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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 8, Number 2, Apr-Jun 2004 Previous Issue / Next Issue Genes ELKS (12p13.3). Tomoko Nakata, Shiro Minami, Mitsuru Emi. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 136-139. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ELKSID503.html PAX5 (paired box gene 5) (9p13). Sabine Strehl. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 140-145. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PAX5ID62.html E2F6 (2p25.1). Matthew Oberley. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 146-152. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/E2F6ID521.html IGF2R (6q25-q27). J Keith Killian. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 153-158. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/IGF2RID380.html RBL2 (retinoblastoma-like 2) (16q12.2). Giuseppe Russo, Antonio Giordano, Pier Paolo Claudio. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 159-163. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RBL2ID443.html TLX3 (T-cell leukemia, homeobox protein 3) (5q35.1). Roderick AF MacLeod, Stefan Nagel. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 164-170. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 I URL : http://AtlasGeneticsOncology.org/Genes/TLX3ID398.html COX6C (cytochrome c oxidase subunit VIc) (8q22.2). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 171-174. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/COX6CID251.html NTRK3 (15q25). Stevan Knezevich. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 175-181. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/NTRK3ID433.html PRDM16 (PR domain containing 16) (1p36.3). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 182-186. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PRDM16MEL1ID408.html SNAI2 (SNAIL HOMOLOG 2) (8q11.21). Manuel Sánchez-Martín, Inés González-Herrero, Isidro Sánchez-García.. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 187-192. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SNAI2ID453.html Leukaemias Castleman's disease. Antonio Cuneo, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 193-196. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/CastlemanID2123.html inv(8)(p11q13). Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 197-200. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/inv8p11q13ID1189.html t(7;12)(q36;p13) - updated. Anne RM von Bergh, H Berna Beverloo. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 201-204. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0712ID1177.html t(8;19)(p11;q13). Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 205-207. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0819p11q13ID1315.html t(8;9)(p12;q33). Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 208-210. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 II URL : http://AtlasGeneticsOncology.org/Anomalies/t0809p12q33ID1129.html t(8;22)(p11;q13). Jacques Boyer. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 211-214. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0822p11q13ID1119.html 11q23 rearrangements in childhood acute lymphoblastic leukemia. Susana C Raimondi. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 215-229. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/11q23ChildALLID1321.html t(1;14)(q21;q32) BCL9/IGH; t(1;22)(q21;q11). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 230-231. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32ID1319.html del (13q). Edmond SK Ma, Thomas SK Wan. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 232-238. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del13qID1310.html NK cell neoplasias. KF Wong. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 239-244. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/NKCellNeoplasiaID2125.html Solid Tumours Ovarian tumours: an overview. Lisa Lee-Jones. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 245-255. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/OvarianTumOverviewID5231.html Ovary: Epithelial tumors. Lisa Lee-Jones. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 256-302. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/OvaryEpithTumID5230.html Lung: Non-small cell carcinoma. Jim Heighway, Daniel C Betticher. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 303-309. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/LungNonSmallCellID5141.html Lung tumors: an overview. Jim Heighway, Daniel C Betticher. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 310-315. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 III URL : http://AtlasGeneticsOncology.org/Tumors/LungTumOverviewID5030.html Cancer Prone Diseases Deep Insights The vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa !. Eric Engel. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 316-328. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/UniparentDisomyID20046.html Transcription factors. Valentina Guasconi, Hakima Yahi, Slimane Ait-Si-Ali. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 329-333. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/TranscripFactorsID20043.html Case Reports Educational Items Microdeletions and Molecular Genetics. Annick Vogels, Jean-Pierre Fryns. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (2): 334-366. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Educ/MicrodeletionID30059ES.html

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Atlas Genet Cytogenet Oncol Haematol 2004; 2 IV Atlas of Genetics and Cytogenetics in Oncology and Haematology

ELKS

Identity Other rab6-interacting protein 2, ERC1 names Location 12p13.3 DNA/RNA Description at least 21 exons. 500 Kb Transcription 9.0 Kb and other smaller mRNAs ; alternative splicing: at least 5 isoforms (a, b, g, d, e) Protein

Description a : 948 amino acids, b: 992 amino acids, g: 720 amino acids, d:1088 amino acids, e:1116 amino acids, containing eight to ten coiled-coil domains. Rich in glutamic acid (E), leucine (L), lysine (K) and serine (S). Mouse homolog of ELKS a subtype binds to RIM (Rab3-interacting molecule) which is presynaptic active zone protein and regulates neurotransmitter release. Mouse homologs of ELKS bind to rab6 which regulate intracellular transport. Expression Ubiquitous, a and b are abundant in the brain. d and e predominate in the testis, thyroid and other tissues. Function unknown Homology CAST or ERC2 Implicated in Disease papillary thyroid carcinoma Hybrid/Mutated 5' ELKS-3' RET in the t(10;12)(q11;p13) Gene Abnormal ELKS-RET Protein Oncogenesis constitutive activation of RET

Breakpoints Note Intron 10 of ELKS and intron 11 of the RET. External links

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -136- Nomenclature GDB RAB6IP2 Entrez_Gene RAB6IP2 23085 RAB6 interacting protein 2 Cards Atlas ELKSID503 GeneCards RAB6IP2 Ensembl RAB6IP2 CancerGene ELKS Genatlas RAB6IP2 GeneLynx RAB6IP2 eGenome RAB6IP2 euGene 23085 Genomic and cartography RAB6IP2 - 12p13.3 chr12:970665-1472958 + 12p13.33 (hg17- GoldenPath May_2004) Ensembl RAB6IP2 - 12p13.33 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RAB6IP2 Gene and transcription

Genbank X58046 [ SRS ] X58046 [ ENTREZ ]

Genbank AB015617 [ SRS ] AB015617 [ ENTREZ ]

Genbank AB029004 [ SRS ] AB029004 [ ENTREZ ]

Genbank AB053468 [ SRS ] AB053468 [ ENTREZ ]

Genbank AB053469 [ SRS ] AB053469 [ ENTREZ ]

RefSeq NM_015064 [ SRS ] NM_015064 [ ENTREZ ]

RefSeq NM_178037 [ SRS ] NM_178037 [ ENTREZ ]

RefSeq NM_178038 [ SRS ] NM_178038 [ ENTREZ ]

RefSeq NM_178039 [ SRS ] NM_178039 [ ENTREZ ]

RefSeq NM_178040 [ SRS ] NM_178040 [ ENTREZ ]

RefSeq NT_086791 [ SRS ] NT_086791 [ ENTREZ ] AceView RAB6IP2 AceView - NCBI TRASER RAB6IP2 Traser - Stanford

Unigene Hs.400431 [ SRS ] Hs.400431 [ NCBI ] HS400431 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 607127 [ map ] GENECLINICS 607127

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -137- SNP RAB6IP2 [dbSNP-NCBI]

SNP NM_015064 [SNP-NCI]

SNP NM_178037 [SNP-NCI]

SNP NM_178038 [SNP-NCI]

SNP NM_178039 [SNP-NCI]

SNP NM_178040 [SNP-NCI]

SNP RAB6IP2 [GeneSNPs - Utah] RAB6IP2 [SNP - CSHL] RAB6IP2] [HGBASE - SRS] General knowledge Family RAB6IP2 [UCSC Family Browser] Browser SOURCE NM_015064 SOURCE NM_178037 SOURCE NM_178038 SOURCE NM_178039 SOURCE NM_178040 SMD Hs.400431 SAGE Hs.400431 Amigo process|protein transport PubGene RAB6IP2 Other databases Probes PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography Ret/PTC3 is the most frequent form of gene rearrangement in papillary thyroid carcinomas in Japan. Kitamura Y, Minobe K, Nakata T, Shimizu K, Tanaka S, Fujimori M, Yokoyama S, Ito K, Onda M, Emi M. Hum Genet 1999; 44(2): 96-102. Medline 10083732

Fusion of a novel gene, ELKS, to RET due to translocation t(10;12)(q11;p13) in a papillary thyroid carcinoma. Nakata T, Kitamura Y, Shimizu K, Tanaka S, Fujimori M, Yokoyama S, Ito K, Emi M. Genes Chrom Cancer 1999; 25: 97-103. Medline 10337992

Genomic organization and chromosomal mapping of ELKS, a gene rearranged in a papillary thyroid carcinoma. Yokota T, Nakata T, Minami S. Inazawa J, Emi M. J Hum Genet 2000; 45: 6-11.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -138- Medline 10697956

Differential expression of multiple isoforms of the ELKS mRNAs involved in a papillary thyroid carcinoma. Nakata T, Yokota T, Emi M, Minami S. Genes Chromosomes Cancer 2002; 35(1): 30-37. Medline 12203787

A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones. Wang Y, Liu X, Biederer T, Sudhof TC. Proc Natl Acad Sci U S A 2002; 99(22): 14464-14469. Medline 12391317

Characterization of novel Rab6-interacting proteins involved in endosome-to- TGN transport. Monier S, Jollivet F, Janoueix-Lerosey I, Johannes L, Goud B. Traffic 2002; 3(4): 289-297. Medline 11929610

Interaction of the ERC family of RIM-binding proteins with the liprin-alpha family of multidomain proteins. Ko J, Na M, Kim S, Lee JR, Kim E. J Biol Chem 2003; 278(43): 42377-42385. Medline 12923177

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Tomoko Nakata, Shiro Minami, Mitsuru Emi 2004 Citation This paper should be referenced as such : Nakata T, Minami S, Emi M . ELKS. Atlas Genet Cytogenet Oncol Haematol. January 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ELKSID503.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -139- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PAX5 (paired box gene 5) (updated: old version not available)

Identity Other BSAP (B-cell lineage specific activator protein) names Hugo PAX5 Location 9p13 DNA/RNA Description The PAX5 coding region extends over a genomic interval of approximately 200kb and comprises 10 exons. Transcription Two alternative transcripts have been identified, originating from alternative promotor usage, containing exon 1A or 1B; full length mRNA is 3650bp; transcription is from centromere to telomere. Protein

Description 391 amino acids, 42 kDa, PAX5 belongs to the paired box family of transcription factors, contains a paired box (DNA binding) domain, a truncated homeo domain homology region, and a transactivation domain. Expression B lymphocytes, the developing CNS, and adult testis. Localisation Nuclear Function Involved in a multitude of developmental processes, PAX5 expression is not only continuously required for B cell lineage commitment during early B cell development but also for B lineage maintenance, involved in the regulation of the CD19 gene, a B-lymphoid-specific target gene. Implicated in Entity t(9;14)(p13;q23) lymphoproliferative disorders Hybrid/Mutated PAX5 - IGH juxtaposition Gene

Entity dic(9;12)(p13;p13) acute lymphoblastic leukemia Hybrid/Mutated PAX5 - ETV6 Gene

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -140-

External links Nomenclature Hugo PAX5 GDB PAX5 Entrez_Gene PAX5 5079 paired box gene 5 (B-cell lineage specific activator) Cards Atlas PAX5ID62 GeneCards PAX5 Ensembl PAX5 CancerGene PAX5 Genatlas PAX5 GeneLynx PAX5 eGenome PAX5 euGene 5079 Genomic and cartography PAX5 - 9p13 chr9:36828531-37024476 - 9p13.2 (hg17- GoldenPath May_2004) Ensembl PAX5 - 9p13.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PAX5 Gene and transcription

Genbank AF074913 [ SRS ] AF074913 [ ENTREZ ]

Genbank AF268279 [ SRS ] AF268279 [ ENTREZ ]

Genbank AF386790 [ SRS ] AF386790 [ ENTREZ ]

Genbank U56835 [ SRS ] U56835 [ ENTREZ ]

Genbank U56836 [ SRS ] U56836 [ ENTREZ ]

RefSeq NM_016734 [ SRS ] NM_016734 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -141- RefSeq NT_086749 [ SRS ] NT_086749 [ ENTREZ ] AceView PAX5 AceView - NCBI TRASER PAX5 Traser - Stanford

Unigene Hs.126365 [ SRS ] Hs.126365 [ NCBI ] HS126365 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q02548 [ SRS] Q02548 [ EXPASY ] Q02548 [ INTERPRO ]

Prosite PS00034 PAIRED_BOX [ SRS ] PS00034 PAIRED_BOX [ Expasy ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ]

Interpro IPR001523 Paired_box_N [ SRS ] IPR001523 Paired_box_N [ EBI ] CluSTr Q02548

Pfam PF00292 PAX [ SRS ] PF00292 PAX [ Sanger ] pfam00292 [ NCBI-CDD ]

Smart SM00351 PAX [EMBL] Blocks Q02548

PDB 1K78 [ SRS ] 1K78 [ PdbSum ], 1K78 [ IMB ]

PDB 1MDM [ SRS ] 1MDM [ PdbSum ], 1MDM [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 167414 [ map ] GENECLINICS 167414

SNP PAX5 [dbSNP-NCBI]

SNP NM_016734 [SNP-NCI]

SNP PAX5 [GeneSNPs - Utah] PAX5 [SNP - CSHL] PAX5] [HGBASE - SRS] General knowledge Family PAX5 [UCSC Family Browser] Browser SOURCE NM_016734 SMD Hs.126365 SAGE Hs.126365 Amigo function|DNA binding Amigo process|cell differentiation Amigo process|development Amigo process|humoral immune response Amigo process|neurogenesis Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo process|spermatogenesis Amigo process|transcription Amigo process|transcription from Pol II promoter

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -142- PubGene PAX5 Other databases Probes Probe PAX5 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography A novel B-cell lineage-specific transcription factor present at early but not late stages of differentiation. Barberis A, Widenhorn K, Vitelli L, Busslinger M. Genes Dev 1990; 4: 849-859. Medline 90337320 t(9;14)(p13;q32) denotes a subset of low-grade non-Hodgkin's lymphoma with plasmacytoid differentiation. Offit K, Parsa NZ, Filippa D, Jhanwar SC, Chaganti RS. Blood 1992; 80: 2594-2599. Medline 93043307

Deregulation of PAX-5 by translocation of the Emu enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma. Busslinger M, Klix N, Pfeffer P, Graninger PG, Kozmik Z. Proc Natl Acad Sci USA 1996; 93: 6129-6134. Medline 96234102

The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. Iida S, Rao PH, Nallasivam P, Hibshoosh H, Butler M, Louie DC, Dyomin V, Ohno H, Chaganti RS, Dalla-Favera R. Blood 1996; 88: 4110-4117. Medline 97099267

Essential functions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. Nutt SL, Urbanek P, Rolink A, Busslinger M. Genes Dev 1997; 11: 476-491. Medline 9042861

Expression of the PAX5/BSAP transcription factor in haematological tumour cells and further molecular characterization of the t(9;14)(p13;q32) translocation in B-cell non-Hodgkin's lymphoma. Hamada T, Yonetani N, Ueda C, Maesako Y, Akasaka H, Akasaka T, Ohno H, Kawakami K, Amakawa R, Okuma M. Br J Haematol 1998; 102: 691-700.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -143- Medline 9722295

Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nutt SL, Heavey B, Rolink AG, Busslinger M. Nature 1999; 401: 556-562. Medline 99452253

The t(9;14)(p13;q32) translocation in B-cell non-Hodgkin's lymphoma. Ohno H, Ueda C, Akasaka T. Leuk Lymphoma 2000; 36: 435-445. Review. Medline 20244973

The Paired Box Domain Gene PAX5 Is Fused to ETV6/TEL in an Acute Lymphoblastic Leukemia Case. Cazzaniga G, Daniotti M, Tosi S, Giudici G, Aloisi A, Pogliani E, Kearney L, Biondi A. Cancer Res 2001; 61: 4666-4670. Medline 11406533

Reversion of B cell commitment upon loss of Pax5 expression. Mikkola I, Heavey B, Horcher M, Busslinger M. Science 2002; 297: 110-113. Medline 22093537

Transcriptional control of B-cell development. Schebesta M, Heavey B, Busslinger M. Curr Opin Immunol 2002; 14: 216-223. Review. Medline 11869895

Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1. Souabni A, Cobaleda C, Schebesta M, Busslinger M. Immunity 2002; 17: 781-793. Medline 12479824

Pax5 is required for recombination of transcribed, acetylated, 5' IgH V gene segments. Hesslein DG, Pflugh DL, Chowdhury D, Bothwell AL, Sen R, Schatz DG. Genes Dev 2003; 17: 37-42. Medline 12514097

The PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13). Strehl S, Konig M, Dworzak MN, Kalwak K, Haas OA. Leukemia 2003; 17: 1121-1123. Medline 12764378

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -144- Transcriptional control of early B cell development. Busslinger M. Annu Rev Immunol 2004; 22: 55-79. Review. Medline 15032574

Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M. Genes Dev 2004; 18: 411-422. Medline 15004008

PAX5 expression in acute leukemias: higher B-lineage specificity than CD79a and selective association with t(8;21)-acute myelogenous leukemia. Tiacci E, Pileri S, Orleth A, Pacini R, Tabarrini A, Frenguelli F, Liso A, Diverio D, Lo- Coco F, Falini B. Cancer Res 2004; 64: 7399-7404. Medline 15492262

PAX5/IGH rearrangement is a recurrent finding in a subset of aggressive B-NHL with complex chromosomal rearrangements. Poppe B, De Paepe P, Michaux L, Dastugue N, Bastard C, Herens C, Moreau E, Cavazzini F, Yigit N, Van Limbergen H, De Paepe A, Praet M, De Wolf-Peeters C, Wlodarska I, Speleman F. Genes Chromosomes Cancer 2005; 44: 218-223. Medline 15942942

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Sabine Strehl 2004 Updated 08- Sabine Strehl 2005 Citation This paper should be referenced as such : Strehl S . PAX5 (paired box gene 5). Atlas Genet Cytogenet Oncol Haematol. January 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PAX5ID62.html Strehl S . PAX5 (paired box gene 5). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PAX5ID62.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -145-

Atlas of Genetics and Cytogenetics in Oncology and Haematology

E2F6

Identity Other E2F-6 names E2F transcription factor 6 E2 Binding Factor 6 Hugo E2F6 Location 2p25.1 DNA/RNA Description In humans, E2F6 has 8 exons that span 20881 bp of genomic sequence. It has an ORF of 843 nt. Transcription There have been 5 mRNA splice variants identified in humans. Transcript variant 1 is the predominant transcript, and it encodes the longest mRNA isoform (a), which is 2342 bp. Transcript variant 2 contains an additional segment (2413 bp mRNA), compared to variant 1, that causes a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform b) is much shorter than isoform a. Transcript variants 2 and 4 encode isoform b. Transcript variant 3 lacks a segment (2287 bp mRNA), compared to variant 1, that causes a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform c) is much shorter than isoform a. Transcript variant 4 contains two additional segments (2546 bp mRNA), compared to variant 1, that cause a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform b) is much shorter than isoform a. Transcript variant 5 contains an additional segment (2475 bp mRNA), compared to variant 1, that causes a frameshift leading to an early stop codon. This transcript may function in a regulatory role with no protein translated. The predicted protein (isoform d) is much shorter than isoform a. Pseudogene There is an E2F6 pseudogene located on chromosome 22q11.2 (LOC376818) containing 2144 bp of the E2F6 gene with no introns. Protein

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -146-

Diagram created by M. Oberley.

Description The predominately expressed isoform is 282 amino acids, and is . The DNA binding domain is thought to be between aa 50 and 129. It has a DEF box between aa 95 to 195. The dimerization domain is thought to reside between aa 130 and 222. There is a leucine zipper domain between aa 143 and 164. The transcriptional repression domain is located on the C terminus from aa 173 to 281. The N-terminal 1-75 aa are missing in isoform B which is predicted to be 206 AA. Expression Ubiquitous, though more highly expressed in the placenta, skeletal muscle, heart, ovary, kidney, small intestine and spleen. Localisation Nuclear Function Heterodimerization with DP1 or 2 creates a sequence specific transcriptional repressor. Overexpression of E2F6 can delay the exit of cells from S-phase, indicating a role for E2F6 in cell-cycle control. E2F6 has been shown via yeast two hybrid and co-IPs to interact with members of the polycomb repressive complex 1, such as Bmi1, RYBP, RING1, MEL-18, and Mph1. The functional outcome of these interactions are as of yet unclear. E2F6 has been biochemically purified in a complex containing polycomb group members h-1(3) mbt like protein, RING1, RING2, hMBLR, as well as YAF and HP1g; this complex also contained a novel euchromatic histone methyltransferase (Eu-HMTase1). This finding led to speculation that E2F6 controlled cellular entry into quiescence, but E2F6 nullizygous MEFs had no kinetic changes or defects in their ability to enter quiescence, or to re- enter into the cell-cycle. However, these animals had homeotic transformations of the axial skeleton, a phenotype that resembled Bmi1 nullizygous mice. This implicated E2F6 in regulation of normal development. Homology E2F6 has homology with E2Fs1-5 in the DNA-binding domain, the dimerization domain, and the marked box domain located between aa 231 and 239. Mutations Note A synthetic mutation in aa 68; L->E: reduced E2F6 transcriptional repressor activity by abrogating DNA binding, but had little effect on S- phase entry. Implicated in

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -147- Entity Development Note E2F6 is required for normal homeotic development in murine models as mice nullizygous for E2F6 display transformations in the axial skeleton. Disease None known.

External links Nomenclature Hugo E2F6 GDB E2F6 Entrez_Gene E2F6 1876 E2F transcription factor 6 Cards Atlas E2F6ID521 GeneCards E2F6 Ensembl E2F6 CancerGene E2F6 Genatlas E2F6 GeneLynx E2F6 eGenome E2F6 euGene 1876 Genomic and cartography E2F6 - 2p25.1 chr2:11536015-11556895 - 2p25.1 (hg17- GoldenPath May_2004) Ensembl E2F6 - 2p25.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene E2F6 Gene and transcription

Genbank AJ493061 [ SRS ] AJ493061 [ ENTREZ ]

Genbank AY083997 [ SRS ] AY083997 [ ENTREZ ]

Genbank AY551345 [ SRS ] AY551345 [ ENTREZ ]

Genbank AF041381 [ SRS ] AF041381 [ ENTREZ ]

Genbank AF059292 [ SRS ] AF059292 [ ENTREZ ]

RefSeq NM_001952 [ SRS ] NM_001952 [ ENTREZ ]

RefSeq NM_198256 [ SRS ] NM_198256 [ ENTREZ ]

RefSeq NM_198257 [ SRS ] NM_198257 [ ENTREZ ]

RefSeq NM_198258 [ SRS ] NM_198258 [ ENTREZ ]

RefSeq NM_198325 [ SRS ] NM_198325 [ ENTREZ ]

RefSeq NM_212540 [ SRS ] NM_212540 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -148- RefSeq NT_086610 [ SRS ] NT_086610 [ ENTREZ ] AceView E2F6 AceView - NCBI TRASER E2F6 Traser - Stanford

Unigene Hs.135465 [ SRS ] Hs.135465 [ NCBI ] HS135465 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O75461 [ SRS] O75461 [ EXPASY ] O75461 [ INTERPRO ]

Interpro IPR003316 E2F_TDP [ SRS ] IPR003316 E2F_TDP [ EBI ] Interpro IPR008994 Nucleic_acid_OB [ SRS ] IPR008994 Nucleic_acid_OB [ EBI ] CluSTr O75461 Pfam PF02319 E2F_TDP [ SRS ] PF02319 E2F_TDP [ Sanger ] pfam02319 [ NCBI-CDD ] Blocks O75461 Polymorphism : SNP, mutations, diseases OMIM 602944 [ map ] GENECLINICS 602944

SNP E2F6 [dbSNP-NCBI]

SNP NM_001952 [SNP-NCI]

SNP NM_198256 [SNP-NCI]

SNP NM_198257 [SNP-NCI]

SNP NM_198258 [SNP-NCI]

SNP NM_198325 [SNP-NCI]

SNP NM_212540 [SNP-NCI]

SNP E2F6 [GeneSNPs - Utah] E2F6 [SNP - CSHL] E2F6] [HGBASE - SRS] General knowledge Family E2F6 [UCSC Family Browser] Browser SOURCE NM_001952 SOURCE NM_198256 SOURCE NM_198257 SOURCE NM_198258 SOURCE NM_198325 SOURCE NM_212540 SMD Hs.135465 SAGE Hs.135465 Amigo process|negative regulation of transcription from Pol II promoter Amigo function|nucleic acid binding Amigo component|nucleus Amigo process|regulation of cell cycle

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -149- Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription corepressor activity Amigo function|transcription factor activity Amigo component|transcription factor complex PubGene E2F6 Other databases Probes Probe E2F6 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography An E2F-like repressor of transcription. Morkel M, Wenkel J, Bannister AJ, Kouzarides T, Hagemeier C. Nature 1997; 390(6660): 567-568. Medline 9403682

E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription. Cartwright P, Muller H, Wagener C, Holm K, Helin K. Oncogene 1998; 17(5): 611-623. Medline 9704927

Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6. Gaubatz S, Wood JG, Livingston DM. Proc Natl Acad Sci U S A 1998; 95(16): 9190-9195. Medline 9689056

E2F-6, a member of the E2F family that can behave as a transcriptional repressor. Trimarchi JM, Fairchild B, Verona R, Moberg K, Andon N, Lees JA. Proc Natl Acad Sci U S A 1998; 95(6): 2850-2855. Medline 9501179

Molecular cloning and characterization of the mouse E2F6 gene. Kherrouche Z, Begue A, Stehelin D, Monte D. Biochem Biophys Res Commun 2001; 288(1): 22-33. Medline 11594747

The E2F6 transcription factor is a component of the mammalian Bmi1- containing polycomb complex. Trimarchi JM, Fairchild B, Wen J, Lees JA. Proc Natl Acad Sci U S A 2001; 98(4): 1519-1524.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -150- Medline 11171983

Two different E2F6 proteins generated by alternative splicing and internal translation initiation. Dahme T, Wood J, Livingston DM, Gaubatz S. Eur J Biochem 2002; 269(20): 5030-5036. Medline 12383262

A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y. Dahme T, Wood J, Livingston DM, Gaubatz S. Science 2002; 296(5570): 1132-1136. Medline 12004135

Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6. Storre J, Elsasser HP, Fuchs M, Ullmann D, Livingston DM, Gaubatz S. EMBO Rep 2002; 3(7): 695-700. Medline 12101104

Sibling rivalry in the E2F family. Trimarchi JM, Lees JA. Nat Rev Mol Cell Biol 2002; 3(1): 11-20. Review. Medline 11823794

Dynamic recruitment of NF-Y and histone acetyltransferases on cell-cycle promoters. Caretti G, Salsi V, Vecchi C, Imbriano C, Mantovani R. J Biol Chem 2003; 278(33): 30435-30440. Medline 12771133

E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9. Oberley MJ, Inman DR, Farnham PJ. J Biol Chem 2003; 278(43): 42466-42476. Medline 12909625

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Matthew Oberley 2004

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -151- Citation This paper should be referenced as such : Oberley M . E2F6. Atlas Genet Cytogenet Oncol Haematol. March 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/E2F6ID521.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -152- Atlas of Genetics and Cytogenetics in Oncology and Haematology

IGF2R

Identity Other M6P/IGF2R names Hugo IGF2R Location 6q25-q27 DNA/RNA Note no known splice variants Description 138376 bp Transcription 9090 bp mRNA Pseudogene None known Protein

Description 2491 aa Expression Subject to parental genomic imprinting in some viviparous mammals. Preferential transcription of maternally-derived allele in some mammals with the exception of primates and close relatives. Humans harbor a parentally imprinted differentially methylated CpG island, but human IGF2R transcripts are not preferentially maternally derived. Function M6P/IGF2R translates to a protein whose diverse functions include lysosomal enzyme trafficking, fetal organogenesis, tumor suppression, and cytotoxic T-cell induced apoptosis. The M6P- and IGF2-binding sites are distinct within the protein, and are thought to have evolved independently, partly explaining the gamut of functions attributable to a single protein: the ancestral M6PR dates back at least 450 million years, and appears to have been a suitable platform for acquiring an IGF2 binding function in ancestral mammals roughly 150 to 200 million years ago; as with M6P-tagged molecules, bound IGF2 is targeted to lysosomes, where IGF2 is degraded. To the extent that the tumor suppressor role of M6P/IGF2R relies on IGF2 binding, the M6P/IGF2R is a very young tumor suppressor. Homology CD-MPR Mutations Note Include genetic and epigenetic derangements. Epigenetics Beyond biochemical and DNA sequence properties, M6P/IGF2R epigenetic traits have been described. In humans, there is a

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -153- differentially methylated region (DMR) in intron 2 of the gene which is preferentially methylated on the maternally inherited copy of the gene; in addition, the human M6P/IGF2R resides in an asynchronously replicating genomic region, such that the gene allele inherited from the mother replicates first.

Despite these parentally pre-programmed epigenetic behaviors, human M6P/IGF2R transcription appears to be equivalent between both parentally-inherited alleles. Thus, human M6P/IGF2R alleles are encoded with information about parental origin, but this information is evidently uncoupled from transcriptional ramifications. This uncoupling is particularly intriguing in light of mouse genetic manipulations which causally link an imprinted M6p/igf2r DMR to imprinted transcription. Thus, the human M6P/IGF2R provides a rare example of uncoupling of stable gene imprinting --evidenced by somatically heritable parent- specific DNA methylation-- from stable imprinted transcription. Interestingly, the marsupial M6P/IGF2R homologue manifests parentally imprinted maternal transcription in the absence of imprinted differential methylation.

M6P/IGF2R, thus, is remarkably divergent across animal species with respect to both biochemical and epigenetic properties. Within the imprinted family of genes, M6P/IGF2R manifests a distinctive uncoupling of imprinted methylation from imprinted transcription, which frustrates efforts to establish the precise role of DNA methylation in the imprinting process. M6P/IGF2R is somewhat of a devil's advocate and a reminder that genes don't always read the journals. Germinal Epigenetic alterations associated with fetal developmental abnormalities. Somatic PCR-platform IGF2R LOH, microsatellite instability, and point mutations described in tumors. Somatic mutations of M6P/IGF2R DNA sequence have been identified in human colon, liver, lung, breast and ovarian cancers, suggestive of Knudson-type two-hit oncogenetics at first glance; however, M6P/IGF2R loss of heterozygosity (LOH) is reported to precede point mutation of the remaining allele in the hepatocellular carcinoma model, in distinction from RB and other genes following the two-hit principle of Knudson. Statistically significant differences in M6P/IGF2R allelic variants have been identified between Japanese and American populations, but any functional significance has not been ascribed. Implicated in Entity Development, immunity, tumorigenesis.

