the synthesised repressor will bind to prevent the transcription of the polypeptide chain. adjacent promotor. Nonsense triplet , see: stop codon. Operon (French: opéron) Transcription unit made of a Northern blot, RNA transfer (French: Northern promotor, operator and one or more structural genes. blot, transfert d’ARN) A gel base procedure that ORF , see: open reading frame. locates mRNA sequences on a gel that are complementary to a piece of DNA used as a probe. Overlapping clones (French: clones superposés) See genomic library. Nucleic acid (French: acide nucléique) A large molecule composed of nucleotide subunits. Overlapping sequence , see: sequence overlapping. Nucleic acid denaturation (French: dénaturation Ovum (French: ovum) A female germ cell; an egg d’acide nucléique) Conversion of double stranded cell; a cell which is capable of developing into a new nucleic acid to a single strand state. member of the same species, in animals usually only after maturation and fertilization. Nucleic acid sequencing (French: décryptage des séquences nucléotidiques) Determination of the linear P order of the nucleic basic chains. Pachytene (French: pachytène) Genetic viral material Nucleic probe (French: sonde nucléique) DNA or inside an infected cell Qualifies The third stage of the RNA sequence marked by a fluorescent isotope or first meiotic division when chromosomes are enzyme used to detect homologue sequences by in situ condensed , chromatids of each chromosome are or in vitro hybridization. visible. Homologue chromosomes appear as bivalent. Nucleosome (French: nucléosome) Element of Packaging (French: encapsidation) Packaging of chromatin made by the coiling of 140 base pairs on an genetic viral material inside an infected cell. octamere of histone. Palindromic sequence (French: sequence Nucleotide (French: nucleotide) A subunit of DNA or palindromique) A nucleotide sequence in which the 5’ RNA consisting of a nitrogenous base (adenine, to 3’ sequence of one strand is the same as that of its guanine, thymine, or cytosine in DNA; adenine, complementary strand. guanine, uracil, or cytosine in RNA), a phosphate Panmixia (French: panmixie) Large human molecule, and a sugar molecule (deoxyribose in DNA population where unions between individuals take and ribose in RNA). Thousands of nucleotides are place at random. Genotypes depend on the gene and linked to form a DNA or RNA molecule. See DNA, allele frequencies. base pair, RNA.

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Parental coefficient (French: coefficient de parenté) Phenocopy (French: phénocopie) A mimic of a The probability that an individual has received both phenotype that is usually determined by a specific alleles of a pair from an identical ancestral source. Also genotype, produced instead by the interaction of some the proportion of loci at which an individual is environmental factor with a different genotype. homozygous by descent. Phenotype (French: phénotype) The biochemical Parental imprinting (French: empreinte parentale) physiological and morphological characteristics of an The differential expression of genetic material, at either individual as determined by his or her genotype and the a chromosomal or an allelic level, depending on environment in which it is expressed. whether the genetic material has been inherited from Philtrum (French: philtrum) Region of the upper lip the male or female patient. bordered by two tissue pillars. Patent ductus arteriosus (French: persistance du Phosphodiester (French: phosphodiester) Molecule canal artériel) Congenital heart defect : persistance of that has one phosphate and two ester functions. the arterial canal. Physical map (French: carte physique) A map of the Patent foramen ovale (French: communication locations of identifiable landmarks on DNA (e.g., inter-auriculaire) Congenital heart defect: persistance restriction enzyme cutting sites, genes), regardless of of the inter auricular communication. inheritance. Distance is measured in base pairs. For the PCR , see polymerase chain reaction. human genome, the lowest- resolution physical map is PDG, preimplantation diagnosis (French: the banding patterns on the 24 different chromosomes diagnostic prenatal pré-implantatoire) Diagnosis of a including X and Y chromosomes the highest- disease before the egg implantation. resolution map would be the complete nucleotide sequence of the chromosome. Pedigree , see family tree. Phytohemagglutinin (French: phytohémagglutinine) Penetrance (French: pénétrance) Frequence with Polysaccharide substance extracted from red beans that which a trait will manifest in a family. has the capacity to agglutinate red cells and facilitate Pentasomy (French: pentasomie) State of a cell or their separation from leukocytes. It also has the individual that has five copies of a chromosome instead property to stimulate lymphocyte division and blastic of two. Example: the 49 XXXXX syndrome. transformation. This property is used in cytogenetic PEPCK, phosphoenolpyruvate carboxylase studies done on cultured lymphocytes. enzyme (French: enzyme phosphoenolpyruvate Pierre Robin syndrome (French: syndrome de carboxylase) Pierre Robin) Syndrome involving the abnormal Peptide signal, Peptide sequence (French: closure of the palate and the inferior mandible that is peptide, séquence) Segment of 15 to 30 amino acids too small. present at the N terminal portion of a protein; it Placebo (French: placebo) Inactive substance indicates to the cell that this protein must be exported substituted for a medication in order to distinguish or secreted. between the psychological and pharmacological effects. PERV virus (French: virus PERV) Pork virus known Placental mosaicism , see: confined placental as the endogen pork virus found in the pork genetic mosaicism. material. This retrovirus can not be identified or Plasmid (French: plasmide) Autonomously eliminated and the laboratory tests showed that it can replicating, extra chromosomal circular DNA infect human cells. We do not know if the retrovirus molecules, distinct from the normal bacterial genome can be transmitted via a xenograft. and non essential for cell survival under non selective Phage (French: phage) A virus for which the natural conditions. Some plasmids are capable of integrating host is a bacterial cell. into the host genome. A number of artificially Phage template (French: phage tempéré) Phage constructed plasmids are used as cloning vector. genome can be integrated into the host cell DNA and Plasmid incompatibility (French: incompatibilité transform its properties. 1- if integrated into the host plasmidique) The inability of two different plasmids to cell genome it is called prophage and 2- the template coexist in the same host cell. phage has the capacity to lyse the bacteria that it Plasmid Ri (French: plasmide Ri) Plasmid carried by infects. the bacteria Agrobacterium rhizo-genes that has a S phase (French: S phase) Interphase which usually transferable DNA segment and that can be integrated lasts much longer than mitosis is itself divided into into the genome of a vegetable host cell. It can serve as stages. Of the interphasic stages, Gap 1 (G1) which lies transformation vector to produce transgenic plants. between the end of telophase and the beginning of the Plasmide Ti (French: plasmide Ti) Plasmid carried by Synthesis (S) periods is the longest; DNA synthesis the bacteria Agrobacterium rhizo-genes that has a DNA takes place during the S period. segment transfeerable and has the property to