External links Nomenclature Hugo IGF2R

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -154- GDB IGF2R Entrez_Gene IGF2R 3482 insulin-like growth factor 2 receptor Cards Atlas IGF2RID380 GeneCards IGF2R Ensembl IGF2R CancerGene IGF2R Genatlas IGF2R GeneLynx IGF2R eGenome IGF2R euGene 3482 Genomic and cartography IGF2R - chr6:160360542-160497992 + 6q25.3 (hg17- GoldenPath May_2004) Ensembl IGF2R - 6q25.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene IGF2R Gene and transcription

Genbank AF069333 [ SRS ] AF069333 [ ENTREZ ]

Genbank AF109291 [ SRS ] AF109291 [ ENTREZ ]

Genbank AL035691 [ SRS ] AL035691 [ ENTREZ ]

Genbank AL353625 [ SRS ] AL353625 [ ENTREZ ]

Genbank AY293855 [ SRS ] AY293855 [ ENTREZ ]

RefSeq NM_000876 [ SRS ] NM_000876 [ ENTREZ ]

RefSeq NT_086699 [ SRS ] NT_086699 [ ENTREZ ] AceView IGF2R AceView - NCBI TRASER IGF2R Traser - Stanford

Unigene Hs.487062 [ SRS ] Hs.487062 [ NCBI ] HS487062 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P11717 [ SRS] P11717 [ EXPASY ] P11717 [ INTERPRO ] Prosite PS00023 FIBRONECTIN_2 [ SRS ] PS00023 FIBRONECTIN_2 [ Expasy ]

Interpro IPR000479 CIMR [ SRS ] IPR000479 CIMR [ EBI ]

Interpro IPR000562 FN_Type_II [ SRS ] IPR000562 FN_Type_II [ EBI ] Interpro IPR009011 Man6php_recept [ SRS ] IPR009011 Man6php_recept [ EBI ] CluSTr P11717

Pfam PF00878 CIMR [ SRS ] PF00878 CIMR [ Sanger ] pfam00878 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -155- Pfam PF00040 fn2 [ SRS ] PF00040 fn2 [ Sanger ] pfam00040 [ NCBI-CDD ]

Smart SM00059 FN2 [EMBL]

Prodom PD000995 FN_Type_II[INRA-Toulouse] Prodom P11717 MPRI_HUMAN [ Domain structure ] P11717 MPRI_HUMAN [ sequences sharing at least 1 domain ] Blocks P11717

PDB 1E6F [ SRS ] 1E6F [ PdbSum ], 1E6F [ IMB ]

PDB 1GP0 [ SRS ] 1GP0 [ PdbSum ], 1GP0 [ IMB ]

PDB 1GP3 [ SRS ] 1GP3 [ PdbSum ], 1GP3 [ IMB ]

PDB 1GQB [ SRS ] 1GQB [ PdbSum ], 1GQB [ IMB ]

PDB 1JWG [ SRS ] 1JWG [ PdbSum ], 1JWG [ IMB ]

PDB 1LF8 [ SRS ] 1LF8 [ PdbSum ], 1LF8 [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 147280 [ map ] GENECLINICS 147280

SNP IGF2R [dbSNP-NCBI]

SNP NM_000876 [SNP-NCI]

SNP IGF2R [GeneSNPs - Utah] IGF2R [SNP - CSHL] IGF2R] [HGBASE - SRS] General knowledge Family IGF2R [UCSC Family Browser] Browser SOURCE NM_000876 SMD Hs.487062 SAGE Hs.487062 Amigo function|insulin-like growth factor receptor activity Amigo component|integral to plasma membrane Amigo component|lysosome Amigo function|receptor activity Amigo process|receptor mediated endocytosis Amigo process|signal transduction Amigo process|transport Amigo function|transporter activity PubGene IGF2R Other databases Probes Probe IGF2R Related clones (RZPD - Berlin) PubMed PubMed 25 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -156- Bibliography Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. Kornfeld S. Annu Rev Biochem 1992; 61: 307-330. (REVIEW) Medline 92359495

Conservation of a maternal-specific methylation signal at the human IGF2R locus. Smrzka OW, Fae I, Stoger R, Kurzbauer R, Fischer GF, Henn T, Weith A, Barlow DP. Hum Mol Genet 1995; 4(10): 1945-1952. Medline 96121594

Imprinted expression of the Igf2r gene depends on an intronic CpG island. Wutz A, Smrzka OW, Schweifer N, Schellander K, Wagner EF, Barlow DP. Nature 1997; 389(6652): 745-749. Medline 9338788

Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis. Yamada T, De Souza AT, Finkelstein S, Jirtle RL. Proc Natl Acad Sci U S A 1997; 94(19): 10351-10355. Medline 9294214

Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Motyka B, Korbutt G, Pinkoski MJ, Heibein JA, Caputo A, Hobman M, Barry M, Shostak I, Sawchuk T, Holmes CF, Gauldie J, Bleackley RC. Cell 2000; 103(3): 491-500. Medline 20531885

Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary Killian JK, Nolan CM, Wylie AA, Li T, Vu TH, Hoffman AR, Jirtle RL. Hum Mol Genet 2001; 10(17): 1721-1728. Medline 21423776

Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations. Killian JK, Oka Y, Jang HS, Fu X, Waterland RA, Sohda T, Sakaguchi S, Jirtle RL. Hum Mutat 2001; 18(1): 25-31. Medline 21331686

Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -157- Young LE, Fernandes K, McEvoy TG, Butterwith SC, Gutierrez CG, Carolan C, Broadbent PJ, Robinson JJ, Wilmut I, Sinclair KD. Nat Genet 2001; 27(2): 153-154. Medline 21096972

Mannose 6-phosphate receptors: new twists in the tale. Ghosh P, Dahms NM, Kornfeld S. Nat Rev Mol Cell Biol 2003; 4(3): 202-212. (REVIEW) Medline 22500058

Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Sandovici I, Leppert M, Hawk PR, Suarez A, Linares Y, Sapienza C. Hum Mol Genet 2003; 12(13): 1569-1578. Medline 22697205

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- J Keith Killian 2004 Citation This paper should be referenced as such : Killian JK . IGF2R. Atlas Genet Cytogenet Oncol Haematol. March 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/IGF2RID380.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -158- Atlas of Genetics and Cytogenetics in Oncology and Haematology

RBL2 (retinoblastoma-like 2)

Identity Other PRB2; RBR-2 names 130 kDa retinoblastoma-associated protein H. sapiens p130 mRNA for 130K protein P130 Retinoblastoma-related gene RB2 Rb2 Retinoblastoma-like protein 2 Hugo RBL2 Location 16q12.2 DNA/RNA

Exons are represented by solid blue rectangles and introns by black bars. The drawing is not in scale. The positions of the A and B domains, which contain the pocket domain, in the Rb2/p130 gene, are indicated.

Description The gene is composed of 22 exons spanning in a region of 57.159 bp (Localized from 53,246,963 to 53,304,161 from pter). Transcription The sequence is supported by 286 sequences from 262 cDNA clones and produces, by alternative splicing, 9 different protein isoforms. The transcripts differ by truncation of the N-terminus, truncation of the C- terminus, presence or absence of a cassette exon, common exons with different boundaries. Pseudogene None Protein

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -159-

Note pRb2/p130,130 kDa retinoblastoma-associated protein, PRB2, P130, RBR-2 Description pRb2/p130 belongs to the retinoblastoma (RB) family of proteins. Amino acids: 1139; Molecular Weight: 128356 Dalton. The phosphorylation on Ser-672 in G1 leads to its ubiquitin-dependent proteolysis. Expression pRb2/p130 is ubiquitously expressed in normal tissues. Localisation Nuclear Function pRb2/p130 acts as a tumor suppressor and it is a potent inhibitor of E2F-mediated trans-activation. pRb2/p130 may have a function in cell cycle regulation, proliferation and differentiation during human placental development. Homology The percent Identity below represents identity over an aligned region using pairwise alignment function of ClustalW software. M. musculus : 92 (Percentage Identity) R. norvegicus : 91 D. melanogaster : 27 A. thaliana : 23 C. elegans : 22 Implicated in Entity This oncosuppressor gene is involved in Breast Cancer, Burkitt's lymphomas, Choroidal melanoma, Endometrial Cancer, Lung Cancer, Malignant Lymphomas, Mesothelioma, Glioblastoma, Ovarian Cancer, Oral malignant melanoma, Vulvar Carcinoma. Note Recent studies show a link between pRb2/p130 and chromatin- modifying enzymes in the regulation of estrogen receptor-alpha transcription. pRb2/p130 expression predicts outcome in squamous cell carcinoma of the esophagus, lung, mouth and endometrium carcinomas. Analyses of gene expression profiles identified pRb2/p130 target genes in non-small-cell lung neoplasms. HIV-1/pRb2/p130 interaction may be a possible mechanism in the pathogenesis of AIDS- related lymphomas. pRb2/p130 and its truncated form might substitute Rb in mediating p53-induced cell cycle arrest in Rb(-/-) Saos2 cells. Some reports have shown that pRb2/p130 turn-over is regulated by Cdk-dependent G1 phosphorylation.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -160- External links Nomenclature Hugo RBL2 GDB RBL2 Entrez_Gene RBL2 5934 retinoblastoma-like 2 (p130) Cards Atlas RBL2ID443 GeneCards RBL2 Ensembl RBL2 CancerGene RBL2 Genatlas RBL2 GeneLynx RBL2 eGenome RBL2 euGene 5934 Genomic and cartography RBL2 - 16q12.2 chr16:52025901-52083060 + 16q12.2 (hg17- GoldenPath May_2004) Ensembl RBL2 - 16q12.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RBL2 Gene and transcription

Genbank U53220 [ SRS ] U53220 [ ENTREZ ]

Genbank BC034490 [ SRS ] BC034490 [ ENTREZ ]

Genbank BX537767 [ SRS ] BX537767 [ ENTREZ ]

Genbank S67171 [ SRS ] S67171 [ ENTREZ ]

Genbank X74594 [ SRS ] X74594 [ ENTREZ ]

RefSeq NM_005611 [ SRS ] NM_005611 [ ENTREZ ]

RefSeq NT_086849 [ SRS ] NT_086849 [ ENTREZ ] AceView RBL2 AceView - NCBI TRASER RBL2 Traser - Stanford

Unigene Hs.513609 [ SRS ] Hs.513609 [ NCBI ] HS513609 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q08999 [ SRS] Q08999 [ EXPASY ] Q08999 [ INTERPRO ]

Interpro IPR006670 Cyclin [ SRS ] IPR006670 Cyclin [ EBI ]

Interpro IPR011028 Cyclin_like [ SRS ] IPR011028 Cyclin_like [ EBI ]

Interpro IPR002720 RB_A [ SRS ] IPR002720 RB_A [ EBI ]

Interpro IPR002719 RB_B [ SRS ] IPR002719 RB_B [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -161- CluSTr Q08999

Pfam PF01858 RB_A [ SRS ] PF01858 RB_A [ Sanger ] pfam01858 [ NCBI-CDD ]

Pfam PF01857 RB_B [ SRS ] PF01857 RB_B [ Sanger ] pfam01857 [ NCBI-CDD ]

Smart SM00385 CYCLIN [EMBL] Blocks Q08999 Polymorphism : SNP, mutations, diseases OMIM 180203 [ map ] GENECLINICS 180203

SNP RBL2 [dbSNP-NCBI]

SNP NM_005611 [SNP-NCI]

SNP RBL2 [GeneSNPs - Utah] RBL2 [SNP - CSHL] RBL2] [HGBASE - SRS] General knowledge Family RBL2 [UCSC Family Browser] Browser SOURCE NM_005611 SMD Hs.513609 SAGE Hs.513609 Amigo function|DNA binding Amigo process|cell cycle Amigo process|negative regulation of cell cycle Amigo component|nucleus Amigo function|protein binding Amigo process|regulation of transcription, DNA-dependent BIOCARTA Cell to Cell Adhesion Signaling BIOCARTA CXCR4 Signaling Pathway BIOCARTA METS affect on Macrophage Differentiation BIOCARTA Integrin Signaling Pathway BIOCARTA PTEN dependent cell cycle arrest and apoptosis BIOCARTA Links between Pyk2 and Map Kinases PubGene RBL2 Other databases Other ASAP database Other EASED database Other CGED database Other HGVD database

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -162- Other JSNP database Other CleanEx database Probes Probe RBL2 Related clones (RZPD - Berlin) PubMed PubMed 26 Pubmed reference(s) in LocusLink REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Giuseppe Russo, Antonio Giordano, Pier Paolo Claudio 2004 Citation This paper should be referenced as such : Russo G, Giordano A, Claudio PP . RBL2 (retinoblastoma-like 2). Atlas Genet Cytogenet Oncol Haematol. March 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/RBL2ID443.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -163- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TLX3 (T-cell leukemia, homeobox protein 3)

Identity Other RNX names HOX11L2 Hugo TLX3 Location 5q35.1

TLX3 (5q35.1): FISH with BAC clone ctb-45L16 (red) showing a breakpoint signal in the consensus breakpoint region split between der(5) and der(14) partners. Analysis was performed on the pediatric T-ALL cell line HPB-ALL (DSMZ ACC-483) which carries t(5;14)(q35.1;q32.2) as part of a complex 4-way rearrangement involving chromosomes 1 and 16. Normally (in the absence of secondary translocations) the breakpoints on both partners lie closely equidistant to the q-arm telomeres rendering the translocation cryptic and difficult to detect even with chromosome painting.

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -164-

Description 3 exons on 2.23 kb Transcription In a centromeric --> telomeric orientation; 876 bp mRNA (coding) Protein

Description 291 amino acids, 31.8 kDa; contains one homeobox domain (residues 166-221) Expression Narrowly restricted to brain. Localisation Probably nuclear Function Murine Tlx-3 and Tlx-1 together sustain expression of Drg-11, and control development of somatic and visceral relay sensory neurons. Homology With homeobox genes, especially with those of the NK-like family. Implicated in Entity t(5;14)(q35;q32) in T-ALL-->TLX3 - BCL11B Disease T-cell acute lymphocytic leukemia (T-ALL) Prognosis TLX3 expression may denote poor prognosis. Cytogenetics Cryptic translocation detectable by locus specific FISH. t(5;14) may exclude del(1)(p32) SIL-TAL1 fusion. Hybrid/Mutated 5' TLX3-3' BCL11B on der(14). Gene Oncogenesis Ectopic expression in T-cells

Entity t(5;14)(q35;q11) in T-ALL --> TLX3 - TCRD Disease T-cell acute lymphocytic leukemia (T-ALL) Cytogenetics Apparent variant of t(5;14) Hybrid/Mutated 5' TLX3-TCRD on der(14) Gene

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -165-

Note Within the upstream region or within the neighboring gene RanBP17. External links Nomenclature Hugo TLX3 GDB TLX3 Entrez_Gene TLX3 30012 T-cell leukemia, homeobox 3 Cards Atlas TLX3ID398 GeneCards TLX3 Ensembl TLX3 CancerGene HOX11L2 Genatlas TLX3 GeneLynx TLX3 eGenome TLX3 euGene 30012 Genomic and cartography TLX3 - 5q35.1 chr5:170668893-170671742 + 5q35.1 (hg17- GoldenPath May_2004) Ensembl TLX3 - 5q35.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TLX3 Gene and transcription

Genbank AJ223798 [ SRS ] AJ223798 [ ENTREZ ]

Genbank BC017291 [ SRS ] BC017291 [ ENTREZ ]

RefSeq NM_021025 [ SRS ] NM_021025 [ ENTREZ ]

RefSeq NT_086682 [ SRS ] NT_086682 [ ENTREZ ] AceView TLX3 AceView - NCBI

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -166- TRASER TLX3 Traser - Stanford

Unigene Hs.249125 [ SRS ] Hs.249125 [ NCBI ] HS249125 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O43711 [ SRS] O43711 [ EXPASY ] O43711 [ INTERPRO ]

Prosite PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Expasy ]

Prosite PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Expasy ]

Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ] CluSTr O43711

PF00046 Homeobox [ SRS ] PF00046 Homeobox [ Sanger Pfam ] pfam00046 [ NCBI-CDD ]

Smart SM00389 HOX [EMBL]

Prodom PD000010 Homeobox[INRA-Toulouse] Prodom O43711 TLX3_HUMAN [ Domain structure ] O43711 TLX3_HUMAN [ sequences sharing at least 1 domain ] Blocks O43711 Polymorphism : SNP, mutations, diseases OMIM 604640 [ map ] GENECLINICS 604640

SNP TLX3 [dbSNP-NCBI]

SNP NM_021025 [SNP-NCI]

SNP TLX3 [GeneSNPs - Utah] TLX3 [SNP - CSHL] TLX3] [HGBASE - SRS] General knowledge Family TLX3 [UCSC Family Browser] Browser SOURCE NM_021025 SMD Hs.249125 SAGE Hs.249125 Amigo process|development Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity PubGene TLX3 Other databases Probes Probe TLX3 Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -167- Bibliography Assignment of the HOX11L2 gene to human chromosome band 5q35.1 and of its murine homolog to mouse chromosome bands 11A4-A5 by in situ hybridization. Cinti R, Fava M, Sancandi M, Matera I, Ravazzolo R, Ceccherini I. Cytogenet Cell Genet 2001; 92(3-4):354-355. Medline 11435716

Assignment of the human homeobox 11-like 2 gene (HOX11L2) to chromosome 5q34-->q35 by radiation hybrid mapping. Lee-Kirsch MA, Engel K, Paditz E, Rosen-Wolff A, Lee YA, Gahr M. Cytogenet Cell Genet 2001; 92(3-4): 358. Medline 11435718

A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia. Bernard OA, Busson-LeConiat M, Ballerini P, Mauchauffe M, Della Valle V, Monni R, Nguyen Khac F, Mercher T, Penard-Lacronique V, Pasturaud P, Gressin L, Heilig R, Daniel MT, Lessard M, Berger R. Leukemia 2001; 15(10): 1495-1504. Medline 11587205

Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm FG, Pui CH, Downing JR, Gilliland DG, Lander ES, Golub TR, Look AT. Cancer Cell 2002; 1(1): 75-87. Medline 12086890

HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. Ballerini P, Blaise A, Busson-Le Coniat M, Su XY, Zucman-Rossi J, Adam M, van den Akker J, Perot C, Pellegrino B, Landman-Parker J, Douay L, Berger R, Bernard OA. Blood 2002; 100(3): 991-997. Medline 12130513

Disruption of the RanBP17/Hox11L2 region by recombination with the TCRdelta locus in acute lymphoblastic leukemias with t(5;14)(q34;q11). Hansen-Hagge TE, Schafer M, Kiyoi H, Morris SW, Whitlock JA, Koch P, Bohlmann I, Mahotka C, Bartram CR, Janssen JW. Leukemia 2002; 16(11): 2205-2212. Medline 12399963

High incidence of Hox11L2 expression in children with T-ALL.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -168- Mauvieux L, Leymarie V, Helias C, Perrusson N, Falkenrodt A, Lioure B, Lutz P, Lessard M. Leukemia 2002; 16(12): 2417-2422. Medline 12454747

Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG. Genes Chromosomes Cancer 2003; 37(1): 84-91. Medline 12661009 t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Berger R, Dastugue N, Busson M, Van Den Akker J, Perot C, Ballerini P, Hagemeijer A, Michaux L, Charrin C, Pages MP, Mugneret F, Andrieux J, Talmant P, Helias C, Mauvieux L, Lafage-Pochitaloff M, Mozziconacci MJ, Cornillet-Lefebvre P, Radford I, Asnafi V, Bilhou-Nabera C, Nguyen Khac F, Leonard C, Speleman F, Poppe B, Bastard C, Taviaux S, Quilichini B, Herens C, Gregoire MJ, Cave H, Bernard OA; Groupe Francais de Cytogenetique Hematologique (GFCH). Leukemia 2003; 17(9): 1851-1857. Medline 12970786

The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Nagel S, Kaufmann M, Drexler HG, MacLeod RA. Cancer Res 2003; 63(17): 5329-5334. Medline 14500364

Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951. Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A, Malet M, Boutard P, Benoit Y, Mauvieux L, Lutz P, Mechninaud F, Grardel N, Mazingue F, Dupont M, Margueritte G, Pages MP, Bertrand Y, Plouvier E, Brunie G, Bastard C, Plantaz D, Velde IV, Hagemeijer A, Speleman F, Lessard M, Otten J, Vilmer E, Dastugue N. Blood 2004; 103: 442-450 Medline 14504110

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Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -169- Written 03- Roderick AF MacLeod, Stefan Nagel 2004 Citation This paper should be referenced as such : MacLeod RAF, Nagel S . TLX3 (T-cell leukemia, homeobox protein 3). Atlas Genet Cytogenet Oncol Haematol. March 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TLX3ID398.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -170- Atlas of Genetics and Cytogenetics in Oncology and Haematology

COX6C (cytochrome c oxidase subunit VIc)

Identity Other Cytochrome c oxidase polypeptide VIc precursor names Hugo COX6C Location 8q22.2 DNA/RNA Description The gene spans 15.5 kb; orientation : reverse strand; 4 exons; this cytochrome C oxidase subunit 6c is encoded by the nuclear DNA (some other subunits are encoded by the mitochondrial DNA). Protein

Description 75 amino acids, 8.8 kDa; contains a transmembrane domain Expression wide Localisation mitochondria (inner membrane) Function subunit of the cytochrome C oxidase (respiratory chain complex of the mitochondria); catalytic activity. Implicated in Entity Uterine fibromyoma Disease The most common benign tumors of the female genital tract. Hybrid/Mutated HMGA2 HMGA2 exon 3 was found fused to COX6C exon 2 in one Gene case without cytogenetic analysis; HMGA2 (previously named HMGIC), sitting in 12q15, is the most frequently involved gene in uterine leiomyoma. Abnormal The 3 N-term DNA binding domains (AT hooks) of HMGA2 is fused Protein to the C-term of COX6C

External links Nomenclature Hugo COX6C GDB COX6C Entrez_Gene COX6C 1345 cytochrome c oxidase subunit VIc Cards Atlas COX6CID251

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -171- GeneCards COX6C Ensembl COX6C CancerGene COX6C Genatlas COX6C GeneLynx COX6C eGenome COX6C euGene 1345 Genomic and cartography COX6C - 8q22.2 chr8:100959548-100975071 - 8q22.2 (hg17- GoldenPath May_2004) Ensembl COX6C - 8q22.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene COX6C Gene and transcription

Genbank AF067636 [ SRS ] AF067636 [ ENTREZ ]

Genbank AF067637 [ SRS ] AF067637 [ ENTREZ ]

Genbank BC000187 [ SRS ] BC000187 [ ENTREZ ]

Genbank BT007007 [ SRS ] BT007007 [ ENTREZ ]

Genbank S82616 [ SRS ] S82616 [ ENTREZ ]

RefSeq NM_004374 [ SRS ] NM_004374 [ ENTREZ ]

RefSeq NT_086743 [ SRS ] NT_086743 [ ENTREZ ] AceView COX6C AceView - NCBI TRASER COX6C Traser - Stanford

Unigene Hs.351875 [ SRS ] Hs.351875 [ NCBI ] HS351875 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P09669 [ SRS] P09669 [ EXPASY ] P09669 [ INTERPRO ]

Interpro IPR004204 COX6C [ SRS ] IPR004204 COX6C [ EBI ] CluSTr P09669 Pfam PF02937 COX6C [ SRS ] PF02937 COX6C [ Sanger ] pfam02937 [ NCBI- CDD ]

Prodom PD015032 COX6C[INRA-Toulouse] Prodom P09669 COXH_HUMAN [ Domain structure ] P09669 COXH_HUMAN [ sequences sharing at least 1 domain ] Blocks P09669 Polymorphism : SNP, mutations, diseases OMIM 124090 [ map ] GENECLINICS 124090

SNP COX6C [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -172- SNP NM_004374 [SNP-NCI]

SNP COX6C [GeneSNPs - Utah] COX6C [SNP - CSHL] COX6C] [HGBASE - SRS] General knowledge Family COX6C [UCSC Family Browser] Browser SOURCE NM_004374 SMD Hs.351875 SAGE Hs.351875

Enzyme 1.9.3.1 [ Enzyme-SRS ] 1.9.3.1 [ Brenda-SRS ] 1.9.3.1 [ KEGG ] 1.9.3.1 [ WIT ] Amigo function|cytochrome-c oxidase activity Amigo process|electron transport Amigo component|inner membrane Amigo component|integral to membrane Amigo component|mitochondrion Amigo function|oxidoreductase activity KEGG Oxidative Phosphorylation PubGene COX6C Other databases Probes Probe COX6C Related clones (RZPD - Berlin) PubMed PubMed 5 Pubmed reference(s) in LocusLink Bibliography Structural organization and transcription regulation of nuclear genes encoding the mammalian cytochrome c oxidase complex. Lenka N, Vijayasarathy C, Mullick J, Avadhani NG. Prog Nucleic Acid Res Mol Biol. 1998; 61: 309-344. Medline 9752724

Novel gene fusion of COX6C at 8q22-23 to HMGIC in a uterine leiomyoma. Kurose K, Mine N, Doi D, Ota Y, Yoneyama K, Konoshi H, Araki T, Emi M. Genes Chromosomes Cancer 2000; 27: 303-307. Medline 10679920

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Jean-Loup Huret, Sylvie Senon

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -173- 2004 Citation This paper should be referenced as such : Huret JL, Senon S . COX6C (cytochrome c oxidase subunit VIc). Atlas Genet Cytogenet Oncol Haematol. April 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/COX6CID251.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -174- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NTRK3

Identity Other TrkC names Neurotrophin 3 Receptor Hugo NTRK3 Location 15q25 DNA/RNA Description The gene for NTRK3 is located on chromosome 15 q25 and is encoded by 20 exons. Exon 1 codes for the translation initiation codon (ATG) and the signal sequence (SS), while the stop codon is located in exon 18. Exons 1 to 4 encode the Neurotrophin ligand binding domain (also known a the Immunoglobulin - like domain 2). Exons 10 and 11 encode the transmembrane domain while the tyrosine kinase domain is encoded by exons 13-18. Pseudogene Variant transcripts exist for NTRK3, which have been termed noncatalytic (NC) as they do not contain enough sequence to mount an appropriate autophosphorylation event. These have been named NTRK3-NC1 and NTRK3 NC2. Protein

The NTRK3 protein is composed of several regions. Starting at the amino terminus is the signal sequence (SS) responsible for directing the newly translated protein to the cell surface. Next is the Extracellular Ligand Binding Domain (ECD-LB), which binds Neurotrophin 3 and subsequent homo-dimerization with autophosphorylation of key tyrosine residues. The transmembrane domain (TM) spans the plasma membrane. The intracellular portion is composed of the protein tyrosine kinase domain (PTK) which has both the key tyrosines for autophosphorylation as well as tyrosines that are phosphorylated and act as activators of downstream molecules including Shc, PI3- Kinase and PLC-g.

Description 145 kDa protein, located on plasma membrane with an extra-cellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Ligand for NTRK3 is Neurotrophin 3; after binding to NTRK3, it causes dimerization and autophosphorylation of specific tyrosine phosphates, which in turn act as anchors and activators of downstream molecules such as Shc, PI3-K and PLC-g.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -175- Expression Primarily in central nervous system tissue with specific emphasis in hippocampus, cerebral cortex, and the granular cell layer of the cerebellum. In addition, there is a minor amount expressed in a variety of other tissues. Localisation Plasma membrane; transmembrane receptor tyrosine kinase. Function Tyrosine kinase cell surface receptor responsible for the proliferation and differentiation of neuraly derived cells; Homology Acid sequence is 97% and 98% homologous to the rat and porcine TRKC sequences, respectively. Implicated in Entity Medulloblastoma Note Over-expression of NTRK3 mRNA was found to be associated with a much favorable prognosis over medulloblastomas with a comparatively low expression of NTRK3.

Entity Congenital Fibrosarcoma (CFS) and Congenital Mesoblastic Nephroma-cellular variant (cellular CMN). Disease CFS and cellular CMN are pediatric tumors of spindle cell origin (mesoblastic origin). CFS primarily presents at birth up to 2 years of age, usually affecting the extremities. Cellular CMN, on the other hand is a pediatric spindle cell tumor of the kidney. Prognosis The presence of the ETV6-NTRK3 gene fusion in both CFS and cellular CMN indicate an excellent prognosis when compared to their histologically similar and more aggressive counterparts. Cytogenetics The ETV6-NTRK3 gene fusion is the result of a t(12;15)(p13;q25).

The amino terminus is composed of the first 5 exons from ETV6, which carries the Helix-Loop-Helix Domain (HLH) responsible for dimerization. The remainder of the protein is composed of the Protein Tyrosine Kinase domain from NTRK3. The arrow represents the point at which the ETV6 contribution ends and the NTRK3 contribution begins.

Hybrid/Mutated ETV6-NTRK3 Gene Oncogenesis Current speculation regarding the oncogenic mechanism of the fusion protein is related to its putative activation of the MAP Kinase pathway with resultant activation of various downstream proteins such as transcription factors. Native NTRK3 requires extracellular ligand binding of Neurotrophin 3 prior to its dimerization and autophosphorylation. ETV-6-NTRK3, however, bypasses this requirement as it contains the HLH domain from ETV6 which allows the molecule to dimerize in the absence of Neurotrophin 3 and thus

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -176- remain in a constitutively activated (phosphorylated) state. Once again, the presence of ETV6-NTRK3 seems to make these particular neoplasms behave more indolent than their aggressive Ductal Carinoma counterparts, which do not harbor the ETV6-NTRK3 gene fusion.

Entity Secretory Breast Carcinoma (a variant of ductal carcinoma of the breast) Note Virtually all cases of CFS and cellular CMN to date have been associated with the ETV6-NTRK3 gene fusion. In addition these malignancies almost always have an additional copy of chromosome 11. This additional copy of chromosome 11 is not found in secretory breast carcinoma. Finally, the ETV6-NTRK3 gene fusion was found in secretory breast carcinomas of all ages (the youngest case being a 6 year old female). Disease Secretory Breast Carcinoma is an epithelially derived breast cancer, as opposed to the mesoblastic CFS and cellular CMN above. It can occur in the pediatric population and much more commonly in adults. Cytogenetics The ETV6-NTRK3 gene fusion is the result of a t(12;15)(p13;q25). Hybrid/Mutated ETV6-NTRK3 Gene Please see above diagrams and explanations for the protein and proposed oncogenic mechanism.

External links Nomenclature Hugo NTRK3 GDB NTRK3 Entrez_Gene NTRK3 4916 neurotrophic tyrosine kinase, receptor, type 3 Cards Atlas NTRK3ID433 GeneCards NTRK3 Ensembl NTRK3 CancerGene NTRK3 Genatlas NTRK3 GeneLynx NTRK3 eGenome NTRK3 euGene 4916 Genomic and cartography NTRK3 - 15q25 chr15:86321602-86600665 - 15q25.3 (hg17- GoldenPath May_2004) Ensembl NTRK3 - 15q25.3 [CytoView]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -177- NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NTRK3 Gene and transcription

Genbank AJ224521 [ SRS ] AJ224521 [ ENTREZ ]

Genbank AF052184 [ SRS ] AF052184 [ ENTREZ ]

Genbank AF058389 [ SRS ] AF058389 [ ENTREZ ]

Genbank AY065844 [ SRS ] AY065844 [ ENTREZ ]

Genbank BC013693 [ SRS ] BC013693 [ ENTREZ ]

RefSeq NM_001007156 [ SRS ] NM_001007156 [ ENTREZ ]

RefSeq NM_001012338 [ SRS ] NM_001012338 [ ENTREZ ]

RefSeq NM_002530 [ SRS ] NM_002530 [ ENTREZ ]

RefSeq NT_086832 [ SRS ] NT_086832 [ ENTREZ ] AceView NTRK3 AceView - NCBI TRASER NTRK3 Traser - Stanford

Unigene Hs.410969 [ SRS ] Hs.410969 [ NCBI ] HS410969 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q16288 [ SRS] Q16288 [ EXPASY ] Q16288 [ INTERPRO ]

Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 Prosite PROTEIN_KINASE_TYR [ Expasy ]

PS00239 RECEPTOR_TYR_KIN_II [ SRS ] PS00239 Prosite RECEPTOR_TYR_KIN_II [ Expasy ]

Interpro IPR003599 Ig [ SRS ] IPR003599 Ig [ EBI ]

Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR001611 LRR [ SRS ] IPR001611 LRR [ EBI ]

Interpro IPR000483 LRR_Cterm [ SRS ] IPR000483 LRR_Cterm [ EBI ]

Interpro IPR000372 LRR_Nterm [ SRS ] IPR000372 LRR_Nterm [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ]

Interpro IPR002011 RecepttyrkinsII [ SRS ] IPR002011 RecepttyrkinsII [ EBI ]

Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]

Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ] CluSTr Q16288

Pfam PF00047 ig [ SRS ] PF00047 ig [ Sanger ] pfam00047 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -178- Pfam PF00560 LRR [ SRS ] PF00560 LRR [ Sanger ] pfam00560 [ NCBI-CDD ] Pfam PF01462 LRRNT [ SRS ] PF01462 LRRNT [ Sanger ] pfam01462 [ NCBI- CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00409 IG [EMBL]

Smart SM00082 LRRCT [EMBL]

Smart SM00013 LRRNT [EMBL]

Smart SM00219 TyrKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom Q16288 NTRK3_HUMAN [ Domain structure ] Q16288 NTRK3_HUMAN [ sequences sharing at least 1 domain ] Blocks Q16288

PDB 1WWC [ SRS ] 1WWC [ PdbSum ], 1WWC [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 191316 [ map ] GENECLINICS 191316

SNP NTRK3 [dbSNP-NCBI]

SNP NM_001007156 [SNP-NCI]

SNP NM_001012338 [SNP-NCI]

SNP NM_002530 [SNP-NCI]

SNP NTRK3 [GeneSNPs - Utah] NTRK3 [SNP - CSHL] NTRK3] [HGBASE - SRS] General knowledge Family NTRK3 [UCSC Family Browser] Browser SOURCE NM_001007156 SOURCE NM_001012338 SOURCE NM_002530 SMD Hs.410969 SAGE Hs.410969

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -179- Amigo function|protein serine/threonine kinase activity Amigo function|receptor activity Amigo function|transferase activity Amigo function|transmembrane receptor protein tyrosine kinase activity process|transmembrane receptor protein tyrosine kinase signaling Amigo pathway process|transmembrane receptor protein tyrosine kinase signaling Amigo pathway PubGene NTRK3 Other databases Probes Probe NTRK3 Related clones (RZPD - Berlin) PubMed PubMed 18 Pubmed reference(s) in LocusLink Bibliography The Trk family of neurotrophin receptors. Barbacid M. J Neurobiol 1994; 25(11): 1386-1403. Review. Medline 7852993

Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant. McGregor LM, Baylin SB, Griffin CA, Hawkins AL, Nelkin BD. Genomics 1994; 22: 267-272. Medline 7806211

Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL. Proc Nat Acad Sci 1994; 91: 12867-12871. Medline 7809137

Genomic characterization of the human trkC gene. Ichaso N, Rodriguez RE, Martin-Zanca D, Gonzalez-Sarmiento R. Oncogene 1998; 17(14): 1871-1875. Medline 9778053

ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH. Cancer Res 1998; 58(22): 5046-5048. Medline 9823307

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -180- A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PHB. Nature Genet 1998; 18: 184-187. Medline 9462753

Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association. Menn B, Timsit S, Calothy G, Lamballe F. J Comp Neurol 1998; 401(1): 47-64. Medline 9802700

Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH. Cancer Cell 2002; 2(5): 367-376. Medline 12450792

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Stevan Knezevich 2004 Citation This paper should be referenced as such : Knezevich S . NTRK3. Atlas Genet Cytogenet Oncol Haematol. April 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NTRK3ID433.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -181- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PRDM16 (PR domain containing 16)

Identity Other MEL1 (MDS1/EVI1-like gene) names PR-domain zinc finger protein 16 Hugo PRDM16 Location 1p36.3; orientation plus strand DNA/RNA Description spans 369 kb; 17exons; 3827 bp coding sequence. Transcription alternative transcripts MEL1 and MEL1S (MEL1 short) Protein

Description 17O kDa (MEL1) and 150 Da (MEL1S); like MDS1/EVI1, The MEL1contains a PR domain (homologous to the SET domain present in MLL ) in the N term, two DNA binding domains (made of 7 and 3 zing fingers) separated by a repression domain, and an acidic domain at the C-term. MEL1S lacks the PR domain, like EVI1 alone. MEL1 and MEL1S, in a "yin-yang fashion", are hypothezised to display antagonistic properties; the PR domain may act as an inhibitor of tumorigenesis. Expression wide, contrarily to what was previously found Localisation nuclear Homology 63% homology with MDS1/EVI1; both are members of the PR domain family Implicated in Entity t(1;3)(p36;q21) myeloid leukemias --> involving RPN1 and MEL1 Disease myelodysplastic syndromes (MDS), acute non lymphoblastic leukemias (ANLL), therapy-related leukemias and myeloprolifrative syndromes; with features similar to those of the 3q21q26 syndrome, including megakaryocytic dysplasia (see also 3q rearrangements in myeloid malignancies). Prognosis very poor Hybrid/Mutated juxtaposition of the enhancer of the constitutively expressed Gene housekeeping gene RPN1, normally sitting in 3q21, in 5' of MEL1 on der(1); both genes are orientated telomere to centromere; the same

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -182- situation occurs between RPN1 in 5' of EVI1 in the t(3;3)(q21;q26) ) Oncogenesis the translocation results in either an ectopic expression of MEL1 driven by RPN1or by disruption of its PR domain; this probable heterogenity may be associated with different clinical features. The short form, MEL1S, is mainly expressed

External links Nomenclature Hugo PRDM16 GDB PRDM16 Entrez_Gene PRDM16 63976 PR domain containing 16 Cards Atlas PRDM16MEL1ID408 GeneCards PRDM16 Ensembl PRDM16 CancerGene PRDM16 Genatlas PRDM16 GeneLynx PRDM16 eGenome PRDM16 euGene 63976 Genomic and cartography PRDM16 - 1p36.3; orientation plus strand chr1:3008901-3378340 GoldenPath + 1p36.32 (hg17-May_2004) Ensembl PRDM16 - 1p36.32 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PRDM16 Gene and transcription

Genbank AL008733 [ SRS ] AL008733 [ ENTREZ ]

Genbank AL354743 [ SRS ] AL354743 [ ENTREZ ]

Genbank AL512383 [ SRS ] AL512383 [ ENTREZ ]

Genbank AL590438 [ SRS ] AL590438 [ ENTREZ ]

Genbank AB051462 [ SRS ] AB051462 [ ENTREZ ]

RefSeq NM_022114 [ SRS ] NM_022114 [ ENTREZ ]

RefSeq NM_199454 [ SRS ] NM_199454 [ ENTREZ ]

RefSeq NT_086572 [ SRS ] NT_086572 [ ENTREZ ] AceView PRDM16 AceView - NCBI TRASER PRDM16 Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -183- Unigene Hs.99500 [ SRS ] Hs.99500 [ NCBI ] HS99500 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9HAZ2 [ SRS] Q9HAZ2 [ EXPASY ] Q9HAZ2 [ INTERPRO ]

Prosite PS50280 SET [ SRS ] PS50280 SET [ Expasy ]

PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 Prosite ZINC_FINGER_C2H2_1 [ Expasy ]

PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 Prosite ZINC_FINGER_C2H2_2 [ Expasy ]

Interpro IPR001214 SET [ SRS ] IPR001214 SET [ EBI ]

Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr Q9HAZ2 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ]

Smart SM00317 SET [EMBL]

Smart SM00355 ZnF_C2H2 [EMBL]

Prodom PD000003 Znf_C2H2[INRA-Toulouse] Prodom Q9HAZ2 PRDG_HUMAN [ Domain structure ] Q9HAZ2 PRDG_HUMAN [ sequences sharing at least 1 domain ] Blocks Q9HAZ2 Polymorphism : SNP, mutations, diseases OMIM 605557 [ map ] GENECLINICS 605557

SNP PRDM16 [dbSNP-NCBI]

SNP NM_022114 [SNP-NCI]

SNP NM_199454 [SNP-NCI]

SNP PRDM16 [GeneSNPs - Utah] PRDM16 [SNP - CSHL] PRDM16] [HGBASE - SRS] General knowledge Family PRDM16 [UCSC Family Browser] Browser SOURCE NM_022114 SOURCE NM_199454 SMD Hs.99500 SAGE Hs.99500 Amigo function|DNA binding Amigo component|nucleus Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity Amigo function|zinc ion binding

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -184- PubGene PRDM16 Other databases Probes Probe PRDM16 Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography

A novel gene MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K. Blood 2000; 96: 3209-3214. Medline 11050005

A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. Nishikata I, Sasaki H, Iga M, Tateno Y, Imayoshi S, Asou N, Nakamura T, Morishita K. Blood. 2003; 102: 3323-3332. Medline 12816872

Breakpoints at 1p36.3 in three MDS/AML(M4) patients with t(1;3)(p36;q21) occur in the first intron and in the 5' region of MEL1. Xinh PT, Tri NK, Nagao H, Nakazato H, Taketazu F, Fujisawa S, Yagasaki F, Chen YZ, Hayashi Y, Toyoda A, Hattori M, Sakaki Y, Tokunaga K, Sato Y. Genes Chromosomes Cancer. 2003; 36: 313-316. Medline 12557231

Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells. Lahortiga I, Agirre X, Belloni E, Vazquez I, Larrayoz MJ, Gasparini P, Coco FL, Pelicci PG, Calasanz MJ, Odero MD. Oncogene. 2004; 23: 311-316. Medline 14712237

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Jean-Loup Huret, Sylvie Senon

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -185- 2004 Citation This paper should be referenced as such : Huret JL, Senon S . PRDM16 (PR domain containing 16). Atlas Genet Cytogenet Oncol Haematol. April 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PRDM16MEL1ID408.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -186- Atlas of Genetics and Cytogenetics in Oncology and Haematology

SNAI2 (SNAIL HOMOLOG 2)

Identity Other SLUG names SLUGH Neural Crest Transcription Factor SLUG Location 8q11.21

DNA/RNA Description SNAI2 is a neurogenic transcription factor belonging to the SNAIL family implicated in the epithelial-mesenchymal transition and cell survival, in important morphogenetic processes during embryo development and in tumor metastasis. The gene has 3 exons (243bp, 546bp,1299bp). Transcription Transcript length: 2.2Kb. Protein

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -187-

Description SNAI2 is a zinc-finger transcription factor. Translation length: 268 residues (79bp 1st exon, 546bp 2nd exon, 181bp 3rd exon). Zinc-finger information : Type: C2H2 ; Number of domains: 5. 1st(from residue 128 to 150) 2nd(from residue 159 to 181) 3rd(from residue 185 to 207) 4th(from residue 213 to 235) 5th(from residue 241 to 264) Expression Placenta, adult heart, pancreas, liver, kidney and skeletal muscle. Localisation Nuclear (probable). Function Transcriptional repressor implicated in the epithelial-mesenchymal transition and cell survival. Homology The human SLUG protein is 95, 93, and 88% homologous to mouse, chicken, and Xenopus slug, respectively, but it shows only 47% homology to mouse Snail. The zinc finger region is 100% identical between human and mouse Slug. Implicated in Note SNAI2 is a vertebrate gene encoding a zinc finger protein of the Snail family implicated in the epithelial-mesenchymal transition and cell survival. It was identified in the neural crest and in mesodermal cells emigrating from the primitive streak in chick embryos. It is involved in chick limb development and has conserved and divergent roles in the chick and mouse embryo. Human SNAI2 maps to the long arm of chromosome 8 (8q11.21), contains 3 exons and codes for a protein of 268bp (29KDa) with 5 zinc finger regions. This gene has been identified as downstream target of E2A-HLF oncoprotein and its expression is strongly correlated with loss of E-cadherin. SNAI2 contributes to the function of the stem cell factor c-kit signaling pathway and mediates the radioresistance biological function of the SCF/kit. The alterations of this gene have been associated to different human syndromes. Disease Missense mutation has been identified in patients with neural tube defects. Deletions of the SNAI2 gene results in human piebaldism, a cancer prone disease, and has been detected in patients with Waardenburg disease. Duplication of SNAI2 gene is implicated in a rare congenital heart disease (data submitted).

External links Nomenclature GDB SNAI2 Entrez_Gene SNAI2 6591 snail homolog 2 (Drosophila) Cards Atlas SNAI2ID453 GeneCards SNAI2

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -188- Ensembl SNAI2 CancerGene SNAI2 Genatlas SNAI2 GeneLynx SNAI2 eGenome SNAI2 euGene 6591 Genomic and cartography SNAI2 - 8q11.21 chr8:49992796-49996541 - 8q11.21 (hg17- GoldenPath May_2004) Ensembl SNAI2 - 8q11.21 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene SNAI2 Gene and transcription

Genbank AF042001 [ SRS ] AF042001 [ ENTREZ ]

Genbank AF084243 [ SRS ] AF084243 [ ENTREZ ]

Genbank AA410443 [ SRS ] AA410443 [ ENTREZ ]

Genbank BC014890 [ SRS ] BC014890 [ ENTREZ ]

Genbank BC015895 [ SRS ] BC015895 [ ENTREZ ]

RefSeq NM_003068 [ SRS ] NM_003068 [ ENTREZ ]

RefSeq NT_086742 [ SRS ] NT_086742 [ ENTREZ ] AceView SNAI2 AceView - NCBI TRASER SNAI2 Traser - Stanford

Unigene Hs.360174 [ SRS ] Hs.360174 [ NCBI ] HS360174 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O43623 [ SRS] O43623 [ EXPASY ] O43623 [ INTERPRO ]

PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 Prosite ZINC_FINGER_C2H2_1 [ Expasy ]

PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 Prosite ZINC_FINGER_C2H2_2 [ Expasy ]

Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr O43623 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ]

Smart SM00355 ZnF_C2H2 [EMBL]

Prodom PD000003 Znf_C2H2[INRA-Toulouse] Prodom O43623 SLUG_HUMAN [ Domain structure ] O43623 SLUG_HUMAN [ sequences sharing at least 1 domain ] Blocks O43623 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -189- OMIM 602150 [ map ] GENECLINICS 602150

SNP SNAI2 [dbSNP-NCBI]

SNP NM_003068 [SNP-NCI]

SNP SNAI2 [GeneSNPs - Utah] SNAI2 [SNP - CSHL] SNAI2] [HGBASE - SRS] General knowledge Family SNAI2 [UCSC Family Browser] Browser SOURCE NM_003068 SMD Hs.360174 SAGE Hs.360174 Amigo function|DNA binding Amigo process|development Amigo process|ectoderm and mesoderm interaction Amigo process|negative regulation of transcription from Pol II promoter Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|zinc ion binding PubGene SNAI2 Other databases Probes PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Nieto MA, Sargent MG, Wilkinson DG, Cooke J. Science 1994; 264 (5160): 835-839.

Slug, a zinc finger gene previously implicated in the early patterning of the mesoderm and the neural crest, is also involved in chick limb development. Ros MA, Sefton M, Nieto MA. Development 1997; 124(9): 1821-1829. Medline 9165129

Human SLUG gene organization, expression, and chromosome map location on 8q. Cohen ME, Yin M, Paznekas WA, Schertzer M, Wood S, Jabs EW. Genomics 1998; 51(3): 468-471. Medline 9721220

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -190- Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Sefton M, Sanchez S, Nieto MA. Development 1998; 125(16): 3111-3121. Medline 9671584

SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K, Mao M, Inaba T, LookAT. Mol Cell 1999; 4(3): 343-352. Medline 10518215

Human transcription factor SLUG: mutation analysis in patients with neural tube defects and identification of a missense mutation (D119E) in the Slug subfamily-defining region. Stegmann K, Boecker J, Kosan C, Ermert A, Kunz J, Koch MC. Mutat Res 1999; 406(2-4): 63-69. Medline 10479723

The SLUG zinc-finger protein represses E-cadherin in breast cancer. Hajra KM, Chen DY, Fearon ER. Cancer Res 2002; 62(6): 1613-1618. Medline 11912130

Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Inoue A, Seidel MG, Wu W, Kamizono S, Ferrando AA, Bronson RT, Iwasaki H, Akashi K, Morimoto A, Hitzler JK, Pestina TI, Jackson CW, Tanaka R, Chong MJ, McKinnon PJ, Inukai T, Grosveld GC, Look AT. Cancer Cell 2002; 2(4): 279-288. Medline 12398892

Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway. Perez-Losada J, Sanchez-Martin M, Rodriguez-Garcia A, Sanchez ML, Orfao A, Flores T, Sanchez-Garcia I. Blood 2002; 100(4): 1274-1286. Medline 12149208

SLUG (SNAI2) deletions in patients with Waardenburg disease. Sanchez-Martin M, Rodriguez-Garcia A, Perez-Losada J, Sagrera A, Read AP, Sanchez-Garcia I. Hum Mol Genet 2002; 11(25): 3231-3236. Medline 12444107

The radioresistance biological function of the SCF/kit signaling pathway is

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -191- mediated by the zinc-finger transcription factor Slug. Perez-Losada J, Sanchez-Martin M, Perez-Caro M, Perez-Mancera PA, Sanchez- Garcia I. Oncogene 2003; 22(27): 4205-4211. Medline 12833143

Deletion of the SLUG (SNAI2) gene results in human piebaldism. Sanchez-Martin M, Perez-Losada J, Rodriguez-Garcia A, Gonzalez-Sanchez B, Korf BR, Kuster W, Moss C, Spritz RA, Sanchez-Garcia I. Am J Med Genet 2003; 122A(2): 125-132. Medline 12955764

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Manuel Sánchez-Martín, Inés González-Herrero, Isidro 2004 Sánchez-García. Citation This paper should be referenced as such : Sánchez-Martín M, González-Herrero I, Sánchez-García I . SNAI2 (SNAIL HOMOLOG 2). Atlas Genet Cytogenet Oncol Haematol. April 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SNAI2ID453.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -192- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Castleman's disease

Identity Other Angiofollicular lymph node hyperplasia names Clinics and Pathology Phenotype / The disease appears to be polyclonal in origin in the majority of cases, cell stem however evidence for clonal expansion was documented in some origin cases, possibly representing transformation into non Hodgkin's lymphoma. In approximately 1/3 of the cases studied a monoclonal IgH rearrangement was documented. A minor T-cell clone, mostly in a polyclonal background, was also documented in some cases. Epidemiology The disease is very rare. Clinics The disease may present as a solitary mass frequently occurring in the mediastinum or as a systemic disorder (multicentric Castleman's disease) with diffuse adenopathies, systemic symptoms and recurrent infections. Splenomegaly, hepatomegaly and neurologic symptoms may occur frequently as is the case with autoimmune manifestations. Pathology There are two variants: the hyaline-vascular and the plasma cell subtype. In the former subtype there are shrunken germinal centres with concentric expansion of the mantle zones with eosinophils and hyalinization around the vessels; in the latter subtype an extensive infiltrate by plasma cells is seen in the interfollicular areas. Some patients may be infected by human herpervirus-8 which may induce interleuchin-6 (IL6) overproduction. IL6 is believed to play an essential role in the pathogenesis of the disease.

The hyaline-vascular type is usually diagnosed in asymptomatic patients whereas systemic symptoms are present in the majority of patients with the plasma cell subtype. Patients with "multicentric" Castleman disease show histologic features consistent with the plasma cell subtype. Treatment The patients can be treated by surgical excision if the mass is localized. Steroid treatment is recommended in cases with disseminated disease and combination chemotherapy utilized for lymphoma must be reserved to unresponsive patients. Some patients with HIV associated Castleman's disease were successfully treated with the anti CD20 monoclonal antibody or with the antiviral agent ganciclovir targeting the HHV-8.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -193- Prognosis The prognosis varies greatly depending on the histologic type and disease presentation. If the disease is localized, surgery with or without radiotherapy may be curative. Those patients with multicentric disease who fail to respond to steroid treatment have a serious disease. Cytogenetics Cytogenetics Many of the cases so far studied showed a normal karyotyope. Morphological Occasional abnormalities were found in a few patients. One case with the hyaline vascular type showed a t(1;6)(p11;p11), a del(7)(q21q22) and a del(8)(q12q22). In this patient no clonal expansion of lymphoid cells was present, suggesting that the clonal proliferation involved dysplastic stromal cells. Another patient was shown to carry a clonal abnormality in CD21- positive follicular dendritic cells. Abnormal chromosomes in this patient were add(1)(q21), der(6)t(6;12)(q23;q15), add(7)(p22), -9, inv(9)p11q13), del(12)(q15). One patient carried a t(7;14)(p22;q22).

Bibliography Clonal rearrangement for immunoglobulin and T-cell receptor genes in systemic Castleman's disease. Association with Epstein-Barr virus. Hanson CA, Frizzera G, Patton DF, Peterson BA, McClain KL, Gajl-Peczalska KJ, Kersey JH. Am J Pathol 1988; 131: 84-91. Medline 2833104

Atypical lymphoproliferative diseases. Greiner T, Armitage J, Gross T. American Society of Hematology Educational book, 1992.

Chromosomal abnormalities in Castleman's disease with high levels of serum interleukin-6. Nakamura H, Nakaseko C, Ishii A, Kogure K, Kawano E, Hashimoto S, Nishimura M, Matsuura Y, Oh H, Yoshida S, et al. Rinsho Ketsueki 1993; 34: 212-217. Medline 8492420

Molecular analysis of clonality in Castleman's disease. Soulier J, Grollet L, Oksenhendler E, Miclea JM, Cacoub P, Baruchel A, Brice P, Clauvel JP, d'Agay MF, Raphael M. Blood 1995; 86: 1131-1138. Medline 7620166

A chromosomal abnormality in hyaline vascular Castleman's disease: evidence for clonal proliferation of dysplastic stromal cells. Pauwels P, Dal Cin P, Vlasveld LT, Aleva RM, van Erp WF, Jones D.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -194- Am J Surg Pathol 2000; 24: 882-888. Medline 10843293

Atypical lymphoproliferative disorders. Frizzera G. In Knowles DM (Ed) Neoplastic hemopathology IInd edition. Lippincott WW Philadelphia 2001; 569-622.

Lack of cytogenetic abnormalities in Castleman's disease. Menke DM, DeWald GW. South Med J 2001; 94: 472-474. Medline 11372793

Hyaline vascular Castleman's disease with HMGIC rearrangement in follicular dendritic cells: molecular evidence of mesenchymal tumorigenesis. Cokelaere K, Debiec-Rychter M, De Wolf-Peeters C, Hagemeijer A, Sciot R. Am J Surg Pathol 2002; 26: 662-669. Medline 11979097

Remission of HHV-8 and HIV-associated multicentric Castleman's disease with ganciclovir treatment. Casper C, Nichols WG, Huang ML, Corey L, Wald A. Blood 2003 Nov 13 [Epub ahead of print] Medline 14615380

A case of multicentric Castleman's disease associated with advanced systemic amyloidosis treated with chemotherapy and anti-CD20 monoclonal antibody. Gholam D, Vantelon JM, Al-Jijakli A, Bourhis JH. Ann Hematol 2003; 82: 766-768. Medline 12898190

Rituximab therapy for HIV-associated Castleman disease. Marcelin AG, Aaron L, Mateus C, Gyan E, Gorin I, Viard JP, Calvez V, Dupin N. Blood 2003; 102: 2786-2788. Medline 12842986

Contributor(s) Written 12- Antonio Cuneo, Gianluigi Castoldi 2003

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Citation This paper should be referenced as such : Cuneo A, Castoldi G . Castleman's disease. Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/CastlemanID2123.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -196- Atlas of Genetics and Cytogenetics in Oncology and Haematology

inv(8)(p11q13)

Identity Note Two distinct clinical syndromes have been associated with the 8p11-12 region : Stem-cell myeloproliferative disorder with FGFR1 rearrangement AML M4 or M5 erythrophagocytosis-associated with MOZ rearrangement. the inv(8)(p11q13) involves MOZ

The partners of 8p11 are 8q13, 14q11, 16p13, 19q13, 22q13 and 3q27, 17q12 in a complexe translocation t(3;8;17)(q27;p11; q12). Clinics and Pathology Disease Acute myelomonocytic or monocytic leukaemia (M4, M5a, M5b FAB) with erythrophagocytosis by blasts. Acute myeloblastic leukemia M0/M1 FAB (one case). Epidemiology Rare. Young age (6 patients, median : 23.5 years) and female sexe. Cytology Morphology feature observed in AML with t(8;16). Prognosis Probably poor. Cytogenetics Cytogenetics Inv(8) (p11q13) is a variant of t(8;16) (p11;p13) Morphological Additional In one case der(10)t(1;10)(q25;p15) anomalies Genes involved and Proteins Gene MOZ Name Location 8p11 Note MOZ contains a LAP (Leukemia associated protein) zinc finger domain , a HAT domain (Histone acetyltransferase) and a acidic domain. Detection by FISH : YAC 176C9. Protein ZNF220 Monocytic leukemia zinc finger protein. 2004 amino acids and 225 kDa nuclear protein, with 2 LAP/PHD-type zinc fingers.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -197- MOZ is a histone acetyltransferase (HAT) and the founding member of the MYST family of HATs, a family that includes proteins involved in cell cycle regulation, chromatin remodeling and dosage compensation. MOZ plays an important role during hematopoiesis with his transcriptional coregulator activity. Gene TIF2 Name Location 8q13 Note Aliases : GRIP1, NCoA-2. Nuclear receptors are ligand-inductible transcription factors with three structural domains : an activation function AF-1, a DNA-binding domain and a second activation function AF-2 that is mediated by nuclear coactivators (NRCoAs) : TIF2 was recently shown to be one such mediators of AF-2 function. Detection by FISH : PAC clone 192D10 Protein The TIF-2 protein is homologous to other NRCoAs specically SRC-1 (alias NcoA-1). This protein have HAT activity and also interacts directly with CBP. It is likely that TIF-2 mediates transcriptional activation by a mechanism involving chromatin remodeling. Result of the chromosomal anomaly Hybrid The fusion gene produces a mRNA containing the 5¹ end of MOZ gene appended in translational frame to the 3¹ end of TIF2. Description The inv(8) MOZ breakpoint is distinct from the breakpoint in the MOZ - CBP fusion. The fusion product retains the zinc fingers, the HAT domain of MOZ along with the HAT domains and CBP interacting domain of TIF2.

Fusion Protein MOZ-TIF2 Description Oncogenesis The ability of HATs to affect the chromatin structure and regulate gene expression is well appreciated. How the MOZ-TIF2 fusion protein is involved in acute leukemia is not known, but it probably affects the chromatin condensation. It may modulate or augment the transcriptional activity of genes normaly regulated by MOZ or it may serve as a bridge between MOZ and CBP. Recently, it was demonstrated that MOZ-TIF2 has transforming properties in vitro and causes AML. The C2HC nucleosome recognition motif of MOZ and MOZ-TIF2 interaction with CBP are essential for transformation.

External links Other inv(8)(p11q13) Mitelman database (CGAP - NCBI)

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -198- database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography A new specific chromosomal rearrangement t(8 ;16)(p11 ;p13) in acute monocytic leukaemia. Heims S, Avanzi GC, Billstrom R, Kristofferson U, Mandahl N, Mitelman F. Br J Haematol 1987; 66: 323-326. Medline 3476150

Three cases of translocation t(8 ;16)(p11 ;p13) observed in acute myelomonocytic leukaemia : a new specific subgroup? Lai JL, Zandecki M, Jouet JP, Savary KB, Lambiliotte A, Bauters F, Cosson A, Deminatti M. Cancer Genet Cytogenet 1987; 27: 101-109. Medline 3472640

FGFR1 and MOZ, two key genes invilved in malignant hemopathies linked to rearrangements within the chromosomal region 8p11-12. Pebusque MJ, Chaffanet M, Popovici C, Birnbaum D Bull Cancer 2000; 87(12): 887-894. Medline 11174118

Abnormalities of chromosome band 8p11 in leukemia : two clinical syndromes can be distinguished on the basis of MOZ involvement. Aguiar R, Chase A, Coulthard S, Macdonald D, Carapeti M, Reiter A, Sohal J, Lennard A, Goldman J, Cross N. Blood 1997; 90(8): 3130-3135. Medline 9376594

A novel fusion between MOZ and the nuclear receptor coactivator TIF-2 in acute myeloid leukemia. Carapeti M, Aguiar R, Goldman JM, Cross N. Blood, 1998, May 1 ; 91(9) : 3127-3133 Medline 9558366

MOZ-TIF2 - induced acute myeloid leukemias requires the MOZ nucleosome binding motif and TIF-2 - mediated recruitment of CBP. Deguchi K, Ayton PM, Carapeti M, Kutok JL, Snyder CS, Williams IR, Cross NC, Glass CK, Cleary ML, Gilliland DG. Cancer Cell 2003; 3(3): 259-271. Medline 12676584

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Contributor(s) Written 12- Jacques Boyer 2003

Citation This paper should be referenced as such : Boyer J . inv(8)(p11q13). Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/inv8p11q13ID1189.html

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t(7;12)(q36;p13)

Clinics and Pathology Phenotype / Mainly cases of acute myeloid leukemia (AML) of various subtypes: cell stem M0 , M1, M2, M4, M5, M6, M7, and RAEB-t. Four cases of acute origin lymphoblastic leukemia (ALL) are reported. Epidemiology at least 29 cases known; the translocation may be overlooked, and therefore underestimated; was found in 3% of children cases of ANLL, that was also 15% of infant cases of ANLL under 18 mths; sex ratio 15M/14F, age : 0-24 mths (n= 29), median 7 mth (n=29) Clinics WBC range 8-230 x 109/L, median 12 x10 9/L; organomegaly, central nervous system involvement in 3 of 6 cases Prognosis probably poor prognosis: median survival is 13 months. Of 6 cases, one case had no remission and died at 7 mths; 4 case had relapse (duration first remission 1-20 mths), 2 cases are still alive (16 mths + and 33 mths +) Cytogenetics

Left: example of FISH performed on bone marrow metaphase from a patient with t(7;12)(q36;p13). Dual colour FISH using whole chromosome paint specific for chromosome 7 (in

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -201- green) and chromosome 12 (in red) shows the reciprocal translocation. The arrow indicates the der(7) and the arrowhead indicates the der(12) - Sabrina Tosi; Right: Example of double colour FISH performed on bone marrow metaphase from a patient with t(7;12)(q36;p13). The PAC clone 1121A15 for the breakpoint region at chromosome band 7q36 (in green) and a cosmid cocktail for ETV6 at chromosome band 12p13 (in red) show one green signal for the normal chromosome 7, one red signal for the normal chromosome 12 and two fusion signals at both the derivative chromosomes 7 and 12 - Anne RM von Bergh and H. Berna Beverloo.