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integrated into the DNA of a vegetable host cell . Ti variations occurring in more than 1% of a population means tumor inductor. would be considered useful polymorphisms for genetic Pleiotropy (French: pléïotropie) Multiple phenotypic linkage analysis. effects of a single gene or gene pair. The term is used Polypeptide chain termination (French: particularly when the effects are ordinarily thought to Terminaison de la chaîne peptidique) End of the proteic be unrelated. chain. Ploidy (French: ploïdie) A term referring to the Polyploidy (French: polyploïdie) Cells, tissues or number of chromosome sets per cell. Example: haploid; individuals that have more than a diploid set of diploid; polyploid. chromosomes. Triploid and tetraploid embryos are non Pluripotent stem cell , see: stem cell. viable, they are often found in spontaneous abortions. Point mutation (French: mutation ponctuelle) Polyribosome (French: polyribosome) Complex Mutation interesting only one base. Addition or made of a mRNA molecule and ribosomes. The protein deletion are mutation mechanisms. synthesis takes place on this complex. Polar body (French: globule polaire) Hypoploid cell Prader Willi syndrome , see: Angelman syndrome. resulting from the first two meiotic divisions. It Precursor RNA , see pre-messenger RNA. contains mainly nuclear material, the cytoplasmic Preimplantation diagnosis , see PDG. material being reserved for the ovocyte and the ovotid. Pre messenger RNA, Heterogeneous nuclear Polar mutation (French: mutation polaire) Mutation RNA (French: Pré ARN messager) The probable in one gene that reduces the expression of one gene precursor of messenger RNA, mRNA, so named further from the promoter in the same operon. because its size distribution is heterogeneous and its Nonsence mutations frequently are polar. location is strictly nuclear; no base sequences have Poly A tail, polyadenylated end, polyA region been found in cytoplasmic mRNA that are not also pre- (French: séquence polyA) Long segment of adenosine messenger RNA. polymerized monophosphates present at the 3’ end of Premutation (French: prémutation) Stage of eukaryotes mRNAs. expansion mechanism in which the mucleotide Polydactyly (French: polydactylie) Presence of one or expansion is above normal but still insufficient to more fingers, or duplication of one finger or toe. translate into clinical manifestations. For instance in Polygenic disorders (French: maladies myotonic dystrophy a 50 to 80 triplet repeat is polygéniques) Genetic disorders resulting from the considered as a premutation. combined action of alleles of more than one gene like Prevalence (French: prévalence) Frequency of a heart disease, diabetes, and some cancers). Although disease in a population, counting both old and new such disorders are inherited, they depend on the cases. simultaneous presence of several alleles; thus the Primer (French: amorce) Short preexisting hereditary patterns are usually more complex than polynucleotide chain to which new those of single- gene disorders. deoxyribonucleotides can be added by DNA Polymerase chain reaction, PCR (French: polymerase. réaction en chaîne de la polymérase, PCR) A method Proband , see propositus. for amplifying a DNA base sequence using a heat- Probe (French: sonde) Single-stranded DNA or RNA stable polymerase and two 20- base primers, one molecules of specific base sequence, labeled either complementary to the (+)- strand at one end of the radioactively or immunologically, that are used to sequence to be amplified and the other complementary detect the complementary base sequence by to the (-)- strand at the other end. Because the newly hybridization. synthesized DNA strands can subsequently serve as additional templates for the same primer sequences, Processing RNA, post transcriptional successive rounds of primer annealing, strand processing (French: maturation de l’ARN) elongation, and dissociation produce rapid and highly Modifications of messengerRNA made of additions and specific amplification of the desired sequence. PCR deletions at the time of transcription. also can be used to detect the existence of the defined Prognathism (French: prognathisme) Excessive sequence in a DNA sample. development of the lower jaw. Polymerase, DNA or RNA (French: polymérase, Prokaryote (French: procaryote) Cell or organism ADN ou ARN) Enzymes that catalyze the synthesis of lacking a membrane- bound, structurally discrete nucleic acids on preexisting nucleic acid templates, nucleus and other subcellular compartments. Bacteria assembling RNA from ribonucleotides or DNA from are prokaryotes. deoxyribonucleotides. Promoter (French: promoteur) A site on DNA to Polymorphism (French: polymorphisme) Difference which RNA polymerase will bind and initiate in DNA sequence among individuals. Genetic transcription. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 110