Cytogenetics Not always visible by chromosome banding techniques alone; may also be Morphological misdiagnosed as del(12)(p13) Cytogenetics Detectable by dual colour FISH. A cosmid cocktail or YAC 964c10 shows a split Molecular signal on the der(12) and der(7). Also the commercial probe LSI TEL/AML1 (ES) for the detection of the t(12;21) shows a split signal on the der(7) and the der(12) in the t(7;12) cases since the breakpoint in these cases falls within the first three exons, which are contained in this probe. FISH using the PAC clone RP5- 1121A15 mapping to 7q36 shows a split signal on the der(7) and der(12). Probes Chromosome 7 paint, wcp7 directly labelled with SpectrumGreen Chromosome 12 paint, wcp12 directly labelled with SpectrumOrange YAC 964c10 (CEPH, Paris) LSI TAL/AML1 (ES) PAC H_DJ1121A15 Additional +19 in 23 of 29 cases, +8 in 7 of 29 cases (+8,+19 in 6 cases) anomalies Genes involved and Proteins Gene HLXB9 Name Location 7q36 Note HLXB9 mutation are found in patients with Currarino syndrome Dna / Rna 3 exons, 2061 bp mRNA Protein 403 AA; Homeobox protein HB9; Highly expressed in CD34+ bone marrow cells; Possibly involved in the regulation of growth and differentiation of progenitor cells. Gene ETV6 Name Location 12p13 Dna / Rna 9 exons; alternate splicing Protein contains a Helix-Loop-Helix and ETS DNA binding domains; wide expression; nuclear localisation; ETS-related transcription factor Result of the chromosomal anomaly Hybrid 5' HLXB9 - 3' ETV6 gene

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -202- Description

Fusion The t(7;12) is heterogeneous at the molecular level. The presence of an Protein HLXB9-ETV6 fusion transcript has been described in only 2 out of 29 Note t(7;12) cases. Description N-terminal HLXB9, including its polyalanine repeat region, is fused to a large C-terminal part of the ETV6 protein including its HLH domain and ETS domain; the homeobox domain of HLXB9 is not retained in the fusion protein; the reciprocal transcript is not expressed.

External links Other Mitelman database t(7;12)(q36;p13) database (CGAP - NCBI) Other CancerChromosomes t(7;12)(q36;p13) database (NCBI) Probe http://www.genet.sickkids.on.ca/chromosome7

Bibliography Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies. Tosi S, Giudici G, Mosna G, Harbott J, Specchia G, Grosveld G, Privitera E, Kearney L, Biondi A. Genes Chromosom Cancer 1998; 21: 223-229. Medline 98183798

Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den Berghe H, Marynen P. Blood 1998; 91: 1399-1406. Medline 98122793

Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants. Satake N, Maseki N, Nishiyama M, Kobayashi H, Sakurai M, Inaba H, Katano N, Horikoshi Y, Eguchi H, Miyake M, Seto M, Kaneko Y. Leukemia 1999; 7:1013-1017. Medline 99326003 t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia. Tosi S, Harbott J, Teigler-Schlegel A, Haas OA, Pirc-Danoewinata H, Harrison CJ, Biondi A, Cazzaniga G, Kempski H, Scherer SW, Kearney L. Genes Chromosom Cancer 2000; 4:325-332.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -203- Medline 20519166 t(7;12)(q36;p13) and t(7;12)(q32;p13) translocations involving ETV6 in children 18 months of age or younger with myeloid disorders. Slater RM, von Drunen E, Kroes WG, Weghuis DO, van den Berg E, Smit EM, van der Does-van den Berg A, van Wering E, Hahlen K, Carroll AJ, Raimondi SC, Beverloo HB. Leukemia 2001;15(6): 915-920. Medline 21311152

Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13) Beverloo HB, Panagopoulos I, Isaksson M, van Wering E, van Drunen E, de Klein A, Johansson B, Slater R. Cancer Research 2001; 61: 5374-5377. Medline 21347207

Heterogeneity of the 7q36 breakpoints in the t(7;12) involving ETV6 in infant leukemia. Tosi S, Hughes J, Scherer SW, Nakabayashi K, Harbott J, Haas OA, Cazzaniga G, Biondi A, Kempski H, Kearney L. Genes Chromosomes Cancer 2003; 38(2): 191-200. Medline 22820333

Contributor(s) Written 04- Jean-Loup Huret 2000 Updated 06- Sabrina Tosi 2001 Updated 12- Anne RM von Bergh, H. Berna Beverloo 2003 Citation This paper should be referenced as such : Huret JL . t(7;12)(q36;p13). Atlas Genet Cytogenet Oncol Haematol. April 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0712ID1177.html Tosi S . t(7;12)(q36;p13). Atlas Genet Cytogenet Oncol Haematol. June 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0712ID1177.html von Bergh ARM, Beverloo HB . t(7;12)(q36;p13). Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0712ID1177.html

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t(8;19) (p11;q13)

Identity Note Two distinct clinical syndromes have been associated with the 8p11-p12 region : Stem-cell myeloproliferative disorder with FGFR1 rearrangement AML M4 or M5 erythrophagocytosis-associated with MOZ rearrangement. This t(8;19)(p11;q13) with MOZ involvement should not be confused with the t(8;19)(p11;q13) with FGFR1 involvement found in the stem-cell myeloproliferative disorder.

The partners of 8p11 are 8q13, 14q11, 16p13, 19q13, 22q13 and 3q27, 17q12 in a complexe translocation t(3;8;17)(q27;p11;q12). Clinics and Pathology Disease Acute myelomonocytic or monocytic leukaemia (M4, M5a, M5b) associated with erythrophagocytosis by blasts noted to various degree. Epidemiology Rare Cytology Morphology feature observed in AML with t(8;16). Prognosis probably poor Cytogenetics Cytogenetics t(8;19) (p11;q13) is a variant of t(8;16) (p11;p13) Morphological Additional Two cases : anomalies 46,XX,t(8;19)(p11;q13.2)/idem,-16,-16q+ 46,XX, t(8;19)(p11;q13) sole anomaly Genes involved and Proteins Gene MOZ Name Location 8p11 Note MOZ contains a LAP (Leukemia associated protein) zinc finger domain, a HAT domain (Histone acetyltransferase) and a acidic domain. Detection by FISH : YAC 176C9. Protein ZNF220 Monocytic leukemia zinc finger protein

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -205- 2004 amino acids and 225 kDa nuclear protein, with 2 LAP/PHD-type zinc fingers. MOZ is a histone acetyltransferase (HAT) and the founding member of the MYST family of HATs, a family that includes proteins involved in cell cycle regulation, chromatin remodeling and dosage compensation. MOZ plays an important role during hematopoiesis with his transcriptional coregulator activity. Gene The partner of MOZ is unknown in this translocation. Name Location 19q13 Result of the chromosomal anomaly Fusion Protein In the t(8 ;19) the fusion protein is unknown. Note

External links Other t(8;19) (p11;q13) Mitelman database (CGAP - NCBI) database Other t(8;19) (p11;q13) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography A new specific chromosomal rearrangement t(8 ;16)(p11 ;p13) in acute monocytic leukaemia. Heims S, Avanzi GC, Billstrom R, Kristofferson U, Mandahl N, Mitelman F. Br J Haematol 1987; 66: 323-326. Medline 3476150

A complex t(3 ;8 ;17) involving breakpoint 8p11 in a case of M5 acute nonlymphocytic leukemia with erythrophagocytosis.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -206- Bertheas MF, Jaubert J, Vasselon C, Reynaud J, Pomier G, Le Petit JC, Hagemeijer A, Brizard CP. Cancer Genet Cytogenet 1989; 42(1): 67-73. Medline 2790748

A distinct subtype of M4/M5 acute myeloblastic leukaemia associated with t(8 ;16)(p11 ;p13) in a patient with the variant t(8 ;19)(p11 ;q13) a case report and review of the literature Stark B, Resnitzky P, Jeison M, Luria D, Blau O, Zaivov R. Leuk Res 1995; 19: 367-379. Medline 7596149

Contributor(s) Written 12- Jacques Boyer 2003 Citation This paper should be referenced as such : Boyer J . t(8;19) (p11;q13). Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0819p11q13ID1315.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -207- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(8;9)(p12;q33)

Identity Note 8p12 myeloproliferative syndrome (EMS) / stem cell leukemia- lymphoma syndrome (SCLL) belongs to the tyrosine kinase fusion genes chronic myeloproliferative diseases . It is associated with recurent translocations : t(6;8)(q27;p12), t(8;9)(p12;q33), t(8;11)(p12;p15), t(8;12)(p12;q15), t(8;13)(p12;q12), t(8;17)(p12;q25), t(8;19)(p12;q13), t(8;22)(p12;q11) Clinics and Pathology Disease Myeloproliferative disorder that is frequently associated with T-cell, or less commonly B-cell non Hodgkin lymphoma. Phenotype / cell stem May involve a stem cell. origin Epidemiology 9 cases are described ; sexe ratio : 6M/3F. Clinics Agressive disease ; myeloid hyperplasia progressing to myelodysplasia and T or B-cell lymphoma, splenomegaly, lymph node. High WBC with myelemia with frequently eosinophilia and sometimes monocytosis (near CMLL). Evolution The disease transforms to ANLL or occasionally ALL in a median of 6 months. Prognosis Median survival : 12 months. Cytogenetics Cytogenetics This translocation is a variant of the t(8 ;13)(p12 ;q12). Morphological Additional +der(9), +21 anomalies Genes involved and Proteins Gene FGFR1

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -208- Name Location 8p12 Gene CEP110 Name Location 9q33 DNA : 26kb - 19 exons Dna / Rna RNA : Three mains transcripts of approximatly 7.5, 4.5 and 1.5 kb. CEP transcripts are barely expressed in thymus and peripheral blood cells. Protein CEP110 gene codes for a 994-amino acid coiled-coil protein with 4 consensus leucine zippers (centrosome associated P110 protein). Result of the chromosomal anomaly Hybrid The t(8;9) breakpoint in the FGFR1 gene is localized in exon 8, 12 bp gene upstream of the exon 8/intron 8 junction. It is distinct from the Description breakpoints in the t(6;8) and t(8;13) but it preserves the same FGFR1 sequence in the chimeric protein. The breakpoint in the CEP110 is localized in exon 15. The translocation leads to the formation of the two reciprocal transcripts.

Fusion The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine Protein kinase of 150-kd wich retains most of CEP110 with the leucine zipper Description motif and the catalytic domain of FGFR1. The CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm contrasting with the centrosome and membrane localizations of the wildtype respective proteins. The FGFR1-CEP110 protein contains the FGFR1 N-terminal region with its ligand-binding and transmembrane domains and the CEP110 C-terminal region. Oncogenesis Activated aberrant tyrosine kinase are likely to promote leukemogenesis through contitutive activation of the FGFR1 kinase. This activation may be mediated by dimerisation of the portion of the fusion protein wich contains the leucine zippers. This activation may interacts with the cell proliferation and the apoptose, additional anomalies may also play an important role in the evolution of the disease.

External links Other t(8;9)(p12;q33) Mitelman database (CGAP - NCBI) database Other t(8;9)(p12;q33) CancerChromosomes (NCBI) database To be noted

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -209- Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Réarrangements chromosomiques et syndromes myéloprolifératifs mixtes. Popovici C. Thèse Aix Marseille II, 1998.

FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33). Guasch G, Mack GJ, Popovici C, Dastugue N, Birnbaum D, Rattner JB, Pebusque MJ. Blood 2000; 95(5): 1788-1796 Medline 10688839

Identification of four new translocations involving FGFR1 in myeloid disorders. Sohal J, Cross NC and al. Genes Chromosomes Cancer 2001; 32(2): 155-163. Medline 11550283

Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Cross NC, Reiter A. Leukemia 2002; 16: 1207-1212. Medline 12094244

The 8p11 myeloproliferative syndrome : a distinct clinical entity caused by constitutive activation of FGFR1. MacDonald D, Reiter A, Cross NC. Acta Haematol 2002; 107(2): 101-107 Medline 11919391

Contributor(s) Written 01- Jacques Boyer 2004 Citation This paper should be referenced as such : Boyer J . t(8;9)(p12;q33). Atlas Genet Cytogenet Oncol Haematol. January 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0809p12q33ID1129.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -210- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(8;22) (p11;q13)

Identity Note Two distinct clinical syndromes have been associated with the 8p11-p12 region : Stem-cell myeloproliferative disorder with FGFR1 rearrangement. AML M4 or M5 erythrophagocytosis-associated, with MOZ rearrangement. the t(8;22) (p11; q13) involves MOZ

The partners of 8p11 are 8q13, 14q11, 16p13, 19q13, 22q13 and 3q27, 17q12 in a complexe translocation t(3;8;17)(q27;p11; q12). Clinics and Pathology Disease Acute myelomonocytic or monocytic leukemia (M4, M5a, M5b) associated with erythrophagocytosis by blasts noted to various degree, one case is probably a therapy-related leukemia. Epidemiology Rare Cytology Erythrophagocytosis by blasts cells is occasionally found but not marked. Prognosis probably poor Cytogenetics Cytogenetics t(8;19) (p11;q13) is a variant of t(8;16) (p11;p13) Morphological Additional In one case association with trisomy 8 anomalies Genes involved and Proteins Gene MOZ Name Location 8p11 Note MOZ contains a LAP (Leukemia associated protein) zinc finger domain , a HAT domain (Histone acetyltransferase) and a acidic domain. Detection by FISH : YAC 176C9. Protein ZNF220 Monocytic leukemia zinc finger protein 2004 amino acids and 225 kDa nuclear protein, with 2 PHD-type zinc

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -211- fingers. MOZ is a histone acetyltransferase (HAT) and the fouding member of the MYST family of HATs, a family that includes proteins involved in cell cycle regulation, chromatin remodeling and dosage compensation. MOZ plays an important role during hematopoiesis with his transcriptional coregulator activity. Gene P300 Name Note Detection: FISH with the bacterial artificial chromosome clone H59D10 Protein Adenoviral E1A-associated protein p300 with acethyltransferase activity Result of the chromosomal anomaly Hybrid Gene fusion MOZ/P300 gene Note Description MOZ is disrupted within the sequences encoding the acidic domain. Both fusion transcripts are expressed. The t(8;22) breakpoints occurs in MOZ codon 1117 within an exon of 4 kb.

Fusion MOZ-p300 fusion is similar to MOZ-CBP described in the t(8;16) but Protein involve p300 instead of CBP. The translocation creates in-frame fusion Description proteins (MOZ-p300 and p300-MOZ). The two fusion proteins retain the N-terminus portion of MOZ including the HAT domain. Oncogenesis How the MOZ-p300 fusion protein is involved in acute leukemia is not known, but it probably affects the chromatin condensation.

External links Other t(8;22) (p11;q13) Mitelman database (CGAP - NCBI) database Other t(8;22) (p11;q13) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography A new specific chromosomal rearrangement t(8 ;16)(p11 ;p13) in acute monocytic leukaemia. Heims S, Avanzi GC, Billstrom R, Kristofferson U, Mandahl N, Mitelman F. Br J Haematol 1987; 66: 323-326. Medline 3476150

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -212-

A complex t(3 ;8 ;17) involving breakpoint 8p11 in a case of M5 acute nonlymphocytic leukemia with erythrophagocytosis. Bertheas MF, Jaubert J, Vasselon C, Reynaud J, Pomier G, Le Petit JC, Hagemeijer A, Brizard CP. Cancer Genet Cytogenet 1989; 42(1): 67-73. Medline 2790748

Acute Monocytic Leukemia with (8 ; 22)(p11 ; q13) translocation. Involvement of 8p11 as in classical t(8 ; 16)(p11 ; p13). Lai JL, Zandecki M, Fenaux P, Preudhomme C, Facon T, Deminatti M. Cancer Genet Cytogenet 1992 ; 60: 180-182. Medline 1606561

Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Lawrence JB, Livingston DM. Genes Dev 1994; 8: 869-884. Medline 7523245

MOZ is fused to p300 in an acute monocytic leukemia with t(8 ; 22) Chaffanet M, Gressin L, Preudhomme C, Soenen-Cornu V, Birnbaum D, Pebusque MJ Genes Chromosomes Cancer 2000; 28(2): 138-144. Medline 10824998

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -213- Medline 11174118

Secondary acute monocytic leukemia with a t(8;22)(p11;q13) translocation. Tasaka T, Nagai M, Matsuhashi K, Uehara E, Tamura T, Ishida T, Kakazu N, Abe T. Haematologica 2002; 87(05): ECR19. Medline 12010682

Contributor(s) Written 12- Jacques Boyer 2003 Citation This paper should be referenced as such : Boyer J . t(8;22) (p11;q13). Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0822p11q13ID1119.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -214- Atlas of Genetics and Cytogenetics in Oncology and Haematology

11q23 rearrangements in childhood acute lymphoblastic leukemia

Identity Note Clinical aspects of 11q23 abnormalities in childhood acute lymphoblastic leukemia (ALL) are herein described. Clinics and Pathology Disease Childhood acute lymphoblastic leukemia (11q23) Note Acute lymphoblastic leukemia (ALL) in infants is a clinically distinct entity from that diagnosed in older children. Infant ALL, which represents 3% of all cases of childhood ALL, is clinically aggressive and strongly associated with a poor prognosis. As mentioned below, leukemic cells in infants show preferential involvement of 11q23 chromosomal abnormalities / MLL gene rearrangements. Phenotype / Leukemic cells with 11q23 abnormalities, which include MLL gene cell stem rearrangements, are usually not hyperdiploid, have an early pre-B cell origin immunophenotype, and express myeloid antigens but not CD10. A few studies have found a strong association between 11q23 abnormalities and the expression of the human homolog of the rat chondroitin sulfate proteoglycan NG2. Therefore, the common immunophenotypes are CD19+, CD10-, CD15+, and/or CD65+, NG2+. Etiology There is strong molecular evidence that 11q23 abnormalities in infants with ALL occur in utero. The 11q23 band/MLL gene has an important role in normal hematopoietic growth and differentiation. Abnormalities in this region can occur very early in hematopoietic stem cell development. Indeed, in utero exposure to natural or synthetic substances that inhibit topoisomerase II (e.g., genistein, catechins, flavonoids) may result in acute leukemia. It has been suggested that rearrangement of the MLL gene leads to the inhibition of apoptosis and leukemogenesis. Epidemiology Depending on the method of detection, the incidence of 11q23 abnormalities among infants with ALL ranges from 60% to 80%. Among children who are older than 1 year and have ALL, the incidence of MLL gene rearrangements ranges from 4.5% to 5.7%. The t(4;11), one of the most common 11q23 abnormalities, occurs in 2% of children and adults with ALL.

The following information was obtained from 2 published reports of a multinational collaborative study of 497 pediatric patients with 11q23

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -215- abnormalities and ALL. In this study, some data for a few patients were unavailable.

Table 1. Frequency of five types of 11q23 abnormalities among three age groups of patients.

11q23 Total Number of patients (%)* abnormality >10 - - <1 year old 1-9 years old years old t(4;11) 252 149 (70) 58 (31) 45 (49) t(11;19) 49 27 (13) 12 (6) 10 (11) t(9;11) 19 8 (38) 10 (5) 1 (1) t(11q23;V) 77 23 (11) 44 (23) 10 (11) del(11q23) 94 5 (2) 64 (34) 25 (27) Total 491 212 (43) 188 (38) 91 (18) Abbreviation: V, variable chromosome *Percentage within the indicated age group.

Clinics Children who have ALL and 11q23 abnormalities often experience organomegaly, high leukocyte counts, and involvement of the central nervous system (CNS) at the time of diagnosis.

Table 2. The clinico-biological presenting features of 497 patients with ALL and 11q23/MLL rearrangement.

11q23 No. of Median Median No. of No. of abnormality Cases Age in WBC patients patients (%) Years Counts, with CNS with T- t(4;11) 256 (52) 0.65 (0.01- 224 (1- 30 (12) 2 (0.8) 20.9) 1400)

t(11;19) 49 (10) 0.87 (0.03 - 184 (3- 5 (10) 8 (16) 16.7) 1000)

t(9;11) 20 ( 4) 1.46 (0.12 - 51 (1- 4 (20) 0 12.7) 520)

t(11q23;V) 77 (15) 2.60 (0.02 - 32 (2- 8 (10) 17 (22) 15.1) 1400)

del(11q23) 95 (19) 5.34 (0.12 - 14 (1- 5 (5) 13 (14) 16.7) 785)

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -216- Abbreviations: V, indicates a variable chromosome *Fifty-two (11%) of 482 patients had CNS involvement. **Forty (8.7%) of 459 patients had T-lineage ALL. Abbreviations: V, indicates a variable chromosome *Fifty-two (11%) of 482 patients had CNS involvement. **Forty (8.7%) of 459 patients had T-lineage ALL.

Treatment Because ALL in infants has distinctive biological characteristics and because infants have a high risk of leukemia recurrence, infants with ALL are usually treated on specifically designed protocols. Current intensified treatment approaches may offer better disease control in infants than do previously tested, less intensive approaches, but long-term outcome and toxicity are unknown.

Leukemic cells from infants with ALL are significantly more resistant to prednisone and L-asparaginase in vitro than are leukemic cells from older patients with ALL. However, leukemic cells in infants are highly sensitive to cytosine arabinoside (ara-C). These findings were incorporated into two cooperative treatment protocols for infants with ALL: the international Interfant-99 protocol and a protocol of the Children's Oncology Group in the United States.

New therapeutic regimens are needed to cure infants with 11q23 abnormalities and high-risk ALL. Recent studies have shown high levels of FLT3 expression in patients with MLL rearrangements; therefore, inhibitors of FLT3 (a tyrosine kinase) may prove to be beneficial. Prognosis The 11q23 abnormality/MLL gene rearrangement is generally associated with a high risk of treatment failure; in contrast, deletion or inversion of 11q23 is not. Although infants and adults with the t(4;11) are at higher risk of treatment failure, children aged 1 to 9 years appear to have a better outcome. For more details, see below

Table 3. The impact of age and phenotype on the 5-year event-free survival (EFS) estimates for children with ALL and different types of 11q23 abnormality.

Type of 11q23 Age, Lineage 5-year P abnormality EFS, % value (s.e.)

t(4;11) <1 year, B 19 (3) <0.001 lineage 42 (5) >1 year, B lineag<1 year,e B lineage 38 (15) Atlas Genet Cytogenett(9;11) Oncol Haematol 2004; 2 0.27 -217- >1 year, B 46 (14) lineage <1 year, B lineage 38 (15) t(9;11) 0.27 >1 year, B 46 (14) lineage <1 year, B lineage 26 (8) t(11;19) >1 year, B 46 (14) 0.01 lineage 88 (13) T lineage <1 year, B lineage 22 (8) t(11q23;variable) <0.001 >1 year, B 65 (7) lineage <1 year, B lineage 40 (22) del(11)(q23) 0.05 >1 year, B 73 (5) lineage

Cytogenetics Cytogenetics t(4;11) Morphological • The t(4;11) was the sole chromosomal abnormality in 200 (79%) of the 252 cases in which a t(4;11) was detected by conventional cytogenetics. The t(4;11) was observed in 41 cases that had other cytogenetic changes and in 11 cases that had variant translocations. In 4 cases, only molecular information (MLL-AF4+) was available. • The t(4;11) was present in 70% (149/212) of infants, 31% (58/188) of children aged 1 to 9 years, and 49% (45/91) of patients aged 10 years or more. • Infants with the t(4;11) had a worse outcome than did those who were older than 1 year (5-year event-free survival [EFS] estimates, 19% ± 3% vs. 42% ± 5%; P=0.0001). • The outcome of infants with the t(4;11) and poor prednisone response (n=12) was dismal (5-year EFS estimate, 0%), whereas infants with the same abnormality and a good prednisone response (n=11) had a slightly better outcome (5-year EFS estimate, 23% ± 12%; P=0.0005). • The outcome of infants who were younger than 3 months and had ALL and a t(4;11) was worse than that of infants who were older than 3 months and had ALL and the same chromosomal abnormality (5-year EFS estimates, 5% ± 5% vs. 23.4% ± 4%; P=0.0003). • A poor prednisone response also appeared to confer a poor outcome for ALL patients 1 year of age or older with a t(4;11) (5-year EFS estimate, 33% ± 16%). ALL patients in the same age group and with a t(4;11) and a good prednisone response had a 5-year EFS estimate of 80% ± 18% (P=0.077). • Leukocyte counts at initial examination had only a marginal prognostic impact for infants with t(4;11)-positive ALL and lacked significance for older pediatric patients in this genetic subgroup. • In a retrospective analysis of 256 patients with the t(4;11) treated between 1983 and 1995, allogeneic stem cell transplantation provided no greater benefit than did intensive chemotherapy alone.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -218- t(11;19)

• The t(11;19) was the sole chromosomal abnormality in 31 (63%) of the 49 cases in which the t(11;19) was detected. In 15 cases (31%) with a t(11;19), additional changes were present, and in 3 additional cases, variant translocations were observed. • The t(11;19) was found in 13% (27/212) of infants, 6% (12/188) of children aged 1 to 9 years, and in 11% (10/91) of children aged 10 years or more. • Patients who had this translocation and were younger than 1 year had a worse outcome than did older patients (5-year EFS estimates, 26% ± 8% vs. 64% ± 12%; P=0.003). • In the subgroup of infants with the t(11;19), age less than 6 months and female sex were associated with a poor treatment outcome; however, these findings from a multivariate analysis lacked statistical significance. • None of the 26 infants with a t(11;19) had T-cell ALL, but this type of ALL was present in 8 (38%) of the 21 children who were older than 1 year and had a t(11;19). • Of the patients with the t(11;19)(q23;p13.3) and the MLL-ENL fusion, those who had T-lineage ALL and were older than 1 year had a better outcome than did patients who had a t(11;19), were older than 1 year, and had B-lineage ALL (5-year EFS estimates, 88% ± 13% vs. 46% ± 14%, P=0.065). This finding confirmed previous observations.

t(9;11)

• The t(9;11) was identified by RT-PCR only in 1 of 20 cases. Six (32%) of the other 19 cases had additional chromosomal changes; in 4 cases, a variant translocation was present. • The t(9;11) was found in 3.8% (8/212) of infants, 5% (10/188) of children aged 1 to 9 years, and 1% (1/91) of patients aged 10 years or more. • Age was not a predictor of outcome for infants with t(9;11)-positive ALL. • Patients who had ALL and a t(9;11) and were younger than 1 year had a 5- year EFS estimate of 38% ± 15%, whereas those who had ALL and a t(9;11) and were older than 1 year had a 5-year EFS estimate of 46% ± 14% (P=0.27).

t(11q23;variable)

• Of the 77 patients with a t(11q23;variable), 23 were infants. Southern blot analysis detected the abnormality in 6 infants. • The t(11q23;variable) was found in 11% (23/212) of infants, 23% (44/188) of children aged 1 to 9 years, and 11% (10/91) of patients aged 10 years or more. • The following recurrent chromosomal abnormalities were observed in 18 of the 23 infants: inv(11)(p15q23) (n=5), t(1;11)(p32;q23) (n=5), t(10;11)(p14- 15;q23) (n=4), t(1;11)(q23;q23) (n=2) and t(10;11)(p13;q23) (n=2). • For patients younger than 1 year who had the t(11q23;variable), the 5-year

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -219- EFS estimate was 22% ± 8%, whereas those older than 1 year who also had this abnormality had a 5-year EFS estimate of 65% ± 7% (P<0.0001).

del(11)(q23)

• The del(11)(q23) occurred in 2% (5/212) of infants, 34% (64/188) of children aged 1 to 9 years, and 27% (25/91) of patients aged 10 years or more. • Only 5 infants had a del(11)(q23), and their treatment outcome was worse than that of 89 older children with the same abnormality (5-year EFS estimates, 40% ± 22% vs. 73% ± 5%; P=0.05). • Although patients with the del(11)(q23) were a very heterogeneous group, the National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance: the 5-year EFS estimate was 64% ± 8% for patients with high-risk disease and 83% ± 6% for those with standard-risk disease (P=0.04).

The findings from the international collaborative study can be summarized as follows:

• Only age at initial treatment had a significant effect on EFS estimates of pediatric patients with ALL and 11q23 abnormalities. Infants (n=212) uniformly fared worse than children aged 1 to 9 years (n=188) and those aged 10 years or more (n=91). Furthermore, when the two groups of older patients were further divided by type of 11q23 abnormalities, each group had a similar outcome. • Irrespective of the 11q23 abnormality, infants had a worse treatment outcome than did older patients. • Any category of 11q23 abnormality conferred a dismal outcome for infants, whereas in older patients the t(4;11) (n=103) and the t(9;11) (n=22) were associated with an outcome worse than that associated with other 11q23 changes. • The t(4;11) and the t(11;19) were usually found in the youngest children, whereas the del(11)(q23) was typically detected in the oldest. • The t(4;11) and the t(9;11) were rarely found in patients with T-lineage leukemia. • Patients with the t(4;11) or the t(11;19) were most likely to belong to the high-risk group defined by the National Cancer Institute-Rome criteria, whereas those with the del(11)(q23) were the least likely. • T-lineage ALL was present in 40 (8.7%) of the 459 cases in which the leukemic cells' immunophenotype was known. CNS involvement was observed in 12% (52/430) of patients with 11q23 abnormalities. • For patients with the t(4;11), any type of transplantation, including allogeneic transplantation of hematopoietic stem cells from an HLA-matched related or unrelated donor, was associated with significantly a worse disease- free survival estimate than was chemotherapy alone. Cytogenetics Some MLL gene rearrangements are not detected by conventional cytogenetic Molecular methods. The commercially available dual-color MLL probe (Vysis, Inc.,

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -220- Downers Grove, IL, USA) allows FISH evaluation of derivatives of an MLL translocation in metaphase chromosomes and the splitting of the hybridizing probe's signal in interphase nuclei. In rare instances, this probe detects not only the reciprocal translocation but also a deletion of at least 190 kb from the 3' region of the MLL gene.

Molecular cytogenetic methods have shown that the frequency of MLL gene rearrangements exceeds that of 11q23 translocations detected by conventional cytogenetic methods. In ALL cases in which deletions and inversions affect the 11q23 band (both types of abnormality are associated with favorable clinical features and prognoses), FISH should be done to determine whether a cryptic rearrangement of MLL is present. In a few cases, an 11q23 translocation involves genes other than MLL. Because the translocation partners for 11q23 are markedly heterogeneous, additional molecular methods are needed to further assess the MLL gene in patients with an 11q23 abnormality. Information from such assessments can then be used to better stratify treatment groups. Bibliography Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 cases. Pui C-H, Frankel LS, Carroll AJ, Raimondi SC, Shuster JJ, Head DR, Crist WM, Land VJ, Pullen DJ, Steuber CP, et al. Blood 1991; 77: 440-447. Medline 1991161

Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biological variables and poor outcome. Chen C-S, Sorensen PHB, Domer PH, Reaman GH, Korsmeyer SJ, Heerema NA, Hammond GD, Kersey JH. Blood 1993; 81:2386-2393. Medline 8481519

In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Ford AM, Ridge SA, Cabrera ME, Mahmoud H, Steel CM, Chan LC, Greaves M. Nature 1993; 363:358-360. Medline 8497319

Current status of cytogenetic research in childhood acute lymphoblastic leukemia. Raimondi SC.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -221- Blood 1993; 81:2237-2251. Review. Medline 8481506

Improved survival for acute lymphoblastic leukaemia in infancy: the experience of EORTC-Childhood Leukaemia Cooperative Group. Ferster A, Bertrand Y, Benoit Y, Boilletot A, Behar C, Margueritte G, Thyss A, Robert A, Mazingue F, Souillet G, et al. Br J Haematol 1994; 86:284-290. Medline 8199016

11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. Pui C-H, Behm FG, Downing JR, Hancock ML, Shurtleff SA, Ribeiro RC, Head DR, Mahmoud HH, Sandlund JT, Furman WL, et al. J Clin Oncol 1994; 12:909-915. Medline 8164041

Childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): an update. Pui C-H, Carroll LA, Raimondi SC, Shuster JJ, Crist WM, Pullen DJ. Blood 1994; 83:2384-2385. Medline 8161808

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Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age. Behm FG, Raimondi SC, Frestedt JL, Liu Q, Crist WM, Downing JR, Rivera GK, Kersey JH, Pui C-H. Blood 1996; 87: 2870-2877. Medline 8639906

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Human homologue of the rat chondroitin sulfate proteoglycan, NG2, detected by monoclonal antibody 7.1, identifies childhood acute lymphoblastic leukemias with t(4;11)(q21;q23) or t(11;19)(q23;p13) and MLL gene rearrangements. Behm FG, Smith FO, Raimondi SC, Pui C-H, Bernstein ID. Blood 1996; 87:1134-1139. Medline 8562939

The human homologue of rat NG2, a chondroitin sulfate proteoglycan, is not expressed on the cell surface of normal hematopoietic cells but is expressed by acute myeloid leukemia blasts from poor-prognosis patients with abnormalities of chromosome band 11q23. Smith FO, Rauch C, Williams DE, March CJ, Arthur D, Hilden J, Lampkin BC, Buckley JD, Buckley CV, Woods WG, Dinndorf PA, Sorensen P, Kersey J, Hammond D, Bernstein ID. Blood 1996; 87:1123-1133. Medline 8562938

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The t(10;11)(p12;q23) translocation in acute leukaemia: a cytogenetic and clinical study of 20 patients. Lillington DM, Young BD, Berger R, Martineau M, Moorman AV, Secker-Walker LM. Leukemia 1998; 12:801-804. Medline 9593284

The translocations, t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3): a cytogenetic and clinical profile of 53 patients. European 11q23 Workshop participants. Moorman AV, Hagemeijer A, Charrin C, Rieder H, Secker-Walker LM. Leukemia 1998; 12: 805-810. Medline 9593285

Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia--implications for treatment of infants. Pieters R, den Boer ML, Durian M, Janka G, Schmiegelow K, Kaspers GJ, van Wering ER, Veerman AJ. Leukemia 1998; 12: 1344-1348. Medline 9737681

Acute lymphoblastic leukemia. Pui C-H, Evans WE. N Engl J Med 1998; 339:605-615. Review.

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A multiplex RT-PCR assay for the detection of chimeric transcripts encoded by the risk- stratifying translocations of pediatric acute lymphoblastic leukemia. Scurto P, Hsu Rocha M, Kane JR, Williams WK, Haney DM, Conn WP, Shurtleff SA, Downing JR. Leukemia 1998; 12:1994-2005. Medline 9844930

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants. Swansbury GJ, Slater R, Bain BJ, Moorman AV, Secker-Walker LM. Leukemia 1998; 12:792-800. Medline 9593283

Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Dordelmann M, Reiter A, Borkhardt A, Ludwig WD, Gotz N, Viehmann S, Gadner H, Riehm H, Schrappe M. Blood 1999; 94:1209-1217. Medline 10438708

Cytogenetic studies of infant acute lymphoblastic leukemia: poor prognosis of infants with t(4;11) - a report of the Children's Cancer Group. Heerema NA, Sather HN, Ge J, Arthur DC, Hilden JM, Trigg ME, Reaman GH. Leukemia 1999; 13:679-686. Medline 10374870

Comparison of cytogenetics, Southern blotting, and fluorescence in situ hybridization as methods for detecting MLL gene rearrangements in children with acute leukemia and with 11q23 abnormalities. Mathew S, Behm F, Dalton J, Raimondi S. Leukemia 1999; 13:1713-1720. Medline 10557043

Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study- POG 8821. Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP, Weinstein HJ, Carroll AJ. Blood 1999; 94:3707-3716. Medline 10572083

Treatment outcome and prognostic factors for infants with acute lymphoblastic leukemia treated on two consecutive trials of the Children's Cancer Group. Reaman GH, Sposto R, Sensel MG, Lange BJ, Feusner JH, Heerema NA, Leonard M, Holmes EJ, Sather HN, Pendergrass TW, Johnstone HS, O'Brien RT, Steinherz PG, Zeltzer PM,

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -225- Gaynon PS, Trigg ME, Uckun FM. J Clin Oncol 1999; 17:445-455. Medline 10080584

Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation. Rubnitz JE, Camitta BM, Mahmoud H, Raimondi SC, Carroll AJ, Borowitz MJ, Shuster JJ, Link MP, Pullen DJ, Downing JR, Behm FG, Pui C-H. J Clin Oncol 1999; 17:191-196. Medline 10458233

Biological and therapeutic aspects of infant leukemia. Biondi A, Cimino G, Pieters R, Pui C-H. Blood 2000; 96:24-33. Review. Medline 10891426

Identification and molecular characterization of CALM/AF10 fusion products in T cell acute lymphoblastic leukemia and acute myeloid leukemia. Carlson KM, Vignon C, Bohlander S, Martinez-Climent JA, Le Beau MM, Rowley JD. Leukemia 2000; 14:100-104. Medline 10637483

Treatment outcome in infant acute lymphoblastic leukemia. Children Leukemia Cooperative Group--EORTC. European Organization for Research and Treatment of Cancer. Ferster A, Benoit Y, Francotte N, Dresse MF, Uyttebroeck A, Plouvier E, Thyss A, Lutz P, Marguerite G, Behar C, Mazingue F, Boutard P, Millot F, Rialland X, Mechinaud F, Norton L, Robert A, Otten J, Vilmer E, Philippe N, Waterkeyn C, Suciu S. Blood 2000; 95:2729-2731. Medline 10809540

The "Atlas of genetics and cytogenetics in oncology and haematology" on the internet and a review on infant leukemias. Huret JL, Dessen P, Le Minor S, Bernheim A. Cancer Genet Cytogenet 2000; 120:155-159. Medline 10942808

Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. Alexander FE, Patheal SL, Biondi A, Brandalise S, Cabrera ME, Chan LC, Chen Z, Cimino G, Cordoba JC, Gu LJ, Hussein H, Ishii E, Kamel AM, Labra S, Magalhaes IQ, Mizutani S, Petridou E, de Oliveira MP, Yuen P, Wiemels JL, Greaves MF. Cancer Res 2001; 61:2542-2546. Medline 11289128

Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -226- lymphoblastic leukaemia XI protocol. Hann I, Vora A, Harrison G, Harrison C, Eden O, Hill F, Gibson B, Richards S; UK Medical Research Council's Working Party on Childhood Leukaemia. Br J Haematol 2001; 113:103-114. Medline 11328289

An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Huret JL, Dessen P, Bernheim A. Leukemia 2001; 15:987-989. Medline 11417488

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis. Kolomietz E, Al-Maghrabi J, Brennan S, Karaskova J, Minkin S, Lipton J, Squire JA. Blood 2001; 97:3581-3588. Medline 11369654

Molecular tracking of leukemogenesis in a triplet pregnancy. Maia AT, Ford AM, Jalali GR, Harrison CJ, Taylor GM, Eden OB, Greaves MF. Blood 2001; 98:478-482. Medline 11435320

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Restricted chromosome breakpoint sites on 11q22-q23.1 and 11q25 in various hematological malignancies without MLL/ALL-1 gene rearrangement. Tanaka K, Eguchi M, Eguchi-Ishimae M, Hasegawa A, Ohgami A, Kikuchi M, Kyo T, Asaoku H, Dohy H, Kamada N. Cancer Genet Cytogenet 2001; 124:27-35. Medline 11165319

MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ. Nat Genet 2002; 30:41-47. Medline 11731795

Infant acute lymphoblastic leukemia - combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Borkhardt A, Wuchter C, Viehmann S, Pils S, Teigler-Schlegel A, Stanulla M, Zimmermann M, Ludwig WD, Janka-Schaub G, Schrappe M, Harbott J. Leukemia 2002; 16:1685-1690.

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Molecular analysis of an unusual rearrangement between chromosomes 4 and 11 in adult pre-B-cell acute lymphoblastic leukemia. Chami I, Perot C, Portnoi MF, Jouault H, Rieux C, Pautas C, Kuentz M, Tulliez M, Bories D. Cancer Genet Cytogenet 2002; 133:129-133. Medline 11943339

Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukemia of infancy: report from MRC Childhood Leukemia working party. Chessells JM, Harrison CJ, Kempski H, Webb DKH, Wheatley K, Hann IM, Stevens RF, Harrison G, Gibson BE. Leukemia 2002; 16:776-784. Medline 11986937

Treatment of infants with lymphoblastic leukemia: results of the UK Infant Protocols 1987-1999. Chessells JM, Harrison CJ, Watson SL, Vora AJ, Richards SM. Br J Haematol 2002; 117:306-314. Medline 11972512

Two new translocations involving the 11q23 region map outside the MLL locus in myeloid leukemias. Giugliano E, Rege-Cambrin G, Scaravaglio P, Wlodarska I, Emanuel B, Stul M, Serra A, Tonso A, Pini M, Saglio G, Hagemeijer A. Haematologica 2002; 87:1014-1020. Medline 12368154

Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96). Isoyama K, Eguchi M, Hibi S, Kinukawa N, Ohkawa H, Kawasaki H, Kosaka Y, Oda T, Oda M, Okamura T, Nishimura S, Hayashi Y, Mori T, Imaizumi M, Mizutani S, Tsukimoto I, Kamada N, Ishii E. Br J Haematol 2002; 118: 999-1010. Medline 12199778

A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD, Jones-Bolin S, Ruggeri B, Dionne C, Small D. Blood 2002; 99:3885-3891. Medline 12010785

Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Pui C-H, Gaynon PS, Boyett JM, Chessells JM, Baruchel A, Kamps W, Silverman LB, Biondi A, Harms DO, Vilmer E, Schrappe M, Camitta B.

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Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Pui C-H, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, Carroll A, Eden OB, Evans WE, Gadner H, Harbott J, Harms DO, Harrison CJ, Harrison PL, Heerema N, Janka- Schaub G, Kamps W, Masera G, Pullen J, Raimondi SC, Richards S, Riehm H, Sallan S, Sather H, Shuster J, Silverman LB, Valsecchi MG, Vilmer E, Zhou Y, Gaynon PS, Schrappe M. Leukemia 2003; 17:700-706. Medline 12682627

Contributor(s) Written 02-2004 Susana C Raimondi Citation This paper should be referenced as such : Raimondi SC . 11q23 rearrangements in childhood acute lymphoblastic leukemia. Atlas Genet Cytogenet Oncol Haematol. February 2004 . URL : http://AtlasGeneticsOncology.org/Anomalies/11q23ChildALLID1321.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -229- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(1;14)(q21;q32) BCL9/IGH t(1;22)(q21;q11)

Identity Note the 2 translocations t(1;14)(q21;q32) and t(1;22) are variants of each other This t(1;14)(q21;q32) with BCL9 involvement is different from the t(1;14)(q21;q32) with FCGR2B involvement, from the t(1;14)(q21;q32) with MUC1 involvement and from the t(1;14)(q21;q32) with IRTA1 involvement. Clinics and Pathology Disease Acute lymphoblastic leukemia (ALL) and non Hodgkin lymphoma (NHL) Epidemiology a case of ALL in a 30 yr old male patient, a case of follicular NHL in a 57 yr old female patient, and a case of mantle cell lymphoma in a 87 yr old female patient Prognosis prognosis was poor in 2 cases Cytogenetics Cytogenetics There was a t(14;18)(q32;q21) and a complex karyotype in the Morphological follicular NHL caset, and a t(11;14)(q13;q32) and a complex karyotype in the case of mantle cell lymphoma case Genes involved and Proteins Gene BCL9 Name Location 1q21 Gene Immunoglobulin genes : IGH, IGL Name Location located in 14q32 and 22q11 respectively Protein involved in Wnt signal transduction External links Other t(1;14)(q21;q32) BCL9/IGH Mitelman database (CGAP - NCBI) database Other t(1;14)(q21;q32) BCL9/IGH CancerChromosomes (NCBI)

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -230- database Other t(1;22)(q21;q11) Mitelman database (CGAP - NCBI) database Other t(1;22)(q21;q11) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21. Willis TG, Zalcberg IR, Coignet LJ, Wlodarska I, Stul M, Jadayel DM, Bastard C, Treleaven JG, Catovsky D, Silva ML, Dyer MJ. Blood 1998; 91: 1873-1881. Medline 9490669

Contributor(s) Written 02- Jean-Loup Huret 2004 Citation This paper should be referenced as such : Huret JL . t(1;14)(q21;q32) BCL9/IGH,t(1;22)(q21;q11). Atlas Genet Cytogenet Oncol Haematol. February 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0114q21q32ID1319.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -231- Atlas of Genetics and Cytogenetics in Oncology and Haematology

del (13q)

Identity

Partial karyotype in 2 cases of AML with del(13q): Left panel: Relapsed AML in a 17- year old man; Right panel: Acute monoblastic leukaemia in a 31-year old woman at diagnosis. G-banding with trypsin / Giemsa.

Clinics and Pathology Disease Myeloid disorder

Among myeloid malignancies, deletion 13q is encountered in myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and myeloproloferative disorders (MPD). The deletion is described as interstitial in most cases although a few cases of terminal deletion are reported.

A survey of 640 patients with primary MDS showed that del(13q) was rare, and existed as the sole abnormality in 2 cases of refractory anaemia. Besides de novo MDS and AML, del(13q) was also reported in therapy-related MDS. In a series of 137 cases of therapy-related MDS and AML, del(13q) was detected in 3 cases of the former group but not the latter. Moreover, del(13q) was detected in 2 out of 55 patients with unexplained cytopenia and clonal cytogenetic abnormalities in bone marrow cells but without definite morphological evidence of dysplasia, which might be a harbinger of MDS.

With respect to MPD, del(13q) appeared to be more common in chronic idiopathic myelofibrosis, and was also detected in post-polycythaemic myelofibrosis. A high prevalence of chromosome 13q deletion or translocation was reported as a second aberration in chronic myeloid leukaemia (CML) with persistent or relapsed disease after bone marrow transplantation. In 6 such CML patients, a common region of

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -232- deletion at 13q 12 - 14 was identified by fluorescence in-situ hybridization (FISH) with a panel of 13q YAC clones.

Interestingly, del(13q) was detected in aplastic anaemia and these patients showed hypoplastic bone marrow without morphological dysplasia. Cytogenetics Morphological Cytogenetics Characterization of del(13q) in 20 patients with myeloid malignancies, including MPD, AML and MDS patients, showed that the deletions consistently involved region 13q 14 - 21 by conventional G-banding assessment.

Molecular alterations of 13q may be more common than is suggested by conventional cytogenetics. First, loss of heterozygosity (LOH) at the RB1 locus, which maps to 13q14, has been observed in 15 out of 39 (38%) of BCR-ABL negative MPD patients, with an over-representation in chronic idiopathic myelofibrosis. Second, 13q14 deletion can be demonstrated by FISH in chronic idiopathic myelofibrosis and polycythaemia vera patients without 13q abnormality on conventional cytogenetics. These show that 13q deletions may occur as a submicroscopic lesion only detectable with molecular techniques such as LOH study and FISH.

Molecular Cytogenetics In a series 20 patients with myeloid malignancies, FISH analysis with a panel of DNA probes for 13q13.1 - 14.3 delineated a common deleted region that was flanked by YAC 833A2 and YAC 854D4. Subsequent study on one case of 13q translocation with accompanying cryptic 13q deletion allowed the genomic segment to be narrowed down to around 4 cM that included YAC 937C7, RB1 and YAC 745E3. This overlaps with the critical deleted segment in CLL which is limited by RB1 and D13S25 markers.

A number of genes lie within this region and include RB1, CHCIL and RFP2. Despite initial report of RB1 abnormality in MDS and AML, subsequent reports failed to shows RB1 rearrangement in myeloid malignancies. In one series involving 39 cases of BCR-ABL negative MPD, the RB1 gene displayed a germline configuration in all, suggesting that 13q deletions most probably affect a tumour suppressor locus distinct from RB1. No mutations in candidate genes have been identified in any of the lymphoid neoplasms as well. Prognosis Unlike the lymphoproliferative disorders in which del(13q) shows prognostic significance, for example associating with the longest survival in chronic lymphocytic leukaemia when compared with other chromosomal changes, no data are yet available for the prognostic outcome of del(13q) in the myeloid disorders. Aplastic anaemia with del(13q) appears to be clinically benign. In a series of 9 cases, 6 responded to immunosuppressive therapy while the other 3 improved with steroids. None of these patients developed acute leukaemia. These findings indicated that aplastic anaemia with del(13q) resembled bone marrow failure syndrome without cytogenetic abnormalities rather

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -233- than preleukaemia. Concurrent with this notation was the report of spontaneous clinical and cytogenetic remission in an aplastic anaemia patient with del(13q).

Disease Lymphoid disorder

Del(13q) involving the band q14 occurs frequently in B-cell chronic lymphocytic leukaemia (CLL), being detectable in 8 - 10% of patients by conventional cytogenetics and up to 40 - 50% of patients by FISH. The deletion may occur in isolation or associated with other recurrent cytogenetics abnormalities including +12, del(11q), del(6q) and del(17p). In a large survey of 325 patients with CLL by FISH, del(13q) was the commonest genetic aberration, detected in 55% of cases, and correlated with the longest survival of 92 months. The subcategory of isolated del(13q) was also associated with the longest median survival time of 133 months.

Subsequent investigations showed the presence of del(13q) in other non-Hodgkin's lymphoma (NHL), including both low grade and aggressive lymphoma. A preferential association with mantle cell lymphoma was suggested. It was also reported in 37 out of 74 cases (50%) of splenic lymphoma with villous lymphocytes in one study.

More recently, del(13q) was recognized as a common genetic lesion in multiple myeloma. Cytogenetics and FISH studies detected the presence of del(13q) in 20 - 86% of myeloma, usually within the 13q14 region. The deletion may occur as an early event in the development of monoclonal gammopathies and possibly be involved in evolution of monoclonal gammopathy of uncertain significance (MGUS) into overt myeloma. A long-term follow up study on MGUS showed presence of deletion 13q14 as detected by FISH in 5 out of 18 cases, and all progressed to myeloma within 6 - 12 months after identification of the cytogenetics abnormality. Cytogenetics Morphological Cytogenetics The deletion in CLL, NHL and myeloma uniformly involves 13q14. Commonly used FISH probes to detect the deletion in the lymphoid disorders are chromosome 13q14 specific, including RB1, D13S319 and D13S25. Molecular Cytogenetics The most commonly deleted marker in CLL and NHL initially reported was D13S319, between the retinoblastoma locus and D13S25 locus. The 13q14 deletions usually do not lead to inactivation of the RB1 gene, and del(13q) is associated with the presence of one intact RB1 gene on the homologous chromosome, implying the role of an adjacent locus that may harbour important tumour suppressor gene(s). However, the pathogenesis of splenic lymphoma with villous lymphocytes may be different. In one study, 13q14 deletion was identified in 50% of SLVL cases, in which 47% showed monoallelic loss of RB1, 12% showed hemizygous D13S25 deletion, and cases that displayed both RB1 and D13S25 deletion. It follows therefore that allelic loss of RB1 may indeed play a role in the

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -234- pathogenesis of SLVL.

A recent study on critically deleted region (CDR) at 13q14 in with three probes for 13q14 (RB1, D13S319, and D13S25) showed deletions in 29 out of 82 (35.4%) cases. Subsequently, contiguous YACs, PACs, and a BAC spanning the 13q14-q21 region were employed for deletion mapping in addition to a 13q telomere probe. Large deletions extending to the 13q34 region were found in 55% of the deleted cases, whereas an additional 13.8% showed loss of both 13q34 and 13q14 regions with retention of 13q21. A CDR of approximately 350 kb was identified at 13q14 with the proximal border approximately 120 kb centromeric from D13S319, encompassing an area rich in expressed sequence tagged sites and containing DLEU1, DLEU2, and RFP2 genes. While direct sequencing of the RFP2 gene revealed no mutations in six patients and four myeloma cell lines harboring deletions of the CDR, a role for RFP2 in the pathogenesis of myeloma cannot yet be excluded. Prognosis Sole deletion of 13q14 is associated with a more favourable clinical outcome in CLL, with a reported median survival time of 133 months for this particular cytogenetics subgroup. However, among NHL in general, del(13q) is associated with presence of splenomegaly, peripheral blood dissemination, lower probability of attaining complete remission and a shorter survival. In myeloma, deletion of 13q14 also predicts an adverse prognosis. A recent FISH study on myeloma showed deletion of Rb gene in 48 out of 104 patients (46.2%), and deletion of D13S319 locus in 28 out of 72 patients (38.9%). Myeloma patients with 13q14 deletion were more likely to have stage III disease, high serum levels of b2-microglobulin, and a higher percentage of bone marrow plasma cells than patients with normal 13q14 status on FISH study. The presence of 13q14 deletion on FISH analysis was associated with a significantly lower rate of response to conventional-dose chemotherapy and a shorter overall survival than in patients without the deletion. Bibliography Cytogenetic studies and their prognostic significance in agnogenic myeloid metaplasia: a report on 47 cases. Demory JL, Dupriez B, Fenaux P, Lai JL, Beuscart R, Jouet JP, Deminatti M, Bauters F. Blood 1988; 72: 855-859. Medline 3416075

Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia. Ahuja HG, Jat PS, Foti A, Bar-Eli M, Cline MJ. Blood 1991; 78: 3259-3268. Medline 1683797

Chronic lymphocytic leukemia cells with allelic deletions at 13q14 commonly have one intact RB1 gene: evidence for a role of an adjacent locus.

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13q deletions in lymphoid malignancies. Liu Y, Hermanson M, Grander D, Merup M, Wu X, Heyman M, Rasool O, Juliusson G, Gahrton G, Detlofsson R, Nikiforova N, Buys C, Söderhäll S, Yankovsky N, Zabarovsky E, Einhorn S. Blood 1995; 86: 1911-1915. Medline 7655020

Genetic analysis of chromosome 13 deletions in BCR/ABL negative chronic myeloproliferative disorders. Pastore C, Nomdedeu J, Volpe G, Guerrasio A, Cambrin GR, Parvis G, Pautasso M, Daglio C, Mazza U, Saglio G, Gaidano G. Genes Chromosomes Cancer 1995; 14: 106-111. Medline 8527391

Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P. Blood 1995; 86: 3542-3552. Medline 7579462

Molecular cytogenetic analysis in splenic lymphoma with villous lymphocytes: frequent allelic imbalance of the RB1 gene but not the D13S25 locus on chromosome 13q14. Garcia-Marco JA, Nouel A, Navarro B, Matutes E, Oscier D, Price CM, Catovsky D. Cancer Res 1998; 58: 1736-1740. Medline 9563492

Molecular delineation of 13q deletion boundaries in 20 patients with myeloid malignancies. La Starza R, Wlodarska I, Aventin A, Falzetti D, Crescenzi B, Martelli MF, Van den Berghe H, Mecucci C. Blood 1998; 91: 231-237. Medline 9414289

13q14 deletion in non-Hodgkin¹s lymphoma: correlation with clinicopathologic features. Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Campioni D, Minotto C, Agostini P, Milani R, Bullrich F, Negrini M, Croce C, Castoldi G. Haematologica 1999; 84: 589-593. Medline 10406898

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -236- Frequent chromosome arm 13q deletion in aggressive non-Hodgkin's lymphoma. Wada M, Okamura T, Okada M, Teramura M, Masuda M, Motoji T, Mizoguchi H. Leukemia 1999; 13: 792-798. Medline 10374885

Non-random involvement of chromosome 13 in patients with persistent or relapsed disease after bone-marrow transplantation for chronic myeloid leukemia. Chase A, Pickard J, Szydlo R, Coulthard S, Goldman JM, Cross NC. Genes Chromosomes Cancer 2000; 27: 278-284. Medline 10679917

Genomic aberrations and survival in chronic lymphocytic leukemia. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P. N Engl J Med 2000; 343: 1910-1916 Medline 11136261

Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Espanol de Citogenetica Hematologica. Sole F, Espinet B, Sanz GF, Cervera J, Calasanz MJ, Luno E, Prieto F, Granada I, Hernandez JM, Cigudosa JC, Diez JL, Bureo E, Marques ML, Arranz E, Rios R, Martinez Climent JA, Vallespi T, Florensa L, Woessner S. Br J Haematol 2000; 108: 346-356. Medline 10691865

Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Zojer N, Konigsberg R, Ackermann J, Fritz E, Dallinger S, Kromer E, Kaufmann H, Riedl L, Gisslinger H, Schreiber S, Heinz R, Ludwig H, Huber H, Drach J. Blood 2000; 15: 1925-1930. Medline 10706856

Long-term follow up with conventional cytogenetics and band 13q14 interphase/metaphase in situ hybridization monitoring in monoclonal gammopathies of undetermined significance. Bernasconi P, Cavigliano PM, Boni M, Astori C, Calatroni S, Giardini I, Rocca B, Caresana M, Crosetto N, Lazzarino M, Bernasconi C. Br J Haematol 2002; 118: 545-549. Medline 12139743

Aplastic anaemia with 13q-: a benign subset of bone marrow failure responsive to immunosuppressive therapy. Ishiyama K, Karasawa M, Miyawaki S, Ueda Y, Noda M, Wakita A, Sawanobori M,

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -237- Nagai H, Nakao S. Br J Haematol 2002; 117: 747-750. Medline 12028052

Spontaneous clinical and cytogenetic remission of aplastic anemia in a patient with del(13q). Saitoh T, Saiki M, Kumagai T, Kura Y, Sawada U, Horie T. Cancer Genet Cytogenet 2002; 136: 126-128. Medline 12237236

Delineation of the minimal region of loss at 13q14 in multiple myeloma. Elnenaei MO, Hamoudi RA, Swansbury J, Gruszka-Westwood AM, Brito-Babapulle V, Matutes E, Catovsky D. Genes Chromosomes Cancer 2003; 36: 99-106. Medline 12461754

Clonal cytogenetic abnormalities in bone marrow specimens without clear morphologic evidence of dysplasia: a form fruste of myelodysplasia? Steensma DP, Dewald GW, Hodnefield JM, Tefferi A, Hanson CA. Leuk Res 2003; 27: 235-242. Medline 12537976

Contributor(s) Written 03- Edmond SK Ma, Thomas SK Wan 2004 Citation This paper should be referenced as such : Ma ESK, Wan TSK . del (13q). Atlas Genet Cytogenet Oncol Haematol. March 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/del13qID1310.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -238- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NK cell neoplasias

Clinics and Pathology Disease Neoplasms of natural killer (NK) cells are rare, and have not been well characterized until the past decade. In the new WHO classification of hematolymphoid tumors, three categories of NK cell neoplasms are recognized: - extranodal NK/T cell lymphoma , - aggressive NK cell leukemia, and - blastic NK cell lymphoma. Blastic NK cell lymphoma is morphologically and immunologically different from the first two categories, lacks EBV association, and there is little compelling evidence that it truly represents an NK cell neoplasm. In fact, recent studies suggest that this may be a neoplasm of probable precursor dendritic cells related to plasmacytoid monocytes (plasmacytoid dendritic cells). Since its lineage is still uncertain, this entity will not be discussed. Phenotype / NK cell represents a distinctive lineage of lymphocyte that is closely cell stem related to T cell. It shows many immunophenotypic and functional origin similarities with cytotoxic T lymphocyte, but differs in the lack of expression of surface CD3 molecule and T-cell receptor, and the absence of rearranged T-cell receptor genes. It characteristically expresses CD56 (neuronal cell adhesion molecule, N-CAM), which is also expressed in some cytotoxic T lymphocytes. NK cells can lyse target cells without prior sensitization (spontaneous antibody- independent MHC-unrestricted cytotoxicity) via the NK receptors. Etiology The exact etiology is unknown, but a very strong association with Epstein Barr virus (EBV) has been demonstrated. Epidemiology NK cell neoplasms show a strong geographic differences in their prevalence. They are more common in Asia, Mexico, and South America, but are very rare in the Western populations. Clinics They occur predominantly in the nose/nasopharynx, but sometimes in extranasal sites (most commonly skin), in middle-aged to elderly patients. Systemic involvement is uncommon at diagnosis but rarely, they may present initially in a leukemic form. The most common presenting symptoms are nasal obstruction, nasal discharge and epistaxis. The full-blown midfacial destructive and ulcerative lesions (hence the name midline granuloma) are much less commonly seen nowadays. Patients with aggressive NK cell leukemia present with high

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -239- swinging fever, systemic symptoms and hepatosplenomegaly; they are usually extremely ill, with deranged liver function and coagulation profile. Cytology The neoplastic NK cells are often heterogeneous in appearance but some (particularly the circulating leukemic cells) may resemble large- sized normal large granular lymphocytes with ample amount of pale or lightly blue cytoplasm that contains fine or coarse azurophilic granules. Pathology The malignant infiltrate is diffuse, often with a prominent angiocentric and angiodestructive component. Coagulative necrosis and apoptosis are common. The cytological spectrum is variable, ranging from small, medium-sized, large or anaplastic cells, to a mixture of these cells. The cells often have irregularly folded nuclei and granular chromatin. In Giemsa-stained cytologic preparations, azurophilic granules are often detected in the cytoplasm. Reactive histiocytes with haemophagocytosis are sometimes found in the bone marrow, particularly for the leukemic form. NK cell neoplasms are characterised by an immunophenotype of CD2+, surface CD3-, cytoplasmic CD3e+, CD56+ and T cell receptor (TCR)-, lack of TCR gene rearrangement, and strong association with EBV. Treatment The disease is often resistant to chemotherapy. For extranodal NK/T cell lymphoma, the best results are obtained by radiotherapy with or without aggressive chemotherapy/stem cell rescue. Plasma or serum EBV DNA and tissue p73 gene hypermethylation assay can be used for monitoring of disease status or detection of minimal residual disease. Aggressive NK cell leukemia is treated by chemotherapy, but response is typically poor. Evolution Although extranodal NK/T cell lymphoma is usually localized at presentation, systemic progression often occurs, usually early in the course of disease. Common distant sites of involvement are the skin, liver, lung, gastrointestinal tract, testis, and rarely bone marrow. Patients with aggressive NK cell leukemia typically exhibits a rapidly progressive clinical course, with multi-organ failure and bleeding tendency. Prognosis Clinical factors reported to have prognostic significance in extranodal NK/T cell lymphoma include stage and hulk of disease, B symptoms, age, performance status and International Prognostic Index. The overall survival for patients with extranodal NK/T cell lymphoma is 30- 40%. Practically all patients with aggressive NK cell leukemia die from the disease within a few weeks or months of presentation. Genetics In contrast to T cells, NK cells do not show rearrangements of the TCR genes. As expected from their proposed normal counterpart, NK cell neoplasms show a germline configuration of the TCR genes and do not express TCR proteins on the cell surface. The detection of single circularised episomal form of EBV in the neoplasm by Southern blot analysis provides indirect evidence to the clonal nature. Molecular demonstration of X chromosome inactivation in female patients with NK

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -240- cell neoplasms also provides evidence for clonality. However, the most direct evidence for clonallity of this group of tumors has been provided by the detection of clonal chromosomal abnormalities (see section below).