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Prophage (French: prophage) Sequence of phage Pulse labelling (French: marquage de brève durée) DNA. An experimental technique in which cells or cell Propositus, proband (French: proband, propositus) extracts are exposed for a short time to a compound The family member through whom the family is labelled with a radio active nucleotide. ascertained. If the propositus is affected, he may be Purine (French: purine) A nitrogen- containing, called the index case. single-ring, basic compound that occurs in nucleic Prosome (French: prosome) Small RNA particle acids. The purines in DNA and RNA are adenine and associated with a free messenger RNA repressed in the guanine. cytoplasm. Purine base (French: base purique) Adenine and Protein (French: protéine) A large molecule composed Guanine. of one or more chains of amino acids in a specific Pyrimidic base (French: base pyrimidique) Cytosine order; the order is determined by the base sequence of and Thymine. nucleotides in the gene coding for the protein. Proteins Pyrimidine (French: pyrimidine) A nitrogen- are required for the structure, function, and regulation containing, double- ring, basic compound that occurs in of the body cells, tissues, and organs, and each protein nucleic acids.The pyrimidines in DNA are cytosine and has unique. Examples are hormones, enzymes, and thymine; in RNA, cytosine and uracil. antibodies. Protein design (French: remodelage) Creation of a protein with new properties by directed mutagenesis or gene synthesis. Q Protein, structural (French: protéine de structure) A Quadriradial pattern (French: image quadriradiale) protein that serves a structural role in the body such as Structure shaped as a cross made of homologue or non collagen. homologue chromosomes observed when a translocation takes place during a mitotic division. Proteomics (French: protéomique) New discipline derived from genomics that concerns research activities Quasidominance (French: quasidominance) The aimed at the collection of all available information on pattern of inheritance produced by the mating of an gene expression of organisms with an identified affected homozygote individual heterozygous for the genome. same recessive trait so that homozygous affected members appear in two or more successive generations. Protooncogen (French: protooncogène) A normal gene that with a slight alteration by mutation or other R mechanism becomes an oncogene. Rare-cutter enzyme , see restriction enzyme cutting Provirus (French: provirus) The state of a virus in site. which it integrates into and replicates in coordination with a host cell chromosome and thus is transmitted Receptor (French: récepteur) A transmembrane or from one cell generation to another. intracellular protein involved in transmission of a cell signal. Pseudoautosomal (French: pseudoautosomique) The distal tip of the Y chromosome short arm, which Recessive (French: récessif) A trait or gene that is undergoes crossover with the distal tip of the X only expressed in homozygotes or hemizgotes. chromosome short arm during meiosis in the male. Recombinant (French: recombiné) An individual Pseudodiploidy (French: pseudodiploïdie) Apparent who has a new recombination of genes not found diploid cell. The karyotype is abnormal, although it together in either parent. Usually applied to linkage carries 46 chromosomes. analysis. Pseudogene (French: pseudogène) The sequence of Recombinant aneusomia (French: aneusomie de pseudogene is similar to the structural gene but does recombinaison) Presence of a duplication or deletion not code for a protein. resulting from a crossing over in an inverted loop. Pseudohermaphrodite (French: Recombinant clones (French: clones recombinants) pseudohermaphrodite) Individual whose gonadal and Clones containing recombinant DNA molecules. See phenotypic sex differ. recombinant DNA technologies. Pterygium colli, webbed neck (French: pterygium Recombinant DNA molecules (French: molécules colli, cou palmé) A thick fold of skin on the lateral side d'ADN recombinant) A combination of DNA of the neck, extending from the mastoid region to the molecules of various origins that are joined using acromion, producing a congenital webbed neck. recombinant DNA technologies. Ptosis (French: ptose) Paralytic drooping of the upper Recombinant DNA technologies (French: eyelid. technologies d’ADN recombinant) Procedures used to join together DNA segments in a cell- free system (an Puff , see: chromosome puff. environment outside a cell or organism). Under Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 111

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appropriate conditions, a recombinant DNA molecule Replication fork (French: fourche de réplication) A can enter a cell and replicate there, either autonomously Y shaped point at which two strands of a DNA or after it has become integrated into a cellular molecule are unwound and separated during chromosome. replication. Recombinant genetic (French: recombinant Replicon (French: réplicon) Any genetic element - génétique) Any of the individual or cells arising as a bacterial chromosome, virus, genome, plasmid - that result of inter-chromosomal and intra-chromosomal,via behaves as an autonomous unit of replication. crossing-over or conversion, genetic recombination. Repressor (French: répresseur) Protein synthesised Recombinant plasmid (French: plasmide by a regulator gene, which, by binding to a specific site recombiné) Plasmid in which a foreign DNA fragment on DNA, the operator gene of an operon, prevents the has been inserted. formation of messenger RNA by the operon’s other Recombinant protein (French: protéine recombinée, structural genes and hence stops protein -enzyme- recombinante) Protein synthesised from a transgene. synthesis. Recombination frequencies (French: fréquences Reproduction, assisted technology ART de recombinaison) Instance when the progeny derive a (French: reproduction assistée, ART) (assisted combination of genes different from that of either reproduction technology, ART) Technology that parent. In higher organisms, this can occur by crossing concerns one or several steps of intervention during the over. process of in vitro reproduction. Recombination, homologous (French: Resistance factor, R factor, R plasmid, recombinaison homologue) Insertion of a transgene in a resistance plasmid (French: facteur de transfert de particular site in lieu of a of a nervous cell specific résistance) Plasmid that codes for one or more enzymes gene. inactivating one or more toxic agents or antibiotics. Recombination, intragenic (French: recombinaison Resolution (French: résolution) Degree of molecular intragénique) The process by which progeny derive a detail on a physical map of DNA, ranging low to high. combination of genes different from that of either Restriction (French: restriction) Mechanism by which parent. In higher organisms, this can occur by crossing a cell degrades foreign DNA. over. Restriction enzyme cutting site (French: site de Regulation, autogenous (French: régulation coupure de l’enzyme de restriction) A specific autogène) Regulation system where the gene product nucleotide sequence of DNA at which a particular controls its own expression. restriction enzyme cuts the DNA. Some sites occur Regulation mutation (French: mutation de frequently in DNA (e.g., every several hundred base régulation) Mutation that affects the regulation of one pairs), others much less frequently (rare- cutter; e.g., or more gene expression, without affecting the coding every 10,000 