It has been shown that in over 90% of NK cell neoplasms, a specific pattern of promoter CpG methylation occurs, with p73 being consistently involved. It has been further suggested that p73 may be an important target in the oncogenesis of NK cell neoplasms, and the demonstration of its methylation may serve as a useful molecular marker for disease monitoring. Cytogenetics Note A variety of genetic abnormalities has been described, but so far no specific and consistent chromosomal translocation has been identified by conventional cytogenetics. In most instances, the genetic changes involve loss or gain of genetic materials such as del(6q), and i(1q). Frequent genetic losses in 6q and 13q have been confirmed by both comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses. Other non-random abnormalities include +X, i(1q), i(7q), +8, i(17q), and 11q23 rearrangement. Chromosomal deletion involving chromosome 6q at around q21-q25 is the commonest recurrent chromosomal abnormality, and fluorescence in situ hybridisation studies have shown that 6q22-q23 is the most frequently involved regions in the chromosome 6 deletions. A recent study using LOH and homozygoisty mapping of deletion (HOMOD) analyses has, however, defined a distinct 3 Mb smallest region of overlapping on 6q25.

A possible involvement of 8p22-p23 in both NK cell neoplasms and NK cell line such as NK-92 has also been suggested. Translocation involving 8p23 has been reported in 3 cases of NK cell neoplasms, with the partner chromosomes being 8q13, 17q24 and 1q10. An add(8)(q23) abnormality has also been demonstrated in one case each of aggressive NK cell leukemia and extranodal NK/T cell lymphoma. Bibliography Neural cell adhesion molecule-positive peripheral T-cell lymphoma: a rare variant with a propensity for unusual sites of involvement. Kern WF, Spier CM, Hanneman EH, Miller TP, Matzner M, Grogan TM. Blood 1992; 79: 2432-2437. Medline 1373974

CD56 (NKH1)-positive hematolymphoid malignancies: an aggressive neoplasm featuring frequent cutaneous/mucosal involvement, cytoplasmic azurophilic granules and angiocentricity. Wong KF, Chan JKC, Ng CS, Lee KC, Tsang WYW, Cheung MMC. Hum Pathol 1992; 23: 798-804. Medline 1377163

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Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Chan JK, Sin VC, Wong KF, Ng CS, Tsang WY, Chan CH, Cheung MM, Lau WH. Blood 1997; 89: 4501-4513. Medline 9192774

CD56+ NK lymphomas: clinicopathological features and prognosis. Kwong YL, Chan AC, Liang R, Chiang AK, Chim CS, Chan TK, Todd D, Ho FC. Br J Haematol 1997; 97: 821-829. Medline 9217183

Identification of del(6)(q21q25) as a recurring chromosomal abnormality of putative NK cell lymphoma/leukemia. Wong KF, Chan JKC, Kwong YL. Br J Haematol 1997; 98: 922-926. Medline 9326190

Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients. Cheung MM, Chan JK, Lau WH, Foo W, Chan PT, Ng CS, Ngan RK. J Clin Oncol 1998; 16: 70-77. Medline 9440725

Comparative genomic hybridization analysis of natural killer cell lymphoma/leukaemia: recognition of consistent patterns of genetic alterations. Siu LLP, Wong KF, Chan JKC, Kwong YL. Am J Pathol 1999; 155: 1419-1425. Medline 10550295

Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia. Is there a consistent pattern? (Review). Wong KF, Zhang YM, Chan JKC. Leuk Lymphoma 1999; 34: 241-250. Medline 10439361

Chromosome aberrations are restricted to the CD56+ CD3- tumour cell population in natural killer cell lymphomas: a combined immunophenotyping and FISH study. Zhang Y, Wong KF, Siebert R, Matthiesen P, Harder S, Eimermacher H, Schlegelberger B. Br J Haematol 1999; 105: 737-742. Medline 10354139

Consistent patterns of allelic loss in natural killer cell lymphoma. Siu LLP, Chan V, Chan JKC, Wong KF, Liang R, Kwong YL.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -242- Am J Pathol 2000; 157: 1803-1809. Medline 11106552

Aggressive NK-cell leukaemia. Chan JKC, Wong KF, Jaffe ES, Ralfkiaer E. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours. Lyon: International Agency for Research on Cancer. 2001, pp. 198-200.

Extranodal NK/T -cell lymphoma, nasal type. Chan JKC, Jaffe ES, Ralfkiaer E. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours. Lyon: International Agency for Research on Cancer. 2001, pp. 204-207.

Bone marrow involvement by nasal NK cell lymphoma at presentation is uncommon. Wong KF, Chan JKC, Cheung MMC, So JCC. Am J Clin Pathol 2001; 115: 266-270. Medline 11211616

Specific patterns of gene methylation in natural killer cell lymphomas: p73 is consistently involved. Siu LLP, Chan JKC, Wong KF, Kwong YL Am J Pathol 2002; 160: 59-66. Medline 11786399

Genetic changes in natural killer cell neoplasms (Editorial). Wong KF. Leuk Res 2002; 26: 977-978. Medline 12363463

Natural killer cell neoplasms: A distinctive group of highly aggressive lymphomas/leukemias. (Review). Cheung MM, Chan JK, Wong KF. Semin Hematol 2003; 40: 221-232. Medline 12876671

Aberrant promoter CpG methylation as a molecular marker for disease monitoring in natural killer cell lymphomas. Siu LL, Chan JK, Wong KF, Choy C, Kwong YL. Br J Haematol 2003; 122: 70-77. Medline 12823347

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -243- A 2.6 Mb interval on chromosome 6q25.2-q25.3 is commonly deleted in human nasal natural killer/T-cell lymphoma. Sun HS, Su IJ, Lin YC, Chen JS, Fang SY. Br J Haematol 2003; 122: 590-599. Medline 12899714

Primary nasal natural killer cell lymphoma: long-term treatment outcome and relationship with the International Prognostic Index. Chim CS, Ma SY, Au WY, Choy C, Lie AK, Liang R, Yau CC, Kwong YL. Blood 2004; 103: 216-221. Medline 12933580

A novel EBV-negative natural killer cell line (Editorial). Wong KF. Leuk Res 2004; 28: 225-227. Medline 14687616

Contributor(s) Written 04- K.F. Wong 2004 Citation This paper should be referenced as such : Wong KF . NK cell neoplasias. Atlas Genet Cytogenet Oncol Haematol. April 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/NKCellNeoplasiaID2125.html

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Ovarian tumours : an overview

Identity Note Ovarian tumours are a group of neoplasms affecting the ovary and have a diverse spectrum of features according to the particular tumour entity. They include benign, low-malignant potential/borderline and malignant subtypes. Classification Ovarian tumours are subdivided into 5 main categories according to the World Health Organization's classification system: Epithelial tumours, which account for about 75% of all ovarian tumours, and 90-95% of ovarian malignancies. Sex cord-stromal tumours, which account for about 5-10 % of all ovarian neoplasms. Germ cell tumours, which account for about 15-20 % of all ovarian neoplasms. Metastatic tumours, accounting for about 5% of ovarian malignancies, and usually arise from breast, colon, endometrium, stomach and cervical cancers. Other, a small number of other types of neoplasms which develop from ovarian soft tissue or non-neoplastic processes. Clinics and Pathology Etiology There are several tumour predisposition syndromes associated with the development of some ovarian tumours.

For ovarian sex cord-stromal tumours these include:

Peutz-Jeghers syndrome, Cushing Syndrome, Meigs Syndrome and Gorlin Syndrome (for further details see Sex Cord-Stromal tumour Review). There have also been accounts of fibromas, a type of sex cord- stromal tumour affecting more than one family member, implying a genetic predisposition in a subset of cases. about 5-10% of ovarian epithelial tumours are associated with one of three syndromes: Hereditary breast-ovarian cancer syndrome; Hereditary nonpolyposis colon cancer; and Site-specific ovarian cancer syndrome (for further details see

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -245- Ovarian Epithelial Tumour Review). Ovarian germ cell tumours, in contrast, rarely develop in individuals with tumour predisposition syndromes. However there have been several reports of ovarian germ cell tumours affecting more than one family member, suggesting a genetic predisposition in a minority of cases. Furthermore, constitutional chromosomal abnormalities involving partial or entire Y chromosome gains, and also dysgenic gonads, are more frequently associated with the development of ovarian germ cell tumours. Epidemiology studies have shown a correlation between increased risk of ovarian epithelial tumours with increased number of ovulation cycles. Other factors which increase the likelihood of developing ovarian epithelial tumours include: use of talc on perineum and vulva, asbestos, pelvic irradiation, viruses, high-fat diet and lactose consumption. Reducing the number of ovulation cycles by multiparity, breast-feeding and oral contraceptives, decreases the probability of ovarian cancer. Epidemiology Generally ovarian tumours are more prevalent in the upper socioeconomic groups, and account for approximately two-thirds of cancers in the 40-65 age group. The incidence of ovarian tumour starts increasing in the third decade, and progressively increases to peak in the seventh decade. The different subtypes of ovarian neoplasms are more prevalent in different age groups. Ovarian germ cell tumours usually affect young women (mean age of presentation is 19 years) with an incidence of 20 per million at 18 years (age of peak presentation). Sex cord-stromal tumours, meanwhile, usually present in the 4th and 5th decades and Ovarian epithelial tumours are usually found in post-menopausal women (mean presentation age is 56 years). The median age for ovarian adenocarinoma is 60-65 years. There is no racial predisposition to ovarian sex cord-stromal tumours or ovarian germ cell tumours. However there is a racial predisposition for ovarian epithelial tumours with higher risks for Caucasians and lower risks for black women. Clear cell adenocarcinoma, a subtype of ovarian epithelial tumours, is more prevalent in Japanese than in Western women. Clinics Ovarian tumours are generally difficult to detect until they are advanced in stage or size, as the symptoms are vague and manifest over time. The principal symptoms include: fatigue, shortness of breath, increased abdominal girth, weight loss, non-productive cough, bloating, amenorrhea for premenopausal women and menstrual irregularity. Most ovarian neoplasms cause symptoms by exerting pressure on contiguous structures, resulting in increased urinary frequency, pelvic discomfort and constipation. Abdominal swelling results from enlargement of the tumour. Upper abdominal metastases or ascites cause nausea, heartburn, bloating, weight loss and anorexia. Irregular vaginal bleeding can be observed. Shortness of

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -246- breath is a symptom of patients with ascites or hydrothorax. Some tumours, including subtypes of sex cord-stromal tumours, produce excess oestrogen which results in isosexual precocious puberty, postmenopausal bleeding, menorrhagia, menometrorrhagia, amenorrhea, endometrial hyperplasia/cancer or fibrocystic breast disease. Some subtypes of sex-cord stromal tumours produce androgens which causes virilization. Pathology Diverse histopathologies are evident reflecting the different cell origins of the tumours: germ cell tumours develop from the primitive germ cells of the embryonic gonad, sex cord-stromal tumours develop from the stroma of the developing ovary, and epithelial tumours arise from the epithelial cells. Examples of both gross and microscopic images of these clinical entities can be viewed at the following websites: Internet Pathology Lab for Medical Education eAtlas of Pathology (Univ of Connecticut) Treatment Some ovarian tumours, notably the sex cord-stromal tumours, require surgical intervention only. Meanwhile others require chemotherapy post-resection; this applies to all germ cell tumours and the vast majority of ovarian epithelial tumours (with the exception of some stage Ia patients). In young patients with germ cell and sex cord- stromal tumours, unilateral salpingo-oophorectomy is performed in order to preserve fertility. Meanwhile when fertility is not a concern, such as in women beyond childbearing age, total abdominal hysterectomy and bilateral salpingo-oophorectomy is performed. Total abdominal hysterectomy and bilateral salpingo-oophorectomy is performed upon diagnosis of ovarian adenocarcinoma. Ovarian germ cell tumours are highly responsive to chemotherapy and radiotherapy, although the former is preferable in order to conserve ovarian function. Ovarian epithelial tumours are initially highly responsive to chemotherapy, but most patients relapse and fail to respond to subsequent chemotherapy regimes. Postoperative radiotherapy is also provided for ovarian adenocarcinoma patients in order to treat minimal residual disease. Platinum-based chemotherapy is used to treat both ovarian germ cell and epithelial tumours. There is very little data available on the treatment of advanced/recurrent ovarian sex cord-stromal tumours due to their rarity and varied indolence, but some responses have been obtained with combination chemotherapy in each subtype. However there is currently no effective treatment for metastatic lipid cell tumours. Evolution The growth potential of ovarian neoplasms differs according to their subtypes, as does their ability to metastasise. Ovarian epithelial tumours initially spread by direct seeding of the peritoneal surfaces, with mucinous tumours generally forming large masses and serous tumours spreading more diffusely. Ovarian germ cell tumours metastasise intraperitoneally or hematogenously, with the exception of dysgerminomas which metastasise via the lymphatic system (and are the only type of ovarian tumour to do so). In general, most ovarian germ cell tumours do not metastasise, with the exception of the lipid cell entity which

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -247- metastasises in 20% of cases, and a very low percentage of granulosa cell tumours (whose metastatic spread is usually limited to the pelvis and abdomen). Prognosis The prognosis of both ovarian germ cell tumours and ovarian sex cord-stromal tumours is generally good, as these tumour entities usually present at stage I, are benign and are highly responsive to treatment. Meanwhile the situation is very different in ovarian carcinomas, which often present at advanced stages with extensive metastases. If ovarian epithelial tumours are diagnosed at stage I (growth limited to the ovaries), 5-year survival rates are >90%, in stark contrast to <25% 5- year survival rates for those diagnosed at advanced stage. Before 45 years of age over 98% of ovarian neoplasms are benign. Genetics Note The contribution of genetic predisposition to the genesis of ovarian tumours varies widely according to the particular subtype. There have been several reports of ovarian germ cell tumours affecting more than one family member, whereas genetic predisposition has only been implicated in one particular subtype of ovarian sex cord- stromal tumours, fibromas. However, genetic predisposition is far more prevalent in ovarian epithelial tumours. Indeed, genetic factors are the most important risk factor for ovarian epithelial carcinoma, and approximately 5-10% of ovarian epithelial cancers are thought to have a hereditary component. Having 1 or 2 first-degree relatives with ovarian cancer increases the lifetime risk to 3-5% and 39% respectively. As mentioned in the aetiology section, three hereditary syndromes are associated with familial aggregation of ovarian carcinoma: hereditary breast-ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome (HNPCC, also known as Lynch Cancer Family syndrome II), and site- specific ovarian cancer syndrome. All 3 patterns of familial ovarian carcinoma are consistent with autosomal-dominant transmission. The age of diagnosis of hereditary epithelial ovarian cancer is approximately 10 years earlier than its sporadic counterpart. BRCA1 and BRCA2 genetic testing identifies individuals who are more likely to benefit from screening for ovarian epithelial tumours. Cytogenetics Cytogenetics There is a paucity of cytogenetic data available on ovarian germ cell Morphological and sex cord-stromal tumours. Trisomy 3, 8, 12, 14 and isochromosome 12p are recurrent findings in ovarian germ cell tumours. Trisomy 12 is a frequent finding, often as a sole anomaly, in the different subtypes of ovarian sex cord-stromal tumours. Trisomy 12 and 14, and monosomy 22 are characteristic recurrent cytogenetic aberrations present in the granulosa cell tumour subtype of ovarian sex cord-stromal tumours. Despite the heterogeneity of ovarian tumours, trisomy 12 is frequently found in the different subtypes of borderline and benign ovarian tumours of germ cell and sex cord- stromal origin, suggesting a common pathogenesis, at least for the

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -248- initial stages of tumourigenesis. Trisomy 14 is also a common finding in both ovarian germ cell tumours and sex cord-stromal tumours.

There is far more cytogenetic data available on ovarian carcinomas (epithelial tumours) due to their higher incidences, with over 400 published karyotypes. Published cytogenetic data on ovarian epithelial tumours are detailed on Mitelman Database of Chromosome Aberrations in Cancer. The cytogenetic aberrations are non-random and complex. However, no pathognomonic rearrangements have been identified thus far. The karyotypes often show severe aneuploidy, with hypodiploid or near-triploid stemline chromosome numbers. The different subtypes of ovarian carcinoma show no marked cytogenetic differences, except seropapillary tumours more frequently display chromosome aberrations than the other subtypes. A correlation exists between karyotypic complexity and tumour grade. Simple chromosome changes (numerical changes only or a single structural rearrangement) were found in well-differentiated carcinomas, whereas complex karyotypes were found in poorly differentiated tumours. Patients with aberrant tumour karyotypes, particularly complex ones, were associated with short survival. The most prevalent numerical changes are gains of chromosomes 1, 2, 3, 6, 7, 9, 12 and 20 losses of chromosomes 4, 8, 11, 13, 14, 15, 17 and 22. Structural rearrangements primarily involve deletions and unbalanced translocations involving 1p, 1q, 3p, 3q, 6q, 7p, 10q, 11p, 11q and 12q. Cytogenetics There are limited FISH, CGH and allelotype studies on ovarian germ Molecular cell tumours and ovarian sex cord-stromal tumours. Of the rudimentary CGH data presently available on ovarian germ cell tumours a high incidence of the gain of the entirety or the short arm of chromosome 12 was found. Other findings were similar to those previously reported for testicular germ cell tumours (i.e. gains of 8, 21 and 1q, and loss of 13). The limited CGH data available on ovarian sex cord-stromal tumours supported the cytogenetic findings, demonstrating gains of chromosomes 12 and 14 and losses of chromosomes 22 as the predominant findings.

In contrast, there is a plethora of CGH and allelotyping data implicating many genomic regions in ovarian epithelial tumours. Interphase cytogenetics demonstrated a high frequency of gain of copy number of 20q13.2 (70%), AIB1 (20q12) and cyclin D1 (CCND1 at 11q13, 72%) in ovarian epithelial tumours which were associated with poor prognosis. For a comprehensive overview of the imbalances identified by CGH in published reports of ovarian epithelial tumours see http://www.helsinki.fi/cmg/cgh_data.html. The commonest imbalances detected by CGH of epithelial neoplasms were gains of 8q, 1q, 20q, 3q and 19p in 69-53% of a series of 106 tumours and under-representations of 13q, 4q and 18q in 54-50% of cases. Under- representation of 11p and 13q and over-representation of 8q and 7q

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -249- correlated with undifferentiated ovarian carcinoma, whereas 12p under-representation and 18p over-representation were more commonly associated with well-differentiated and moderately differentiated tumours. In a study correlating CGH genomic imbalances with clinical endpoints in 60 ovarian carcinomas, the following associations were found:

Loss of chromosome 4 with high-grade tumours Gains of 3q26-qter, 8q24-qter and 20q13-qter and low-grade and low-stage tumours Deletion of 16q24 and >7 independent genomic imbalances and reduced survival times Tumour grade correlated better with genomic progression than clinical stage. Genes involved and Proteins Note The molecular pathogenesis of ovarian sex cord-stromal tumours and germ cell tumours are relatively understudied. Several genes have been analysed for somatic mutations and/or LOH, with largely negative findings. Due to the extensive similarity between ovarian and testicular germ cell tumours in terms of their cytogenetic, pathological and biological features, it is thought that the genes involved in their pathogenesis will be similar. P53 mutations are rare in germ cell tumours (<3% have somatic mutations), and do not seem to be involved in ovarian sex cord-stromal tumours either (although the data seems contradictory).

However P53 mutations are commonly found in ovarian epithelial tumours, suggesting that these tumours have a distinct molecular pathogenesis to the other subtypes. Other genes involved in the molecular aetiology of ovarian epithelial tumours include: CDKN2A, RB, GATA4, RNASET2, BRCA1, KRAS, MYC, ERBB2, CSF1R, ECGF1, EGFR, MYC, SRC, PI3K, AKT2, FGF3 and MDM2.

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Chromosome abnormalities in human epithelial ovarian malignancies. Gallion HH, Powell DE, Smith LW, Morrow JK, Martin AW, van Nagell JR, Donaldson ES. Gynecol Oncol 1990; 38: 473-477. Medline 2227564

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Trisomy of chromosome 12 in a case of thecoma of the ovary. Mrozek K, Nedoszytko B, Babinska M, Mrozek E, Hrabowska M, Emerich J, Limon J. Gynecol Oncol 1990; 36: 413-416. Medline 2156766

Trisomy 12 is a consistent chromosomal aberration in benign ovarian tumors. Pejovic T, Heim S, Mandahl N, Elmfors B, Floderus UM, Furgyik S, Helm G, Willen H, Mitelman F. Genes Chromosomes Cancer 1990; 2: 48-52. Medline 2177641

Cytogenetic study of solid ovarian tumors. Roberts CG, Tattersall MH. Cancer Genet Cytogenet 1990; 48: 243-253. Medline 2397455

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Atlas Genet Cytogenet Oncol Haematol 2004; 2 -254- Last year automatic search in PubMed publications Contributor(s) Written 12- Lisa Lee-Jones 2003 Citation This paper should be referenced as such : Lee-Jones L . Ovarian tumours : an overview. Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/OvarianTumOverviewID5231.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -255- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Ovary: Epithelial tumors

Identity Note Ovarian epithelial tumours are thought to arise from the simple cuboidal surface epithelium of the ovary, and account for 75% of all ovarian tumours, and 90-95% of ovarian malignancies. Classification Note Ovarian epithelial tumours are classified according to the following histological subtypes: serous, mucinous, endometrioid, clear cell, Brenner, transitional cell, small cell, mixed mesodermal and undifferentiated. Usually each subtype can be classified as benign, borderline (low malignant potential, LMP), or malignant (invasive). Serous tumours are further subdivided into the following: Serous cystadenoma Borderline serous tumour Serous cystadenocarcinoma Adenofibroma Cystadenofibroma Mucinous tumours are further classified as: Mucinous cystadenoma Borderline mucinous tumour Mucinous cystadenocarcinoma Adenofibroma Clinics and Pathology Etiology Epidemiology studies have provided data showing increased risk for ovarian cancer with greater numbers of ovulation cycles. Multiple pregnancies and use of oral contraceptives are thought to have a protective effect because of decreased ovulation and hormonal influences. There are two theories explaining for the association of decreased risk with decreased number of ovulation cycles: 1 "Theory of incessant ovulation": repeated ovarian follicular

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -256- rupture and subsequent repair results in increased likelihood of genetic alterations within the surface epithelium. 2. The "Gonadotrophin Theory" hypothesis: persistent stimulation of the ovaries by gonadotrophins, together with local effects of endogenous hormones, results in increased proliferation and mitotic activity of the surface epithelium. This is consistent with ovarian cancer being associated with high gonadotrophin states such as the menopause, and less commonly associated with low gonadotrophin states such as oral contraceptive use and high parity. Epithelial ovarian carcinoma develops sporadically in about 90- 95% of patients. Environmental and dietary factors are thought to have a role. These include use of talc on the perineum and vulva, asbestos, pelvic irradiation, viruses (particularly mumps), high-fat diet, and lactose consumption. Other factors are associated with an increased number of ovulation cycles: low parity, delayed childbearing, early menarche and late menopause. However, genetic factors are the most important risk factor for ovarian epithelial carcinoma (See Genetics section of this review for further details). Factors that decrease the risk for ovarian cancer predominantly reduce the number of ovulation cycles a women encounters- such as the use of oral contraceptives, breast-feeding and multiparity. Long-term use of oral contraceptives has reduced the risk of ovarian cancer by more than 50% in unselected women. Decreased risk of ovarian cancer has also been associated with tubal ligation and hysterectomy. Epidemiology Epithelial ovarian cancer is the sixth most common cancer in women and is the second most common female genital tract malignancy after endometrial cancer. They are usually found in postmenopausal women and are the commonest cause of death among women with gynaecologic malignancies in the USA, accounting for approximately 15,000 deaths annually. The annual lifetime risk for ovarian cancer is 1.4 per 100 women in the USA. Epithelial ovarian cancer can occur in females as young as 15, however the mean presentation age is 56 years. The age-specific incidence gradually rises and peaks at 70 years of age (55 per 100,000 Caucasians), whereas it affects only 3 women per 100,000 before 30 years of age. The median age for ovarian adenocarcinoma (which accounts for 85-90% of all malignant tumours) is between 60-65 years. The LMP ovarian tumours present at a younger age; the mean age of diagnosis is 48 years, and no large peak of incidence is observed. Brenner tumours are diagnosed in peri- or postmenopausal women. The incidence of ovarian epithelial tumours varies globally, with highest rates being observed in Scandinavia, Israel and North America, whereas the lowest rates are found in developing countries and Japan. A racial predisposition to ovarian epithelial tumours is apparent, with lower risks for black women. Clear cell adenocarcinoma is more prevalent in Japanese than western countries.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -257- Clinics Most early ovarian carcinomas and the serous and mucinous cystadenomas are asymptomatic. Two-thirds of patients present with extensive intra-abdominal metastases. Patients with advanced carcinomas usually present with vague abdominal swelling or discomfort, abdominal bloating, dyspepsia and early satiety, lack of appetite, malaise, urinary frequency and weight change (either gain or loss). Pelvic examination revealing firmness, fixation, nodularity, lack of tenderness, ascites, or cul-de-sac nodules are indicative of malignancy. 50% of all ovarian carcinomas are bilateral. Malignant serous tumours constitute over 40% of invasive epithelial carcinomas. Both borderline and malignant serous tumours are often bilateral. Mucinous carcinomas are diagnosed at stage I in approximately half of patients, whereas serous tumours are usually diagnosed at advanced stages. Brenner tumours are virtually always benign, and the exceptional malignant cases resemble transitional cell carcinoma of the bladder. As with the other types of ovarian neoplasm, it is usually asymptomatic until it has grown to a large size. Pathology Serous Benign serous tumours are loculated, have a single layer of flattened or cuboidal epithelium and the absence of mitoses. Papillae are sometimes present on the external or internal surfaces. Examples of serous cystadenomas can be found at: http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM054.html - gross appearance http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM073.html - gross appearance http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM052.html - gross appearance http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM053.html - demonstrates internal papillae http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM051.html - illustrates external papillae http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM056.html - H and E staining http://pathweb.uchc.edu/eAtlas/GYN/1314.htm http://pathweb.uchc.edu/eAtlas/GYN/1315.htm http://pathweb.uchc.edu/eAtlas/GYN/1316.htm http://pathweb.uchc.edu/eAtlas/GYN/61.htm http://pathweb.uchc.edu/eAtlas/GYN/159.htm Histological analysis of borderline serous tumours reveals papillary cystic pattern, stratification, tufting, increased mitotic figures and cytologic atypia. H and E histology of borderline serous tumour can be viewed at:

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -258- http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM055.html. Malignant serous tumours are soft, multiloculated, partially cystic, partially solid tumours with friable papillae. Their capsule may be smooth or irregular or show papillary projections. Internal papillae are soft and tan in colour. Cyst fluid is clear, thin and colourless. The gross appearance of serous cystadenocarcinoma can be viewed at: http://pathweb.uchc.edu/eAtlas/GYN/463.htm Histological review of malignant serous tumours indicates significant stromal invasion. Calcifications (Psammoma bodies) are present in one-third of patients. Characteristic microscopic features include finger-like papillae with fibrovascular core, covered by multilayered cuboidal or columnar epithelium, hyperchromatic nuclei, prominent nucleoli, frequent mitoses, Psammoma bodies and desmoplasia (invasion of stroma with fibrosis). Examples can be viewed at: http://pathweb.uchc.edu/eAtlas/GYN/1927.htm http://pathweb.uchc.edu/eAtlas/GYN/1928.htm http://pathweb.uchc.edu/eAtlas/GYN/1929.htm http://pathweb.uchc.edu/eAtlas/GYN/1097.htm http://pathweb.uchc.edu/eAtlas/GYN/1098.htm http://pathweb.uchc.edu/eAtlas/GYN/1099.htm http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM072.html - shows Psammoma bodies Mucinous Benign mucinous tumours are larger than serous tumours, and may grow to an enormous size. They are usually unilocular cysts or may have a few septae, with a smooth external surface. The cyst fluid is slimy, yellow and clear. Mucinous tumours are the most heterogeneous group of epithelial tumours. Benign mucinous tumours have a single layer of tall, columnar cells and clear, mucin-producing cells, with a bland stroma. Microscopic images of mucinous cystadenoma can be viewed at: http://pathweb.uchc.edu/eAtlas/GYN/1930.htm http://pathweb.uchc.edu/eAtlas/GYN/1931.htm http://pathweb.uchc.edu/eAtlas/GYN/1932.htm http://pathweb.uchc.edu/eAtlas/GYN/1933.htm http://pathweb.uchc.edu/eAtlas/GYN/1310.htm http://pathweb.uchc.edu/eAtlas/GYN/1311.htm http://pathweb.uchc.edu/eAtlas/GYN/1312.htm http://pathweb.uchc.edu/eAtlas/GYN/1313.htm Borderline mucinous tumours have complex patterns, two to three cell layer stratification, cytological atypia and mitotic figures. Carcinoma is diagnosed when the stratification exceeds three cell layers or if there is a significant stromal invasion . Mucinous cystadenocarcinomas contain a smooth capsule, are cystic, multiloculated and large tumours (can be 50 cm in diameter). The cystic fluid is clear, yellow and sticky. The gross appearance of a mucinous cystadenocarinoma can be viewed at:

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -259- http://pathweb.uchc.edu/eAtlas/GYN/530.htm Their microscopic appearance resembles intestinal adenocarcinoma. Multiple glands comprising mucin-containing cells are present, demonstrating nuclear atypia, hyperchromasia with prominent nuclei and desmoplasia. Borderline/LMP Borderline/LMP tumours are characterised by epithelial multilayering of more than 4 cell layers, and less than 4 mitoses per 10 high-power field, mild nuclear atypia, increased nuclear/cytoplasmic ratio, slight-to-complex branching of epithelial papillae and pseudopapillae, epithelial budding and cell detachment into the lumen and no destructive stromal invasion. Borderline mucinous tumours have similar gross morphology to their benign counterparts, cysts with smooth surfaces. The epithelial layer is characterised by stratification of 2-3 layers, nuclear atypia, enlarged nuclei and mitotic figures. Histological examples of borderline mucinous tumours can be found at: http://pathweb.uchc.edu/eAtlas/GYN/1934.htm http://pathweb.uchc.edu/eAtlas/GYN/1935b.htm Approximately 25% of borderline tumours show cell proliferations on the outer surface only. Of these, 90% develop peritoneal implants, which can be invasive or non-invasive. Both have a similar appearance, glandular or papillary proliferations with cell detachments, sometimes Psammoma bodies, cellular atypia and desmoplastic fibrosis. However, epithelial cells infiltrate the stroma in the invasive implants. Brenner tumours Brenner tumours are solid or cystic, yellow-tan colour and firm upon gross examination. Histological examination of Brenner tumour reveals epithelial nests or cysts of cells, resembling urothelium, separated by a cellular, fibrous stroma (composed of spindle-like cells). The nuclei are relatively uniform, lacking pleomorphism, hyperchromasia or macronucleoli, and mitoses are not identified. There is a moderate amount of eosinophilic cytoplasm. Examples of Brenner tumours can be viewed at: http://pathweb.uchc.edu/eAtlas/GYN/1941b.htm http://pathweb.uchc.edu/eAtlas/GYN/1942.htm http://pathweb.uchc.edu/eAtlas/GYN/1943.htm http://pathweb.uchc.edu/eAtlas/GYN/1299.htm http://pathweb.uchc.edu/eAtlas/GYN/1300.htm http://pathweb.uchc.edu/eAtlas/GYN/1301.htm http://pathweb.uchc.edu/eAtlas/GYN/1302.htm Clear Cell Carcinoma Clear cell carcinoma accounts for 5-12% of ovarian adenocarcinomas. The gross appearance of clear cell carcinoma shows a smooth, lobulated external surface. These tumours are usually solid and firm, but can be cystic. They have a yellow-tan colour. Microscopic examination reveals cells arranged in tubules, nests or cysts, with clear, glycogen rich

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -260- cytoplasm, sharply demarcated cell borders, and hyperchromatic, pleomorphic nuclei. "Hobnail" cells with nucleus standing on a stalk of cytoplasm are visible microscopically. Examples of clear cell carcinoma can be found using the following weblinks: http://pathweb.uchc.edu/eAtlas/GYN/1937.htm http://pathweb.uchc.edu/eAtlas/GYN/1938.htm http://pathweb.uchc.edu/eAtlas/GYN/1939.htm http://pathweb.uchc.edu/eAtlas/GYN/1940.htm http://pathweb.uchc.edu/eAtlas/GYN/1049.htm http://pathweb.uchc.edu/eAtlas/GYN/1050.htm http://pathweb.uchc.edu/eAtlas/GYN/1051.htm http://pathweb.uchc.edu/eAtlas/GYN/1052.htm http://pathweb.uchc.edu/eAtlas/GYN/1053.htm Endometrioid Carcinoma Endometrioid carcinomas are solid, white, firm tumours with smooth or irregular surfaces. They may contain a cystic component and have areas of necrosis and haemorrhage. Histological analysis reveals glands, or glands mixed with solid areas, round-oval vesicular, clear nuclei with prominent nucleoli. Endometrioid carcinoma is indistinguishable from endometrial carcinoma. An example of endometrioid carcinoma can be found at: http://pathweb.uchc.edu/eAtlas/GYN/437.htm Mixed Mesodermal The gross appearance of mixed mesodermal ovarian tumours are exemplified in the following weblinks: http://pathweb.uchc.edu/eAtlas/GYN/134.htm http://pathweb.uchc.edu/eAtlas/GYN/135.htm http://pathweb.uchc.edu/eAtlas/GYN/136.htm They are usually large variegated lesions with necrotic and haemorrhagic regions, and may have adhesions. Microscopic examination reveals serous or endometrioid epithelial component displaying squamous differentiation. Stroma may comprise spindle cell or soft tissue differentiation including cartilage, skeletal muscle or smooth muscle. Treatment The primary treatment of epithelial ovarian cancer is aggressive surgical tumour debulking, including total abdominal hysterectomy and bilateral salpingo-oophorectomy. Most women with ovarian epithelial tumours, except some stage Ia patients, receive chemotherapy. Postoperative treatment usually involves taxane-platinum combination chemotherapy; cisplatin or carboplatin with paclitaxel is the usual first- line treatment. High response rates, about 80%, are obtained, however most patients relapse, and other combination therapies fail. The mean disease-free interval for patients with stage III and IV disease is about 18 months. Only 20-30% of stage III and IV cases are long-term survivors. Postoperative intraperitoneal chemotherapy or external radiation therapy are used to treat patients with minimal residual disease. Clear cell adenocarcinoma is usually resistant to platinum- based chemotherapy. A strong association exists between ovarian

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -261- mucinous tumours and appendiceal mucinous neoplasms. Consequently the appendix should be removed in patients with mucinous neoplasms. Repeat laparotomy or peritoneal lavage is required to remove gelatinous material in the persistent recurrences of Pseudomyxoma peritonei . Brenner tumours are cured with surgical resection. Prophylactic oophorectomy at an early age has significantly reduced the risk of coelomic epithelial cancer. Oral contraceptives have a protective effect against ovarian cancer in carriers of BRCA1 or BRCA2 mutations. Evolution Epithelial ovarian cancer initially spreads by direct seeding of the peritoneal surfaces, and is found on the underside of the diaphragm, paracolic gutters, bladder, cul-de-sac, surface of liver, mesentery and serosa of large and small bowel, omentum, uterus and paraaortic and pelvic lymph nodes. The tumour cells may remain confined to the surface of the coated abdominal viscera without penetrating it. They may also spread to the pleural cavity, lungs and groin lymph nodes. Mucinous tumours tend to form large masses, whereas serous tumours tend to distribute more diffusely, and are more often bilateral. Endometrioid and clear cell tumours usually invade locally and retroperitoneally. Sometimes mucus-secreting ovarian carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass, referred to as pseudomyxoma peritonei . Prognosis The most important determinant for a favourable prognosis is diagnosis of ovarian carcinoma at an early stage. The prognosis of invasive epithelial ovarian cancer is poor, and relates to stage (see Tables 1 and 2), tumour grade and residual disease after surgery. The prognosis or early-stage ovarian invasive cancers and borderline tumours of all stages is significantly better. 5-year survival rates for patients with stage I disease are more than 90%, but less than 25% for advanced stage cancers. Patients with borderline tumours have an excellent prognosis. Age at diagnosis and the presence of invasive peritoneal implants are associated with a poorer prognosis in borderline tumours. The recurrence rate is 20%, with a mean time from diagnosis to relapse is 3.1 years in women with borderline serous tumours with non-invasive implants. However, borderline serous tumours with invasive implants have much higher recurrence rates of 32-45%, which occur much earlier (median time 24 months). Clear cell adenocarcinoma has a worse prognosis that the other histological subtypes as it is resistant to platinum-based chemotherapy. Some data suggests familial ovarian cancers have prolonged survival in comparison to the nonfamilial cases. In one study, patients with familial ovarian cancer exhibited a 67% 5-year survival, in comparison with a 17% 5-year survival in the nonfamilial ovarian cancer cases. STAGE DEFINITION

Stage I Growth limited to ovaries

Stage Growth limited to one ovary, no ascites, no tumour on Ia external surface, capsule intact Atlas Genet CytogenetStage OnGrowthcol Haem limitedatol 2004; to both 2 ovaries, no ascites, no tumour on -262- Ib external surface, capsule intact Stage Growth limited to both ovaries, no ascites, no tumour on Ib external surface, capsule intact Tumour either stage Ia or Ib, but with tumour on one or Stage both ovaries, with capsule ruptured, with ascites present Ic containing malignant cells, or with positive peritoneal washings Stage Growth involving one or both ovaries with pelvic II extension Stage Extension and/or metastases to the uterus and/or tubes IIa Stage Extension to other pelvic tissues IIb Tumour either stage IIa or IIb, with tumour on the surface Stage of one or both ovaries, but with capsule(s) ruptured, with IIc ascites present containing malignant cells, or with positive peritoneal washings Tumour involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal Stage or inguinal nodes. Superficial liver metastases equal III stage III. Tumour limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum Tumour grossly limited to the true pelvis with negative Stage nodes but with histologically confirmed microscopic IIIa seeding of abdominal peritoneal surfaces. Tumour involving one or both ovaries with histologically Stage confirmed implants of abdominal peritoneal surfaces, IIIb none exceeding 2cm in diameter. Nodes are negative. Stage Abdominal implants >2cm in diameter and/or positive IIIc retroperitoneal or inguinal nodes. Stage Growth involving one or both ovaries with distant IV metastases. Table 1 Definitions of the FIGO classification scheme for Staging Primary Ovarian Carcinoma (taken from Jones, 2000) STAGE PATIENTS SURVIVAL3-yr SURVIVAL 5-yr No TREATED (%) (%) I 5,559 87.5 82.1 II 3,364 72.1 64.5 III 2,530 47.0 38.1 IV 492 20.7 14.0 TOTAL 11,945 71.6 65.4 Table 2 Survival Rates of Ovarian Carcinoma according to Disease Stage (adapted table from Jones, 2000)

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -263- Genetics Note INHERITED PREDISPOSITION

As mentioned in the Aetiology section, genetic factors are the most important risk factor for ovarian epithelial carcinoma. Having 1 or 2 first- degree relatives with ovarian cancer increases the lifetime risk to 3-5% and 39% respectively. Three hereditary syndromes in which familial aggregation of ovarian carcinoma occurs have been described:

Hereditary breast-ovarian cancer syndrome: clusters of breast and ovarian cancer among first- and second-degree relatives Hereditary nonpolyposis colorectal cancer syndrome, HNPCC, or Lynch Cancer Family syndrome II): ovarian cancer develops in a proband whose close relatives have had cancers of the colon, breast, ovary, endometrium, urinary tract, uterine and other malignancies. Site-specific ovarian cancer syndrome of unknown origin in which two or more first-degree relatives have ovarian cancer

All 3 patterns of familial ovarian cancer are consistent with autosomal- dominant transmission of one or more genes responsible for the development of >1 cancers, with incomplete penetrance and variable expression. The age of diagnosis of hereditary epithelial ovarian cancer is approximately 10 years earlier than its sporadic counterpart.

Breast-Ovarian Syndrome Of the about 10% of ovarian epithelial cancers thought to have a hereditary component, 90% are associated with breast-ovarian syndrome. This syndrome is associated with two genes, BRCA1 at 17q21, and BRCA2 at 13q12.3 (see below), which are involved in DNA repair and transcription regulation. Mutations are distributed throughout the entire coding regions of BRCA1 and BRCA2, and most result in truncation of the protein. Germline mutations in BRCA1 account for about 80% of hereditary breast-ovarian cancers. Germline mutations of BRCA2 account for about 10-35% of familial ovarian cancers. BRCA1 is associated with a 26% cumulative risk for ovarian cancer for most mutation carriers, and a much higher risk, 85%, in a small subset. Women with a germline BRCA1 mutation have an about 40% risk of developing ovarian cancer by 70 years of age. BRCA2 increases susceptibility to a smaller degree. The lifetime risk for developing ovarian cancer in BRCA2 mutation carriers is 27%. However the risks of developing ovarian cancer associated with germline mutations of BRCA1 and BRCA2 vary according to the population studied. A study by revealed a lifetime risk of ovarian cancer of 40-60% for BRCA1 mutation carriers, whereas another one found a 25-30% risk for BRCA1 mutation carriers. Approximately 1/4000 in the general population has a mutation of BRCA1, although some populations have much higher incidences, for example the Ashkenazi Jews. Patients with breast cancer who had BRCA1 or BRCA2 mutations had a tenfold increased

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -264- risk of developing ovarian cancer.

The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors contribute to the pathogenesis in these individuals. One such modifier is a VNTR polymorphism, 1-kb downstream of HRAS. BRCA1 carriers with rare alleles of the VNTR had an 2.11 increased risk of developing ovarian cancer compared with the common alleles (p=0.015).

about 50% of familial ovarian cancers are not associated with germline BRCA1 or BRCA2 mutations. Linkage and LOH analysis has suggested a susceptibility gene for familial ovarian cancer at 3p22-p25. LOH of 3p33-p25 is higher (52%) in non-BRCA1/BRCA2 familial ovarian cancers than in the BRCA1 (29.7%) group.

HNPCC Mutations of the mismatch repair genes (MMR) including MLH1, MSH2 and MSH6 are present in HNPCC syndrome (Lynch 2 Syndrome). This represents the second most common type of ovarian cancer with a hereditary component.

Site-Specific Ovarian Cancer Syndrome The least common of the familial ovarian cancers is the site-specific ovarian cancer syndrome, in which ovarian cancer is the dominant cancer. It has been suggested that site-specific ovarian cancer is a variant of breast-ovarian syndrome attributable to mutation in either BRCA1 or BRCA2, and not a distinct clinical entity.

Early onset ovarian carcinoma (<30 years age) Germline DNA from women with ovarian carcinoma diagnosed before 30 years of age were screened for mutations in BRCA1, BRCA2, MSH2 and MLH1. 2/101 women with invasive ovarian cancer (<30 years) had germline mutations of MLH1, but germline mutations were not identified in any of the other genes analysed. Thus germline mutations of BRCA1, BRCA2, MSH2 and MLH1 contribute to a very small minority of cases of early onset epithelial ovarian cancer.

Other familial cases There have been several reports of small cell carcinoma, a rare form of ovarian carcinoma, occurring in multiple family members, suggesting a genetic predisposition to this tumour. Several familial cases of ovarian carcinomas have been associated with germline P53 mutations. Cytogenetics Cytogenetics There is far more cytogenetic data available on ovarian carcinomas Morphological than for the other subtypes of ovarian tumours (germ cell tumours, sex-cord stromal tumours). At present, there are over 400 published karyotypes of ovarian carcinomas. The cytogenetic aberrations are non-random and complex. However, no pathognomonic rearrangements have been identified thus far. The karyotypes often

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -265- show severe aneuploidy, with hypodiploid or near-triploid stemline chromosome numbers. The different subtypes of ovarian carcinoma show no marked cytogenetic differences, except seropapillary tumours more frequently display chromosome aberrations than the other subtypes. Complex chromosomal aberrations are present in invasive carcinomas, but not in benign or LMP tumours. The complexity of the karyotypes obtained from advanced tumours have obscured the initiating events in the pathogenesis of these tumours. Often normal karyotypes or simple cytogenetic aberrations were found in low-grade tumours. However, a correlation exists between karyotypic complexity and tumour grade. Simple chromosome changes (numerical changes only or a single structural rearrangement) were found in well- differentiated carcinomas, whereas complex karyotypes were found in poorly differentiated tumours. Patients with aberrant tumour karyotypes, particularly complex ones, were associated with short survival. Approximately 10-20% of ovarian carcinomas display homogeneously staining regions (hsr), although the loci they contain are unknown. However dmin are rarely observed. The most prevalent numerical changes are gains of chromosomes 1, 2, 3, 6, 7, 9, 12 and 20 losses of chromosomes 4, 8, 11, 13, 14, 15, 17 and 22. Structural rearrangements primarily involve deletions and unbalanced translocations involving 1p, 1q, 3p, 3q, 6q, 7p, 10q, 11p, 11q and 12q. In the review of 244 primary ovarian adenocarcinomas 201/244 tumours displayed clonal chromosomal abnormalities and hsr were identified in 20 cases. Using log-rank and proportional hazards regression analysis, it has been found that the presence of a chromosome breakpoint in any of 21 nonrandomly involved regions and breaks in 9 distinct regions (1p1, 1q2, 1p3, 3p1, 6p2, 11p1, 11q1, 12q2, and 13p1) were associated with reduced patient survival rate and time. Furthermore, only breakpoints within 1p1 and 3p1 retained independent, deleterious effects on survival and clinical variables associated with survival. In one review, 37% of serous LMP tumours displayed chromosomal anomalies, commonly trisomies of 7, 8 and 12. A much higher proportion, 91%, of invasive serous carcinomas of low-grade malignancy display clonal chromosomal abnormalities. A combination of karyotyping and microsatellite analyses identified a small deletion of 6q27, between D6S149 and D6S193, in both benign and advanced ovarian epithelial tumours, suggesting the presence of a putative tumour suppressor gene which is involved in the early events of the genesis of this tumour.

Invasive serous and undifferentiated ovarian carcinomas have complex cytogenetic rearrangements, including amplification of oncogenes. Complex chromosomal anomalies are rarely found in mucinous and endometrioid carcinomas (mainly in advanced stages), and are never found in serous LMP tumours. Epithelial ovarian tumours are characterised by gains at 3q, 8q and 20q, often with high level amplification. Thus the cytogenetic profiles of ovarian carcinomas differ from that of ovarian granulosa cell tumours, trisomy 14 and monsomy 22 are rarely found in ovarian carcinomas.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -266- Chromosome 1 and 3 abnormalities are the commonest aberrations found in ovarian metastatic tumours. Cytogenetic investigation of 11 individuals with bilateral ovarian carcinoma showed identical baseline karyotypes, suggesting both tumours arise from the same transformed cell, rather than the tumours arising independently.

46/52 ovarian carcinomas had complex karyotypes, often with a stemline chromosome number that was approaching near-triploid or hypodiploid. Chromosome losses of X, 22, 17, 13, 14 and 8, (lost in <20 tumours) were most frequent (compared to the nearest euploid level). Chromosomal gains were less prevalent, trisomy 20 was found in 10 tumours. The most common structural rearrangements are deletions and unbalanced translocations, which frequently involved 19p13 (n=26), 19q13 (n=14), 1p36 (n=13), 11p13 (n=13), 3p12-13 (n=12), 1q23 (n=11), and 6q21 (n=10). In a study, 26/36 ovarian carcinomas displayed aberrant karyotypes. Chromosomal gains of 1, 2, 3, 6, 7, 9 and 12 were common, as were losses of chromosomes X, 4, 8, 11, 13, 15, 17 and 22. Structural rearrangements frequently involved 1p, 1q, 3p, 3q, 7p, 9q, 11q, 17q, 19p and 19q. In a cohort of 54 tumours, the breakpoints of structural anomalies preferentially involved 1p35, 1p11-q21, 3p11-23, 7p, 11p, 11q, 12p13-q12 and 12q24. Loss of the X chromosome and trisomy 7 were the most common numerical changes. A third of all ovarian carcinomas have deletions of distal 11p. The frequent occurrence and variability of the deletions of chromosome 1, both the distal half of 1q and 1p34-36, and the frequent observations of similar entities in other tumour types suggest that they are secondary, non-specific changes. Deletions and unbalanced translocations resulting in loss of 3p, particularly of 3p13- 21 are recurrently found in ovarian carcinomas, but not as sole anomalies.

The cytogenetic findings of 370 cases of ovarian adenocarcinoma can be found listed on the Mitelman Database of Chromosome Aberrations in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman). The imbalances arising from the cytogenetic rearrangements listed in the database are summarised in Table 3. Of the cases listed, 36% had polyploid karyotypes (with chromosome numbers ranging between 58 and 127), 28% had hyperdiploid karyotypes (with 48-57 chromosomes), 22% had hypodiploid karyotypes (<45 chromosomes), and only 14% were peridiploid (45-47).

Imbalance Frequency of imbalance in ovarian carcinoma +1q10- 24 q32 +2p12- 9 q37 +3q10- 18 q29 Atlas Genet Cytogenet Oncol Haematol 2004; 2 -267- +3q10- 18 q29 +6p24- 10 p10 +7p22- 16 q36 +8q10- 11 q24 +12p13 20 -q24 +20p13 11 -q13 -1p36- 28 p32 -1q31- 24 q44 -2p15- 18 p23 -4p16- 27 q35 -5p15- 20 q34 -6q15- 40 q27 -7p22- 22 p15

-7q31- 21 q36 -8p23- 30 q24 -9p24- 20 p21 -10p15- 22 p11 -11p15- 27 p13 -13p13- 28 q34 -14p13- 29 q32 -15p13- 31 q26

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -268- -16p13- 25 q24 -17p13- 30 q25 -18p11- 23 q23 -19p13- 21 q13 -21p13- 22 q22 -22p13- 31 q13 -Xp22- 39 q28

Table 3 A summary of the frequency of imbalances in ovarian carcinomas (table from Hoglund et al., 2003, data from Mitelman Database of Chromosome Aberrations in Cancer)

Very little is known about the sequence of cytogenetic and genetic events accompanying the progression of disease from early to advanced disease. This question has been addressed by analysing the cytogenetic data in the Mitelman Database of Chromosome Aberrations in Cancer and proposed that ovarian carcinomas undergo >3 modes of karyotypic evolution:

Phase I: 1-7 imbalances Phase II: with 8-15 imbalances Phase III: with >15 imbalances Their analyses hypothesised that the temporal order of imbalances were as follows: 1q-, 6q-, +7 and +8q occurred early, -4, -8, +1q, +12 and +20 were intermediate imbalances, and the remaining imbalances were late events. It has been concluded that karyotypic evolution in ovarian carcinomas followed at least 2 cytogenetic pathways. The first pathway involved chromosomal gains of +7/+8q/+12 and was associated with low-stage and low-grade tumours. The second pathway involved chromosomal losses of 6q- and 1q- was found in tumours of moderate stage and grade. The early stages of karyotypic evolution result from the step-wise acquisition of changes resulting in Phase I tumours. Chromosome instability resulted in the transition to Phase II tumours, possibly as a result of extensive telomere crisis and breakage fusion breakage cycles, which is linked to imbalances characteristic of the 6q-/1q- pathway. Consequently, low-grade and borderline tumours cannot progress unless they have mixed-pathway features. The 6q-/1q- pathway was associated with

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -269- triploidization. The 6q-/1q- pathway is instrumental in the progression of ovarian carcinomas. The proposed pathway of karyotypic evolution in ovarian carcinomas is summarised in Figure 1. A cohort of 114 ovarian neoplasms was analysed, including benign, borderline and invasive carcinomas by conventional and molecular cytogenetics. The chromosome abnormalities were categorised as follows: Group 1: Abnormalities found in all subtypes. This included losses of chromosomes 6, 8, 10, 11, 15, 16, 17, 18, 19, 20, 21, 22 and X together with 6q24-qter deletions; and gains of chromosomes 1, 3, 5 and 12. Group 2: Abnormalities present in malignant but not benign subtypes. This included losses of chromosomes 2, 7, 13 and 14, and gains of chromosome 4 and marker chromosomes. Group 3: Abnormalities unique to invasive carcinomas such as loss of chromosome 4, 6q16-q24 deletions, gains of chromosomes 2, 7, 8, 9, 10, 16, 17, 18, 19, 20 and 21, and structural rearrangements of 3p, 3q, 13q and 21q. The presence of cytogenetic aberrations common to all subtypes suggests these tumours develop by progression. The main conclusions from cytogenetic investigations of ovarian epithelial tumours are as follows: Nonrandom breakpoints in ovarian adenocarcinoma do not occur independently. Breakpoints in 1p3 and 11p1 are early events, and associated with poor prognosis Breakpoints in 1p1, 3p1 and 1q2 distinguish a class of ovarian tumours, and breakpoints at 1p1 and 3p1 are associated with a poor prognosis.