base pairs). segment. Restriction enzyme, endonuclease (French: Regulatory gene (French: gène de régulation) A enzyme de restriction, endonucléase) A protein that gene coding for a protein that regulates other genes. recognizes specific, short nucleotide sequences and Regulatory regions or sequences (French: cuts DNA at those sites. Bacteria contain over 400 such régions régulatrices ou séquences) A DNA base enzymes that recognize and cut over 100 different sequence that controls gene expression. DNA sequences. Reject (French: rejet) Immunological reaction against Restriction fragment length polymorphism, a tissue or organ. Elimination by the receiver of the RFLP (French: Variation between individuals in DNA transplanted tissue or organ. fragment sizes cut by specific restriction enzymes; polymorphic sequences that result in RFLPs are used as Release factor (French: facteur de terminaison) Any markers on both physical maps and genetic linkage of the special protein factors which recognize the maps. RFLPs are usually caused by mutation at a terminator codons UAA, UAG, and UGA in messenger cutting site. RNA and stimulate the codon specific release of polypeptides from ribosomes during genetic translation. Retinoblastoma (French: rétinoblastome) The retinoblastoma, uni or bilateral is an embryonic tumor Renaturation of nucleic acid (French: renaturation of the retina. The gene locus for the retinoblastoma is d’acide nucléique) The return by slow conversion of a located in the 13q14.1-14.2 region. In the proximal denatured nucleic acid or protein to its native region of the long arm of chromosome 13. The tumor configuration. can be hereditary due to a germinal mutation or Repeat unit (French: unité de répétition)DNA sporadic due to a somatic mutation. sequence constituting the basic motive in a repeated Retrognathism (French: rétrognathisme) Small region. inferior mandible in a retro position.

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Retrograde transport (French: transport rétrograde) RNA replicase (French: ARN synthétase) ARN Transport going in the other direction. Example: from réplicase (RNA replicase) Enzyme of RNA viruses that the muscle to the nerve. catalyses the reproduction or replication of this Retroinhibition (French: inhibition par rétroaction) molecule. Regulator system in which the terminal product of a RNA satellite (French: ARN satellite) RNA that may biosynthetic chain of reactions stops the activity of the be found in some viruses. first enzyme of this chain. Retrotransposon (French: rétrotransposon) Class of S transposon of which the transposition requires the Sanger method, Sanger sequencing (French: inverse transcription of their transcription product méthode de Sanger) A widely used method to Retrovirus (French: rétrovirus) A virus with an RNA determine the order of bases in DNA. genome that propagates by conversion of the RNA into Satellite DNA (French: satellite, ADN) Molecular: a DNA by the enzyme reverse transcriptase. portion of DNA that differs enough in base Reverse genetics (French: génétique réverse) The composition so that it forms a distinct band on cesium application of human gene mapping to clone the gene chloride gradient centrifugation; usually contains responsible for a particular disease when no highly repetitive sequences. Cytogenetics: small mass information about the biochemical basis of the disease of chromatin located at the extremity of the short arm is available. of acrocentric chromosomes above a small constriction. Reverse mutant (French: mutant réverse) Organism Segregation (French: ségrégation) Separation of two resulting from a reverse mutant. alleles on a locus at meiosis. Reverse transcriptase (French: réverse Sequence (French: séquence) See base sequence. transcriptase) An enzyme used by retroviruses to form Sequence amplified (French: séquence amplifiée) a complementary DNA sequence, cDNA, from their Increased number of intra or extrachromosomic DNA RNA. The resulting DNA is then inserted into the sequences. chromosome of the host cell. Sequence, coding (French: séquence codante) Reversion (French: réversion) Mutation that restores Segment of a gene that directly defines the amino acid a function annulled by a first mutation. sequence of the corresponding protein. RFLP , see: restriction fragment length polymorphism. Sequence consensus (French: séquence RI plasmid , see plasmid RI. consensus) Specific sequence of a given region of a nucleic acid or a protein in which each position Ribonucleic acid, RNA (French: acide represents the base or the amino acid most commonly ribonucléique, ARN) A chemical found in the nucleus found. and cytoplasm of cells; it plays an important role in protein synthesis and other chemical activities of the Sequence highly repeated (French: séquence cell. The structure of RNA is similar to that of DNA. hautement répétée) DNA sequence present in a great There are several classes of RNA molecules, including number of copies in the genome. messenger RNA, transfer RNA, ribosomal RNA, and Sequence, insertion (French: séquence d’insertion) other small RNAs, each serving a different purpose. DNA element showing transposition from one region Ribonucleotides , see nucleotide. of the genome to another. Ribosomal proteins (French: proteins ribosomales) Sequences, inverted repeat (French: séquences A group of protein slinked to rRNA by non covalent répétées inverses) Identical or almost identical bomds giving to the ribosome a tridimention structure. sequences present in several copies in the same DNA molecule with an inverse orientation. Ribosomal RNA, rRNA (French: ARN ribosomal, ARNr ) A class of RNA found in the ribosomes of Sequence leader (French: séquence de tête) cells. Sequence found upstream of the initiation codon of traduction of RNA messengers. Ribosomes (French: ribosomes) Small cellular components composed of specialized ribosomal RNA Sequence, non coding (French: séquence non and protein; site of protein synthesis. See ribonucleic codante) Part of a gene that does not directly define the acid (RNA). amino acid sequence of the corresponding protein. Ring chromosome (French: chromosome en Sequence, overlapping (French: séquence anneau) Structurally abnormal chromosome in which chevauchante) DNA sequence carrying the information the end of each chromosome arm has been broken and related to several genes using a different reading frame. the broken arms reunited to form a ring. Sequence, palindromic (French: séquence RNA , see ribonucleic acid. palindromique) Sequence of DNA that is the same when one strand is read right to left; consists os RNA processing , see: processing. adjacent inverted repeats.

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Sequence poly A (French: séquence polyA) Long there are advantages to both strategies, researchers use segment of polymerized adenosine monophosphates both random (or shotgun) and directed strategies in present at the 3’extremity of mRNA of eukaryotes. combination to sequence the human genome. Sequence repeat (French: séquences répétées Siblings (French: germains) Brothers and sisters; directes) Multiple copies of the same base sequence on couple’s own children. a chromosome; used as a marker in physical mapping. Sibship (French: fratrie) All the sibs in a family. Sequence signal (French: séquence signal) DNA Signal peptide , see peptide sequence. sequence that can be read the same way in both (French: silenceur) DNA region located near a gene directions in relation to a central point : on the same that has the capacity to reduce its transcription. strand example : ATTGC,CGTTA, or on both strands AAGTT and TTGCAA. Silent mutation (French: mutation silencieuse) A mutant gene that has no phenotypic effect. Sequence tagged site, STS (French: courte séquence d’ADN) Short (200 to 500 base pairs) DNA Simian crease (French: pli simiesque) Transverse sequence that has a single occurrence in the human and unique palmar crease frequently found in trisomy genome and whose location and base sequence are 21. known. Detectable by polymerase chain reaction, STSs Single-gene disorder (French: maladie are useful for localizing and orienting the mapping and monogénique) Hereditary disorder caused by a mutant sequence data reported from many different allele of a single gene. Examples: Duchenne muscular laboratories and serve as landmarks on the developing dystrophy, retinoblastoma, sickle cell disease. physical map of the human genome. Expressed Single stranded loop (French: boucle sequence tags (ESTs) are STSs derived from cDNAs. monocaténaire à brin unique) Non pairing loop. Sequence, tandem repeat (French: séquences Sister chromatid exchange, SCE (French: répétées en tandem) Multiple copies of the same base échange de chromatides soeurs) Exchange of sequence on a chromosome; used as markers in equivalent material between two chromatids of a physical mapping. maternal or paternal chromosome.This is not an Sequence, unique (French: unique séquence) exchange between homologue chromosomes and it Selection of a monocatenary nucleic acid after happens only in the first meiotic division by crossing formation of a hybrid molecule with a complementary over. strand. Site specific mutagenesis (French: mutagénèse Sequence untranslated (French: séquence non dirigée) Introduction of a precise mutation in a cloned traduite) A region of mRNA that is not used in the DNA fragment followed by the reinsertion of the synthesis of an amino acids sequence of a given peptide mutant sequence in the original gene to replace the or protein. They usually appear at either end of the corresponding wild DNA. sequence that codes for the amino acid sequence. SKY , see: Spectral karyotype SKY. Sequencing (French: séquençage) Determination of SMA, spinal muscular atrophy (French: the order of nucleotides (base sequences) in a DNA or amyotrophie spinale infantile) Neuromuscular disease. RNA molecule or the order of amino acids in a protein. SMN Survival motor neurone. Sex chromatin, Barr body (French: chromatine sexuelle, corpuscule de Barr) Chromatin mass present SNRNP, small nuclear ribonucleoprotein in interphase nuclei of women and most female (French: petite ribonucléoprotéine nucléaire) Protein mammals representing one of the two Xs that is induced in the cytoplasm, that has affinity with the inactivated. survival motor neuron, that plays a role in DNA splicing. Sex chromosomes (French: chromosomes sexuels) The X and Y chromosomes in human beings that Somatic cell genetic mutation A change in the determine the sex of an individual. Females have two X genetic structure that is neither inherited nor passed to chromosomes in diploid cells; males have an X and a Y offspring. Also called acquired mutations. chromosome. The sex chromosomes comprise the 23rd Somatic cell mutation (French: mutation chromosome pair in a karyotype. somatique) A change in the genetic structure that is Shotgun cloning or method (French: méthode à neither inherited nor passed to offspring. Also called l’aveugle) Cloning of DNA fragments randomly acquired mutation. generated from a genome Sequencing method that Somatic cells (French: cellules somatiques) Any cell involves randomly sequenced cloned pieces of the in the body except gametes and their precursors. genome, without knowledge of where the piece Somatic mutation (French: mutation somatique) originally came from. This can be contrasted with Mutation in a cell that is not germinal. "directed" strategies, in which pieces of DNA from Southern blotting (French: marquage Southern) known chromosomal locations are sequenced. Because Transfer by absorption of DNA fragments, separated in Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 114

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electrophoretic gels, to membrane filters for the DNA sequence by another nucleotide or replacement of detection of specific base sequences by radio labelled one amino acid in a protein by another amino acid. complementary probes. Suppression intergenic, mutation (French: Spacer, DNA (French: espaceur) Untranslated DNA suppression intergénique) Recuperation of a lost sequence separating genes in repeat units. function with the help of a second mutation localized Species (French: espèce) Branch of natural sciences on a gene other than the initial mutant. that concerns similar individuals that can reproduce Suppression intragenic (French: suppression within themselves. intragénique) A compensation mutation inside the Spectral karyotype SKY A graphic of all an mutant gene that will that will restaure its activity. The organism's chromosomes, each labelled with a different second mutation interests the first gene mutation but in color. Useful for identifying chromosomal a different site. abnormalities. Suppressor gene A gene that can suppress the Sperm (French: sperme) The male sex cell action of another gene. Spinal (French: spinal) Pertaining to the spine or Suppressor mutation (French: mutation vertebral column suppressive) Gene action suppressed by another gene. Spliceosome (French: spliceosome) Synapsis (French: appariement, synapse) Pairing Ribonucleoproteic protein formed at the time of between homologous chromosomes of maternal and transcripts splicing paternal origin during the prophase of meiosis, leading to the formation of gametes. Contact zone between two Splicing (French: épissage) The introduction of donor neurones or one neurone and a muscular glandular cell, DNA into a vector for cloning through which the electric or chemical transmission is Splicing, mRNA (French: épissage, ARNm) The completed. natural process by which transcribed mRNA matures to Synaptonemal complex (French: complexe become mRNA that will be translated. synaptonémal) Electron micrographs of paired Staining region homogeneously (French: région chromosomes at the pachytene stage of meiosis. de coloration homogène) Chromosome region that has Syndrome (French: syndrome) The group or a uniform staining property. recognizable pattern of symptoms or abnormalities that Initiation codon (French: codon d’initiation) A indicate a particular trait or disease. codon that codes for the first amino acid in a polypetide Syngeneic (French: syngénique) Genetically identical sequence. members of the same species. Stem cell (French: cellule souche) Pluripotent cell Synteny (French: synténie) The physical presence giving rise to cells with a different function. The origin together on the same chromosome of two or more gene can also be embryonic or germinal. Example: loci, whether or not they are close enough together for undifferentiated, primitive cells in the bone marrow linkage to be demonstrated. that have the ability both to multiply and to differentiate into specific blood cells. System, acellular (French: système acellulaire) void of cells but containing the necessary elements for a Stenosis, arterial (French: sténose artérielle) specific synthesis, like nucleic acids, precursors, Narrowing of an arterial vessel. enzymes except substances to be tested in tissue Stop codon (French: codon non-sens) see nonsense extracts. codon. Stop signal (French: signal stop) Signal indicating T the end of a gene. Tandem repeat sequences (French: séquences Structural gene (French: gene de structure) A gene répétées en tandem) Multiple copies of the same base coding for any RNA or protein product. sequence on a chromosome; used as a marker in physical mapping. Structural genomics (French: génomique de structure) The effort to determine the 3D structures of TATA box (French: boîte TATA) A conserved A-T large numbers of proteins using both experimental rich heptamer found about 25 bp before the start point techniques and computer simulation. of each eucaryotic RNA polymerase II transcription unit. STS , see sequence tagged site. Technology transfer (French: transfert Submetacentric (French: submétacentrique) A technologique) The process of converting scientific chromosome with an off-center centromere and arms of findings from research laboratories into useful products clearly different lengths. by the commercial sector. Substitution (French: substitution) In genetics, a type Telocentric (French: télocentrique) Centromere of mutation due to replacement of one nucleotide in a located at the very end of a chromosome.

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Telomere (French: télomère) The ends of Transcription initiation site (French: site chromosomes. These specialized structures are d’initiation de la transcription) Exact site of the involved in the replication and stability of linear DNA initiation of transcription. molecules. See DNA replication. Transcription unit (French: unité de transcription) Template, RNA or DNA (French: matrice d’ARN ou Region of the genome located between an initiation site ADN) The base sequences found in nucleic acids that and a site of termination of the transcription by the serve as the basis for the synthesis of complementary DNA polymerase. strrands of DNA or RNA. Transcriptional readthrough (French: lecture Teratogen (French: tératogène) Substance or agent transcriptionnelle) Uninterrupted DNA transcription. that can induce congenital malformations by action on Transducing phage (French: phage transducteur) A the embryo. Thalidomide is a teratogenic agent. virus particle that accidentally contains a very small Teratoma (French: tératome) Tumoral formation of portion of its host chromosome, used in . They can embryonic origin made of tissues of program other strains of bacteria to manufacture endoderm,ectoderm and mesoderm origin in which we proteins they normally cannot make. may find nervous cells, hair, teeth that have no Transductor phage (French: phage transducteur) connection with the surrounding tissues.The teratoma Phage that has the property to transfer part of a genome are sometime called twins with an imperfect from the host cell to another. development. Transfection (French: transfection) A gene that upon Terminal transferase (French: transférase transfection converts a previously immortalized cell to terminale) Enzyme that has the capacity to add a the malignant phenotype. desoxy ribonucleotide in the 3’OH of a DNA strand. Transfer RNA (French: ARN de transfert, ARNt) A Terminator (French: terminateur) DNA sequence that class of RNA having structures with triplet nucleotide initiates the end of the transcription. sequences that are complementary to the triplet Tetraploidy (French: tétraploïdie) Cellular content is nucleotide coding sequences of mRNA. The role of made of 4n or 92 chromosomes. tRNAs in protein synthesis is to bond with amino acids Tétrasomy (French: tétrasomie) Presence of two and transfer them to the ribosomes, where proteins are chromosomes in addition to te normal pair of assembled according to the genetic code carried by homologue chromosomes. Example tetrasomy X in a mRNA. 48 chromosome cell. Transformation (French: transformation) A process Tetravalent (French: tétravalent) When two by which the genetic material carried by an individual chromosomes are translocated in the first meiotic cell is altered by incorporation of exogenous DNA into division; there is then a four chromosome formation its genome. called tetravalent instead of two bivalent homologue Transgene (French: transgène) Gene introduced in chromosomes. the genome of an organism by genetics engineering. Thenar (French: éminence thénar) Dermal ridges Transgenesis (French: transgénèse) Operation that between the 5th finger and the wrist. consists in producing transgenic organisms. Thymine,T (French: thymine,T ) A nitrogenous base, Transgenic, animal (French: animal transgénique) one member of the base pair A- T. In reference to a living organism which foreign DNA Totipotent, cells (French: cellules totipotentes) Cells has been introduced in all or the majority of his cells. of the very early embryo that have the capacity to The estrange gene can be transmitted to descents. differentiation into the placenta the embryo and all Animal conceived to bear a gene from another animal. post-embryonic tissues and organs. No stem cell line to Transient expression (French: expression date has been able to show these properties. transitoire) Expression of a gene trecently introduced Trait (French: trait) Element transmitted by heredity. into a cell and not yet integrated into the genome. Recessive character present in a heterozygote form, like Transition (French: transition) A mutation in which for instance the thalassemia trait. either purine is substituted for the other, A for G or G Trans control (French: contrôle en trans) Regulation for A or one pyrimidine is substituted for the other C of genetic expression that manifests through an for T or T for C. intermediate diffusible factor. Traduction (French: traduction) The process of Transcriptase reverse (French: transcriptase forming a specific protein having its own amino acid inverse) Enzymatic complex present in RNA viruses sequence determined by the codons of the messenger assuring the DNA synthesis from RNA. RNA. The ribosome and transfer RNA are necessary for this process. Transcription (French: transcription) The synthesis of an RNA copy from a sequence of DNA or gene; the Translation error, reading mistake (French: first step in gene expression. erreur de traduction) Incorrect placement of one or Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1) 116

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more amino acid residues in a polypeptide chain during True hermaphrodyte (French: hermaphrodisme genetic translation. vrai) Hermaphrodyte individual who has gonadal tissue Translational control (French: contrôle de la of both sexes. traduction) The regulation of gene expression at the Trunctus arteriosus (French: trunctus arteriosus) level of genetic translation. Congenital heart anomaly caracterized by the presence Translational readtrough (French: translecture of only one arterial structure giving rise to aortic and traductionnelle) Translation of a mRNA at ahead of the pulmonary branches. normal termination codon. Tumor suppressor gene (French: Gène Translocation (French: translocation) The transfer of suppresseur de tumeur) A normal gene involved in the a segment of one chromosome to another chromosome. regulation of cell growth. Recessive mutations can lead to tumor development, as in the retinoblastoma gene or Translocation, balanced (French: translocation the p53 gene. équilibrée) The transfer of a segment of one chromosome to another without loss or addition of Tumor transformation (French: transformation chromosomal material. tumorale) Conversion of eucaryotic cells into a stase of unrestrained growth in culture resembling or identical Translocation, insertional (French: translocation with the tumorigenic condition. insertionnelle) The transfer of a segment of one chromosome to another chromosome by insertion of Twinning , see gemellity. the segment following two breaks in the chromosome followed by reunion of the chromosome segments U involved. Ubiquitar molecule (French: molecule ubiquitaire) Translocation, reciprocal (French: translocation Molecule that is present in several tissues of the body. réciproque) Exchange of chromosome pieces between Unequal crossing over (French: malségrégation) two non homologous chromosomes. Crossing over between similar DNA sequences that are Translocation robertsonian (French: translocation misaligned, resulting in sequences with deletion or robertsonienne) Translocation of two acrocentric duplication of DNA segments. A cause of a number of chromosomes by fusion at or near the centromere, with genetic variants. loss of the short arms. Unequal division , see: unequal crossing over. Transposase (French: transposase) Enzyme coded Uniparental disomy (French: disomie uniparentale) by a gene carried by a transposable involved in the Presence in a diploid cell of two homologue transposition. chromosomes inherited from the same parent. The most Transposition (French: transposition) Change of common mechanism is probably the correction of a position of a DNA fragment in the genome. trisomic cell. Transposon (French: gène sauteur, transposon) DNA UPD , see uniparental disomy. fragment susceptible to move from one location to Uracil, U (French : uracil, U) A nitrogenous base another in the genome. normally found in RNA but not DNA. Uracil is capable Transversion (French: transversion) A mutation in of forming of forming a base pair with Adenine. which either purine is substituted for either pyrimidine V or vice versa. Vector (French : vecteur) See cloning vector. Tricuspid atresia (French: atrésie tricuspidienne) Vector, expression (French: vecteur d’expression) Atresia of the heart pulmonary valve between the right Vector that has a region that allows the insertion of a cardiac auricle and the right ventricle. gene coding sequence between the signals essential for Triplet, nonsense , see : nonsense codon. its expression. Triploidy (French: diandrie, triploïdie, digynie) A cell Ventricular septal defect (French: communication with three copies of each chromosoome or an inter-ventriculaire) Congenital heart defect. Persistance individual made up of such cells. of a communication between the two ventricles. Triradius (French: triradius) Point of origin of dermal Villi , see: chorionic villi sampling. ridges in 3 directions. Virulent phage , see lytic phage. Trisomy (French: trisomie) The state of having three Virus (French: virus) A noncellular biological entity representatives of a given chromosome instead of the that can reproduce only within a host cell. Viruses usual pair, as in trisomy 21 or Down syndrome. consist of nucleic acid covered by protein; some animal Tropism cellular (French: cellular tropism) Property viruses are also surrounded by membrane. Inside the of a virus to infect a cell type preferentially. infected cell, the virus uses the synthetic capability of the host to produce progeny virus.

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Virus defective (French: virus défectif) Mutant virus Zoonoses (French: zoonoses) Animal diseases that that can reproduce only in the presence of an assistant can be transmitted to humans in living conditions. virus. Animals and humans can be infected by zoonoses. Virus, helper (French: virus assistant) A defective Examples: rabies, brucellosis, mad cow disease or gene that uses single–stranded RNA as its genetic Creutzfeldt-Jakob disease in humans material. It is only able to replicate when a helper virus Zygote (French: zygote) A fertilized egg formed as the is present in the same host cell. result of the union of male and female sex cell –sperm Virus VONC (French: virus VONC) Gene originating and egg-. from a proto-oncogene and subsequently recuperated by a virus. Selected references VLSI (French: VLSI) Very large-scale integration Le génie du génome. Glossaire. allowing over 100,000 transistors on a chip. http://www.nature.ca/genome/02/022_pqr_f.cfm VONC , see virus Vonc. Conseil de recherches médicales du Canada. et al. Vocabulaire du génie génétique : anglais-français avec index des termes français. Bibl. sc./Réf. Sc. & génie et Bibl. sc./Réf. W Sc. santé et Bibl. Sc. hum. & soc./Réf. P 305 C132 28 Wild (French: sauvage) The normal allele of a rare Université Laval biochimie médical-biochimie ouvrage de mutant gene, sometimes symbolized by +. références. http://www.ulaval.ca/fmed/bcx/refsci.html Williams, syndrome (French: syndrome de Université Laval. Ressources en génétique. Dictionnaires, Williams) Encyclopédies, Glossaires & Lexiques. Whorl (French: tourbillon) Dermatoglyphic pattern http://www.bibl.ulaval.ca/ress/genetiquedictionnaires.html observed on the finger tips. Institut Pasteur Terminologie du génie génétique - Lexique anglais – français http://www.pasteur.fr/recherche/DicoAF.html X Human genome project information, Genome glossary. Xenograft (French: xénogreffes) Living cells, tissues http://www.ornl.gov/TechResources/Human_Genome/publicat/ and organs used in the xenografts Transfer of cells, primer/glossary.html tissues and organs between two organisms that belong Glossaries: Human Genetics/Genome Project. to different species. http://www.kumc.edu/gec/glossary.html Xenotransplantation (French: xénotransplantation) Terminologie du génie génétique. http://www.ens- lyon.fr/RELIE/PCR/glossary/glossary.htm Transfer of cells, tissues or living organs from living animals to humans for medical purposes. Terminologie Génétique – Glossaire. http://www.globenet.org/myonet/GENETIQUE/glossaire.html X fragile , see Fragile X. Le grand dictionnaire terminologique, Office Québécois de la Y langue française. http://www.granddictionnaire.com/btml/fra/r_motclef/index800_ YAC (French: YAC) See yeast artificial chromosome. 1.asp Yeast artificial chromosome,YAC (French: Schlindwein's B. Hypermedia Glossary Of Genetic Terms. chromosome artificiel de levure,YAC) A vector used to http://hal.weihenstephan.de/genglos/asp/genreq.asp?list=1 clone DNA fragments (up to 400 kb); it is constructed GeneTests (National Institute of Health). from the telomeric, centromeric, and replication origin http://www.genetests.org/servlet/access?qry=ALLTERMS&db= sequences needed for replication in yeast cells. Also genestar&fcn=term>report2=true&id=8888891&key=xFQGcJD see: cloning vector, cosmid. 8Bd6xV Z This article should be referenced as such: Dallaire L. Glossary of Medical and Molecular Genetics. Zinc finger proteins (French: proteines à doigt de Atlas Genet Cytogenet Oncol Haematol. 2005; 9(1):92- zinc) Transcription activator proteins, containing finger 118. like structures containing zinc atoms.

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