Figure 1 Summary of karyotypic evolution in Ovarian carcinomas (taken from

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -270- Hoglund et al., 2003)

Cytogenetics Interphase cytogenetics demonstrated a high frequency of gain of Molecular copy number of 20q13.2 (70%) and cyclin D1 (CCND1 at 11q13, 72%) which were associated with poor prognosis. Another study addressing amplification of 20q12-q13.2 using a series of FISH probes in 24 sporadic and 7 hereditary ovarian carcinomas found amplification of at least one of the regions in 54% of sporadic cases and all of the hereditary cases, and amplification of AIB1 (20q12), a steroid receptor coactivator correlated with poor survival. Online access to summaries of the recurrent DNA copy number amplifications and losses identified by CGH in ovarian epithelial neoplasms (and other tumour entities) can be viewed at http://www.helsinki.fi/cmg/cgh_data.html, and undergo regular updates. The criteria for recurrent losses and gains employed were as follows. For losses, 10% of the cases should have the loss, and there must be at least 3 aberrant cases. Highly frequent aberrations which do not meet the criteria of 10% of cases or 3 cases are indicated by parentheses-such as 1p21-p31. Recurrent amplicons were defined as at least 3 cases and >5% frequency display the amplicon. The recurrent losses and gains are summarised in Table 4. Ovarian Loss Amplification Percentage Ovarian Cancer (1p21-p31) 7 (5/72) 1p34.1- 11 (5/44) 1q 7 (5/71) 2p15p22 4 (1/24) 2q22-q24 5 (1/20) 3cen-q23 4 (1/24) 3q25-q27 13 (6/47) 4q21-q32 16 (30/184) 4q32-qter 16 (15/91) 4q32-qter 16 (15/91) 5q12-q23 16 (30/184) 6p21 7 (3/144) 6q13-qter 5 (1/20) 6q16-qter 13 (23/184) 7q36 7 (2/27) 8p21-pter 17 (32/184) 8q 4 (1/24) 8q22-qter 18 (8/44) 9p 10 (16/159) 9p24 4 (1/27)

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -271- 9p24 4 (1/27) 9q 13 (17/136) 10p15 4 (1/27) 10q11-qter 17 (10/59) 12p12 19 (9/47) 12p12 9 (4/47) 12q24-qter 10 (14/140) 13q12-q21 18 (24/135) 13q21-q32 12 (18/160) 16p 13 (12/93) 16q 23 (24/184) 17p 20 (37/184) 17q11.2- 23 (31/137) q32 17q21-qter 6 (3/47) 18p11.3 4 (1/27) 18q12-qter 18 (33/184) 19p 23 (10/44) 19q 16 (11/69) 21q 10 (12/116) 22q 18 (17/93) Xp 19 (35/184) Xq 19 (9/47) Xq11.2-q21 13 (12/89) Xq21-qter 24 (16/68) Primary epithelial 4p15.2 18 (5/28) ovarian cancer 4q23-q24 18 (5/28) 4q26-q27 18 (5/28) 5q14 14 (4/28) 5q15 14 (4/28) 9p22-p24 11 (3/28) 9q22-q31 18 (5/28) 13q14 14 (4/28) 13q31-q32 21 (6/28) 14q24.3- 14 (4/28) q31 15q21.1 25 (7/28)

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -272- 18q21 11 (3/28) Ovarian Inherited (BRCA1 & 1q32-qter 10 (2/20) BRCA2) 3q26.1 10 (2/20) 5p 5 (1/20) 6p22-p24 10 (2/20) 6q21-q22 5 (1/20) 6q25-qter 15 (3/20) 8p23 40 (8/20) 8q23-q24.1 30 (6/20) 12p 5 (1/20) 12q13-q21 5 (1/20) 18p11.2- 15 (3/20) pter 18q21-qter 20 (4/20) 20p 5 (1/20) Xp 15 (3/20) Xq12-21 15 (3/20) Ovarian cancer, sporadic & 1p34-p36 25 (4/18) inherited 4q31.3-q35 19 (3/16) 9q31-q34 40 (8/16) 10q23-q26 25 (4/16) 11q23-q25 19 (3/16) 16p 19 (3/16) 16q22-q24 38 (6/16) 17p 19 (3/16) 19 19 (3/16) 22q12-q13 25 (4/16) Xp 19 (3/18)

Table 4 Recurrent amplifications and losses in epithelial ovarian tumours, including hereditary neoplasms (data taken from http://www.helsinki.fi/cmg/cgh_data.html) Other studies have identified gain of chromosome 8 in 1/10 ovarian carcinomas. A study of 31 primary ovarian carcinomas in Chinese women by CGH identified several non-random changes in copy number including gains of 3q (17 cases, 55%) with a minimum region of gain of 3q25-

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -273- q26, 8q (16 cases, 52%), 19q (12 cases, 39%), Xq (11 cases, 35%), 1q (10 cases, 32%), 12p12-q13 (10 cases, 32%), 17q (10 cases, 32%) with a minimum region of gain at 17q21, and 20q (9 cases, 29%); together with losses of 16q (9 cases, 29%), 1p (7 cases, 23%), 18q (7 cases, 23%) and 22 (7 cases, 23%). High copy number amplifications were observed at 3q25-q26 (4 cases), 8q24 (3 cases) and 12p11.2- q12 (3 cases). The commonest imbalances detected by CGH of epithelial neoplasms were gain of 3q25-26, gain of 8q24, loss of 16q, and loss of 17pter-q21. 12p gains were seen in 8/44 cases, which has been reported previously in both ovarian and testicular germ cell tumours. Another study by Hauptmann et al., 2002 using CGH to analyse ovarian carcinomas identified frequent gains of 3q, 6p, 7, 8q and 20, together with losses of 4q, 6q, 12q, 13q and 16q, which have supported the available cytogenetic data. CGH was used to screen a mucinous ovarian carcinoma and a Brenner tumour coexisting in different ovaries of the same female. Amplification of 12q14-q21 was identified in both tumours, in the presence of other copy number changes, 4 such changes in the Brenner tumour and 6 in the mucinous carcinoma. Correlation of CGH data with Clinical data In a large study of 106 primary ovarian carcinomas, the CGH findings were correlated with clinical parameters such as tumour grade of differentiation. 103 tumours displayed imbalances. Amplifications of 8q, 1q, 20q, 3q and 19p were frequent findings present in 69-53% of the tumours. Underrepresentations of 13q, 4q and 18q were also common, present in 54-50% of cases. Underrepresentation of 11p and 13q and overrepresentation of 8q and 7q correlated with undifferentiated ovarian carcinoma, whereas 12p underrepresentation and 18p overrepresentation were more commonly associated with well-differentiated and moderately differentiated tumours. These findings corroborate other CGH studies including. A CGH study of a cohort of 12 ovarian clear cell carcinomas revealed similarities to the data of other subtypes of epithelial neoplasms, such as gains of 8q and 17q and losses of 19p. They also correlated their findings with disease status (i.e. disease free, recurrent disease, or death from disease). DNA copy number changes present in over 20% of cases included overrepresentation of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22; and underrepresentation of 19p. Overrepresentation of 8q11-q13, 8q21- q22, 8q23, 8q24-qter was more common in disease-free patients than in those with recurrent disease or who had died. Conversely, overrepresentation of 17q25-qter, 20q13-qter was more frequent in patients with recurrent disease or non-survivors, than in disease-free patients. This data suggests ovarian clear cell carcinoma develop along 2 cytogenetic pathways. In a study correlating CGH genomic imbalances with clinical endpoints in 60 ovarian carcinomas, the following associations were found: Loss of chromosome 4 with high-grade tumours Gains of 3q26-qter, 8q24-qter and 20q13-qter and low-grade and low-stage tumours

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -274- Deletion of 16q24 and >7 independent genomic imbalances and reduced survival times Tumour grade correlated better with genomic progression than clinical stage. CGH findings of Sporadic and Hereditary Ovarian Carcinoma CGH profiles were compared from sporadic and hereditary (3 BRCA1 and 1 BRCA2 mutation carriers) ovarian cancers. The commonest imbalance included amplification of 8q22.1-qter (66.6%), 1q22-32.1 (41.1%), 3q (75%) and 10p (33.2 %), and deletion of 9q (41.6%) and 16q21-q24 (33.3%). Deletions of 9q were found in all 3 BRCA1 carriers and 2/8 sporadic tumours, and deletions of 19 were found in 2/3 BRCA1 carriers and none of the sporadic cases. These findings suggest preferential somatic losses of chromosome 9 and 19 in BRCA1 mutation carriers. In contrast, another study identified extensive similarity by CGH between sporadic and hereditary ovarian carcinomas, except for 2q24-q32. CGH analysis of a further 36 hereditary tumours found the majority of imbalances to be similar to that of sporadic tumours (Gains: 8q23-qter, 3q26.3-qter, 11q22, 2q31- 32; losses: 8p21-pter, 16q22-qter, 22q13, 12q24, 15q11-15, 17p12- 13, Xp21-22, 20q13, 15q24-25, 18q21). However some imbalances were identified that were specific to hereditary tumours, including deletions of 15q11-15, 15q24-25, 8p21-pter, 22q13 and 12q24, and gains of 11q22, 13q22 and 17q23-35. Deletions of 15q11-15 and 15q24-25 were found in 16/36 and 12/36 cases respectively which implicated hRAD51 and other tumour suppressor genes in these loci in the genesis of hereditary ovarian cancer. Genes involved and Proteins Note In addition to involvement of germline mutations of BRCA1, BRCA2 and the mismatch repair genes in the predisposition of ovarian epithelial tumours (see Genetics: Inherited Predisposition section), many studies have investigated somatic changes at specific loci. The somatic aberrations are summarised below according to whether the studies involved allelotyping or analysing specific genes (which is further subdivided into oncogenes and tumour suppressor genes).

Allelotyping/LOH/MSI Cytogenetic and loss of heterozygosity (LOH) studies have implicated many regions of the genome in the pathogenesis of ovarian cancer. Numerous allelotype studies have been performed on ovarian carcinomas and identified frequent losses of 1p, 4p, 5q, 6p, 6q, 7p, 8p, 8q, 9p, 9q, 11p, 11q, 12p, 12q, 13q, 14q, 15q, 16p, 16q, 17p, 17q, 18q, 19p, 21q, 22q and Xp. However most of these studies examined ovarian serous adenocarcinoma. From the few studies that have analysed LOH of benign and LMP tumours, LOH is rarely found at most loci, with the exception of the X chromosome in LMP tumours. LOH analysis of early- stage malignant and borderline ovarian tumours displayed similar LOH patterns suggesting that malignant ovarian tumours may develop from benign and borderline tumours. Frequent allelic losses are found at

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -275- 5p15.2, 5q13-21, 6p24-25, 6q21-23, 6q25.1-27, 7q31.1, 11p15.5, 11p13, 11q22, 11q23.3-qter, 17p13.3 and 17p11.2, suggesting the presence of tumour suppressor genes involved in ovarian carcinoma. Microcell-mediated chromosome transfer of normal chromosome 11 and 17 confirmed the presence of tumour suppressor gene(s) on these chromosomes. Complete suppression of tumourigenicity was obtained by transfer of chromosome 11, whereas reduced in vivo and in vitro growth rates together with increased latency period were obtained by the transfer of chromosome 17. Furthermore transfer of 17p11.2 had the same effect as transfer of the entire chromosome. Microsatellite analysis has suggested the presence of a tumour suppressor gene at 22q11-q12 (between D22S301 and D22S304). This was also supported by microcell-mediated chromosome transfer of chromosome 22 into ovarian carcinoma cell line SKOV3 which resulted in complete abrogation of anchorage-independent growth and a dramatic reduction of in vitro doubling times and tumourigenicity in nude mice.

The pattern of allelic loss differs according to the histological subtypes of epithelial ovarian cancer. Clear cell adenocarcinoma predominantly demonstrates LOH of 1p, 19p and 11q. Serous adenocarcinoma demonstrates allelic losses in >50% of cases of 1p, 4p, 5q, 6p, 8p, 9q, 12q, 13q, 15q, 16p, 17p, 17q, 18p, 18q, 19p, 20p and Xp. Endometrioid adenocarcinoma frequently demonstrated LOH of 7p, and mucinous adenocarcinoma demonstrated recurrent LOH at 17p13.1. LOH analysis using RFLP markers in 6q24-q27 demonstrated allelic loss at a few or all loci in 17/33 ovarian serous tumours, 1/15 ovarian mucinous tumours, and 2/12 ovarian clear cell tumours. Allelic loss of 1p31 has been found in about 40% of ovarian carcinomas, where the maternally imprinted tumour suppressor gene ARH1(NOEY2) resides. Approximately 1/3 of epithelial ovarian tumours of all stages demonstrate LOH of 9p. 69% of 78 ovarian epithelial tumours displayed LOH of 17p13.1 where TP53 is located. Allelic loss at 10q23.3 flanking PTEN and within PTGN have been found in 45% of ovarian epithelial cancers (n=68). Loss of PTEN expression was associated with elevated phosphorylated AKT levels. No microsatellite instability (MSI) was apparent among the 23 benign cystadenomas and 31 LMP ovarian tumours examined using 69 microsatellite markers. Thus these findings suggest MSI is not a pathogenic mechanism in the development of LMP tumours, and abnormalities of the DNA mismatch repair mechanisms are not involved. In contrast, about one-third of endometrioid carcinomas and up to 40% of serous LMP tumours display MSI, although in serous LMP tumours the MSI is low level.

LOH of 3p14.2, 11p15.5, 11q23.3, 11q24, 16q24.3 and 17p13.1 are more frequent in advanced than lower stage tumours. LOH of 3p14.2 correlated with tumour metastasis, whereas LOH at 11p15.5 and 11q23.3 were associated with reduced survival. LOH of 11q22.3 was associated with reduced survival and a serous histology, meanwhile LOH of 11q24-25 correlated with a higher tumour stage, serous histology, presence of residual tumour, but not with survival. LOH of

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -276- 1p36 is associated with poor histological grade.

Tumour Suppressor Genes Alterations in tumour suppressor genes such as P53, RB1, ARH1 (NOEY2), BRCA1 are involved in ovarian carcinogenesis.

P53 Allelic deletions of 17p or P53 mutations occur frequently in ovarian carcinoma. P53 mutations are found in about 50-80% of tumours when analysed by complete gene sequencing. LOH of P53 is also a frequent finding in ovarian carcinomas, ranging from 30% to 80%. P53 mutations have been found in ovarian carcinoma and borderline ovarian tumours. Invasive serous and undifferentiated ovarian carcinomas are characterised by P53 mutations with protein accumulation, extensive allelic loss of chromosome 17 and complex cytogenetic aberrations. Functional wild-type P53 is required for chemo- and radio-sensitivity due to its role in apoptosis. Thus mutation of P53 followed by loss of the wild-type results in resistance to therapy. Of the ovarian neoplasms that express nuclear P53, 90% of them have mutations of P53 which increases the half-life of the P53 protein. 50% of advanced ovarian carcinomas have overexpressed or mutant P53 which correlates with high grade and poor survival, but not with chemoresponsiveness. However, P53 does not appear to be involved in the pathogenesis of clear cell adenocarcinoma.

CDKN2A Homozygous deletions or intragenic mutations of CDKN2A (p16INK4A) are also found in ovarian epithelial tumours. CDKN2A encodes an inhibitory protein of cyclin-dependent kinase 4. The CDKN2A complex blocks phosphorylation of the Retinoblastoma (RB) protein. Phosphorylation of the RB protein is a prerequisite for cells to enter the S phase of the cell cycle. Thus CDKN2A is a negative regulator of the cell cycle. RB Abnormalities of the RB gene in epithelial ovarian cancers have been found by immunohistochemical analysis and molecular approaches, however they are thought to affect a minority of tumours and are possibly a late event in tumourigenesis. GATA4 No expression of GATA4, a transcription factor gene located at 8p23.1, was found in the majority of serous carcinomas, whereas it is expressed in most mucinous carcinomas, suggesting that these tumour types develop along discrete pathogenic pathways. RNASET2 Reduced expression of RNASET2 (RNASE6PL), located at 6q27, was found in 30% of ovarian cancers. Transfection of RNASET2 cDNA into ovarian cancer cell lines suppressed tumourigenicity, suggesting it to be a candidate tumour suppressor gene. BRCA1 Somatic mutations of BRCA1 and BRCA2 have not been found in

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -277- sporadic ovarian neoplasms, however allelic losses including 17q21, were BRCA1 is located, were common. This suggests that additional tumour suppressor genes are required in the molecular aetiology of sporadic tumours, one proximal to BRCA1, the other on 17p.

Oncogenes Alterations in oncogenes KRAS, MYC and ERBB2 are frequently involved in ovarian carcinogenesis.

RAS KRAS mutations are found in 30% of ovarian carcinomas, and are frequently observed in mucinous adenoma and thus may be an early event in the pathogenesis of ovarian mucinous tumours. KRAS mutations are present in 40-50% of mucinous LMP tumours and mucinous carcinomas, and also in one-third of serous LMP tumours. Amplification of KRAS has been reported in 3-5% of ovarian cancers. In one study, KRAS2 amplification occurred in 2/53 of ovarian epithelial tumours, (6 borderline serous, 2 low grade serous, 31 high grade serous; 4 low grade mucinous; 2 low grade endometrioid, 8 high grade endometrioid), and only in the aggressive types (2 high grade serous tumours). A mutation in codon 12 of KRAS has been identified in small cell carcinoma.

HRAS acquires transforming activity either as a result of substitution mutations or by increased expression of the normal gene. Mutated HRAS lack GTPase activity, resulting in dysregulation of cell growth.

Growth Factor Receptors Abnormal cell signalling mediated by protein kinases can result from alterations of the growth factor receptors in ovarian epithelial neoplasms. These include: ERBB2 (HER2/Neu) receptor which is amplified and overexpressed in 9-30% of ovarian cancers. The ERBB2 oncogene located at 17q21 encodes a membrane receptor that binds a glycoprotein similar to transforming growth factor-a and is correlated with poor survival of patients. CSF1R (formerly fms, macrophage colony stimulating factor receptor), is expressed in many ovarian cancers, but not benign ovarian tumours or normal ovarian surface epithelium. Amplification of CSF1R has been reported in 3-5% of ovarian cancers. ECGF1, the platelet-derived endothelial growth factor, shows significantly higher levels in primary epithelial ovarian tumours and was more abundant at the higher stages (III and IV than lower stages), also more prevalent in the mucinous than in the serous adenocarcinomas. EGFR which encodes the transmembrane receptor for epidermal growth factor is expressed by most advanced carcinomas and is associated with poor prognosis. MYC Amplification of MYC oncogene, 8q24, occurs in 10-20 % of ovarian cancers, and in about one-third of advanced ovarian carcinomas. MYC

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -278- amplification is more frequently found in the serous subtypes than the mucinous subtypes. MYC encodes a DNA-binding nuclear-associated protein that regulates cell proliferation. Dividing cells have increased amounts of nuclear c-myc, whereas quiescent cells express negligible quantities. MYC amplification is often indicative of biologically aggressive tumours. MYC amplification was not associated with prognosis or survival. Significantly higher levels of p62c-myc were found in serous papillary ovarian carcinoma. LMP tumours expressed MYC at values intermediate between that of normal ovary tissue and carcinoma. PI3K/AKT2 Amplification, altered expression, and malfunction of several protein kinases and phosphatases are involved in the pathogenesis of ovarian epithelial neoplasms, in particular the phosphatidylinositol 3-kinase (PI3K) pathway. Increased PI3K activity is important in the growth and dissemination of ovarian cancer cells. The PIK3CA gene which encodes the catalytic subunit of PI3K, and its downstream effector AKT2 are amplified in primary ovarian tumours. Overexpression of AKT2 is found in high-grade and late-stage tumours. Mutation and/or down-regulation of the PI3K phosphatase PTEN/MMAC1 are frequently observed in ovarian endometrioid carcinomas. AKT2 mediates some of the transforming signals of RAS and SRC which are mutated and overexpressed/activated respectively in late-stage tumours. Downregulation of the cGMP-dependent protein kinase PKG and upregulation of MAP2K6 (MEK6) were significantly correlated with the genesis of ovarian cancer. Amplification of AKT2 has been reported in 3-5% of ovarian cancers. Other oncogenes Amplification of other oncogenes such as FGF3 (formerly INT2) and MDM2 have been reported in 3-5% of ovarian cancers. As mentioned in the Molecular Cytogenetics section, high level amplification of 20q12- q13.2 is a frequent finding in ovarian carcinomas, and a gene located at 20q11.2-12, TGIF2, was amplified and over-expressed in 14 ovarian cancer cell lines. EIF5A2 is a candidate oncogene for the 3q25-q26 amplification in ovarian carcinomas. Overexpression of the Kallikrein gene, KLK4, located at 19q13.4, has been found in 69/147 ovarian tumours and is indicative of a poor prognosis. NME1 is thought to have a role in ovarian neoplastic process. Elevated levels of inhibin are found in most postmenopausal women with mucinous ovarian cancers. Oncogenes involved in endometrioid carcinoma Overexpression of BCL2 is present in about 90% of endometrioid carcinomas, and MSI is present in about one-third of cases, as has been described in endometrioid endometrial carcinomas. Overexpression of P53, EGFR, ERBB2 and ERBB3 was also detected in ovarian endometrioid carcinoma. Expression Profiling Expression microarrays were used to compare differential expression between 7 early stage ovarian carcinomas and 7 late stage ovarian carcinomas, and showed that several genes are aberrantly regulated to the same extent in both groups. Genes which function in cell-cell interaction such as cadherin 11 (CDH11), cadherin 2 (CDH2) and

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -279- nidogen (NID) were downregulated in most tumours. Genes involved in invasion and metastasis such as matrilysin (MMP7), gelatinase (MMP9), matrix metalloproteinase 10 and 12 were upregulated in most tumours. Several other expression profiling studies have been undertaken which identified differentially expressed genes between serous and mucinous carcinomas; and also identified differences in gene expression during progression of ovarian carcinoma.

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Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. Ali IU, Schriml LM, Dean M. J Natl Cancer Inst 1999; 91: 1922-1932. Medline 10564676

BRCA1-associated growth arrest is RB-dependent. Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET. Proc Natl Acad Sci U S A 1999; 96: 11866-11871. Medline 10518542

Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Catteau A, Harris WH, Xu CF, Solomon E. Oncogene 1999; 18: 1957-1965. Medline 10208417

Molecular genetics of ovarian carcinomas. Diebold J. Histol Histopathol 1999; 14: 269-277. Medline 9987671

Inhibin subunit gene expression in ovarian cancer. Fuller PJ, Chu S, Jobling T, Mamers P, Healy DL, Burger HG. Gynecol Oncol 1999; 73: 273-279. Medline 10329046

Prognostic significance of P53 expression in advanced-stage ovarian serous borderline tumors. Gershenson DM, Deavers M, Diaz S, Tortolero-Luna G, Miller BE, Bast RC, Jr., Mills GB, Silva EG Clin Cancer Res 1999; 5: 4053-4058. Medline 10632339

Gains of 1q21-q22 and 13q12-q14 are potential indicators for resistance to cisplatin-based chemotherapy in ovarian cancer patients. Kudoh K, Takano M, Koshikawa T, Hirai M, Yoshida S, Mano Y, Yamamoto K, Ishii K, Kita T, Kikuchi Y, Nagata I, Miwa M, Uchida K. Clin Cancer Res 1999; 5: 2526-2531.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -294- Medline 10499629

Well-differentiated mucinous carcinoma of the ovary and a coexisting Brenner tumor both exhibit amplification of 12q14-21 by comparative genomic hybridization. Pejovic T, Burki N, Odunsi K, Fiedler P, Achong N, Schwartz PE, Ward DC. Gynecol Oncol 1999; 74: 134-137. Medline 10385566

PIK3CA is implicated as an oncogene in ovarian cancer. Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW. Nat Genet 1999; 21: 99-102. Medline 9916799

The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study. Stratton JF, Thompson D, Bobrow L, Dalal N, Gore M, Bishop DT, Scott I, Evans G, Daly P, Easton DF, Ponder BA. Am J Hum Genet 1999; 65: 1725-1732. Medline 10577927

Decreased Src tyrosine kinase activity inhibits malignant human ovarian cancer tumor growth in a nude mouse model. Wiener JR, Nakano K, Kruzelock RP, Bucana CD, Bast RC, Jr., Gallick GE. Clin Cancer Res 1999; 5: 2164-2170. Medline 10473101

NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC Jr. Proc Natl Acad Sci U S A 1999; 96: 214-219. Medline 9874798

The Ovary. Rice LW In Kistner's Gynecology & Women's Health 1999, Ryan KJ (ed) pp 166-189. Mosby

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -295- 20q13 and cyclin D1 in ovarian carcinomas. Analysis by fluorescence in situ hybridization. Diebold J, Mosinger K, Peiro G, Pannekamp U, Kaltz C, Baretton GB, Meier W, Lohrs U J Pathol 2000; 190: 564-571. Medline 10727982

In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Hu L, Zaloudek C, Mills GB, Gray J, Jaffe RB. Clin Cancer Res 2000; 6: 880-886. Medline 10741711

Amplification and overexpression of TGIF2, a novel homeobox gene of the TALE superclass, in ovarian cancer cell lines. Imoto I, Pimkhaokham A, Watanabe T, Saito-Ohara F, Soeda E, Inazawa J. Biochem Biophys Res Commun 2000; 276: 264-270. Medline 11006116

Differential gene expression between normal and tumor-derived ovarian epithelial cells. Ismail RS, Baldwin RL, Fang J, Browning D, Karlan BY, Gasson JC, Chang DD. Cancer Res 2000; 60: 6744-6749. Medline 11118061

Comparison of comparative genomic hybridization and interphase fluorescence in situ hybridization in ovarian carcinomas: possibilities and limitations of both techniques. Jacobsen A, Arnold N, Weimer J, Kiechle M. Cancer Genet Cytogenet 2000; 122: 7-12. Medline 11104025

Ovarian Carcinoma. Jones HW. In Cecil Textbook of Medicine 2000; Goldman L (ed) Saunders

Functional evidence for an ovarian cancer tumor suppressor gene on chromosome 22 by microcell-mediated chromosome transfer. Kruzelock RP, Cuevas BD, Wiener JR, Xu FJ, Yu Y, Cabeza-Arvelaiz Y, Pershouse M, Lovell MM, Killary AM, Mills GB, Bast RC Jr. Oncogene 2000; 19: 6277-6285. Medline 11175342

Loss of heterozygosity at chromosomes 3, 6, 8, 11, 16, and 17 in ovarian cancer: correlation to clinicopathological variables. Launonen V, Mannermaa A, Stenback F, Kosma VM, Puistola U, Huusko P, Anttila

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -296- M, Bloigu R, Saarikoski S, Kauppila A, Winqvist R Cancer Genet Cytogenet 2000; 122: 49-54. Medline 11104033

Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Ono K, Tanaka T, Tsunoda T, Kitahara O, Kihara C, Okamoto A, Ochiai K, Takagi T, Nakamura Y Cancer Res 2000; 60: 5007-5011. Medline 11016619

Comparative genomic hybridization in inherited and sporadic ovarian tumors in Israel. Patael-Karasik Y, Daniely M, Gotlieb WH, Ben Baruch G, Schiby J, Barakai G, Goldman B, Aviram A, Friedman E. Cancer Genet Cytogenet 2000; 121: 26-32. Medline 10958937

Detection of c-erbB-2 and FGF-3 (INT-2) gene amplification in epithelial ovarian cancer. Seki A, Yoshinouchi M, Seki N, Kodama J, Miyagi Y, Kudo T. Int J Oncol 2000; 17: 103-106. Medline 10853025

Genetic aberrations detected by comparative genomic hybridization in ovarian clear cell adenocarcinomas. Suehiro Y, Sakamoto M, Umayahara K, Iwabuchi H, Sakamoto H, Tanaka N, Takeshima N, Yamauchi K, Hasumi K, Akiya T, Sakunaga H, Muroya T, Numa F, Kato H, Tenjin Y, Sugishita T Oncology 2000; 59: 50-56. Medline 10895067

Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -297- Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D, Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L, Magnanini C, Tibiletti MG, Bernasconi B, Daidone MG, Shridhar V, Smith DI, Negrini M, Barbanti-Brodano G, Taramelli R. Oncogene 2001; 20: 980-988. Medline 11314033

Allele loss on chromosome 1p36 in epithelial ovarian cancers. Alvarez AA, Lambers AR, Lancaster JM, Maxwell GL, Ali S, Gumbs C, Berchuck A, Futreal PA. Gynecol Oncol 2001; 82: 94-98. Medline 11426968

Suppression of tumorigenicity in human ovarian carcinoma cell line SKOV-3 by microcell-mediated transfer of chromosome 11. Cao Q, Abeysinghe H, Chow O, Xu J, Kaung H, Fong C, Keng P, Insel RA, Lee WM, Barrett JC, Wang N. Cancer Genet Cytogenet 2001; 129: 131-137. Medline 11566343

[Phenotype--genotype--correlation in ovarian neoplasia]. Diebold J. Verh Dtsch Ges Pathol 2001; 85: 153-160. Medline 11894392

Detection of numerical aberration in chromosome 17 and c-erbB2 gene amplification in epithelial ovarian cancer using recently established dual color FISH. Fukushi Y, Sato S, Yokoyama Y, Kudo K, Maruyama H, Saito Y. Eur J Gynaecol Oncol 2001; 22: 23-25. Medline 11321488

Isolation of a novel candidate oncogene within a frequently amplified region at 3q26 in ovarian cancer. Guan XY, Sham JS, Tang TC, Fang Y, Huo KK, Yang JM. Cancer Res 2001; 61: 3806-3809. Medline 11325856

Serous tumors of low malignant potential of the ovary-molecular pathology: part 2. Hauptmann S, Dietel M. Virchows Arch 2001; 438: 539-551. Medline 11469685

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -298- Cancer 2001; 91: 534-540. Medline 11169935

Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas. Kurose K, Zhou XP, Araki T, Cannistra SA, Maher ER, Eng C. Am J Pathol 2001; 158: 2097-2106. Medline 11395387

Noble J (Ed) Textbook of Primary Care Medicine 2001. Mosby

Higher human kallikrein gene 4 (KLK4) expression indicates poor prognosis of ovarian cancer patients. Obiezu CV, Scorilas A, Katsaros D, Massobrio M, Yousef GM, Fracchioli S, Rigault de la Longrais IA, Arisio R, Diamandis EP. Clin Cancer Res 2001; 7: 2380-2386. Medline 11489816

Nongenetic Screening of Ovarian Malignancies. Schwartz PE Obstetrics and Gynecology Clinics 2001; 28: 637-51 Review. Medline 11766142

Localization of a novel susceptibility gene for familial ovarian cancer to chromosome 3p22-p25. Sekine M, Nagata H, Tsuji S, Hirai Y, Fujimoto S, Hatae M, Kobayashi I, Fujii T, Nagata I, Ushijima K, Obata K, Suzuki M, Yoshinaga M, Umesaki N, Satoh S, Enomoto T, Motoyama S, Tanaka K. Hum Mol Genet 2001; 10: 1421-1429. Medline 11440995

Genetic analysis of early- versus late-stage ovarian tumors. Shridhar V, Lee J, Pandita A, Iturria S, Avula R, Staub J, Morrissey M, Calhoun E, Sen A, Kalli K, Keeney G, Roche P, Cliby W, Lu K, Schmandt R, Mills GB, Bast RC, Jr., James CD, Couch FJ, Hartmann LC, Lillie J, Smith DI. Cancer Res 2001; 61: 5895-5904. Medline 11479231

Changes in gene expression during progression of ovarian carcinoma. Tapper J, Kettunen E, El Rifai W, Seppala M, Andersson LC, Knuutila S. Cancer Genet Cytogenet 2001; 128: 1-6. Medline 11454421

Chromosome 6 abnormalities in ovarian surface epithelial tumors of borderline

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -299- malignancy suggest a genetic continuum in the progression model of ovarian neoplasms. Tibiletti MG, Bernasconi B, Furlan D, Bressan P, Cerutti R, Facco C, Franchi M, Riva C, Cinquetti R, Capella C, Taramelli R Clin Cancer Res 2001; 7: 3404-3409. Medline 11705855

A novel amplification at 17q21-23 in ovarian cancer cell lines detected by comparative genomic hybridization. Watanabe T, Imoto I, Kosugi Y, Ishiwata I, Inoue S, Takayama M, Sato A, Inazawa J. Gynecol Oncol 2001; 81: 172-177. Medline 11330945

Profiling of protein kinases in the neoplastic transformation of human ovarian surface epithelium. Wong AS, Kim SO, Leung PC, Auersperg N, Pelech SL. Gynecol Oncol 2001; 82: 305-311. Medline 11531284

Comparative genomic hybridization of microdissected familial ovarian carcinoma: two deleted regions on chromosome 15q not previously identified in sporadic ovarian carcinoma. Zweemer RP, Ryan A, Snijders AM, Hermsen MA, Meijer GA, Beller U, Menko FH, Jacobs IJ, Baak JP, Verheijen RH, Kenemans P, van Diest PJ. Lab Invest 2001; 81: 1363-1370. Medline 11598149

Borderline Ovarian Cancer 2002 Green A.

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Characteristic pattern of genetic aberrations in ovarian granulosa cell tumors. Mayr D, Kaltz-Wittmer C, Arbogast S, Amann G, Aust DE, Diebold J. Mod Pathol 2002; 15: 951-957. Medline 12218213

Allelotype analysis of common epithelial ovarian cancers with special reference to comparison between clear cell adenocarcinoma with other histological types. Okada S, Tsuda H, Takarabe T, Yoshikawa H, Taketani Y, Hirohashi S. Jpn J Cancer Res 2002; 93: 798-806. Medline 12149146

Recurrent chromosome alterations in primary ovarian carcinoma in Chinese women.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -300- Sham JS, Tang TC, Fang Y, Sun L, Qin LX, Wu QL, Xie D, Guan XY. Cancer Genet Cytogenet 2002; 133: 39-44. Medline 11890988

Cytogenetics and molecular genetics of ovarian cancer. Wang N. Am J Med Genet 2002; 115: 157-163. Medline 12407696

Ferri FF. Ferri's Clinical Advisor: Instant Diagnosis and Treatment 2003. Mosby

Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: from the Danish MALOVA Ovarian Cancer Study. Hogdall EV, Christensen L, Kjaer SK, Blaakaer J, Bock JE, Glud E, Norgaard- Pedersen B, Hogdall CK. Cancer 2003; 98: 66-73. Medline 12833457

Ovarian carcinoma develops through multiple modes of chromosomal evolution. Hoglund M, Gisselsson D, Hansen GB, Sall T, Mitelman F. Cancer Res 2003; 63: 3378-3385. Medline 12810674

Genetic and cytogenetic observations among different types of ovarian tumors are compatible with a progression model underlying ovarian tumorigenesis. Tibiletti MG, Bernasconi B, Taborelli M, Facco C, Riva C, Capella C, Franchi M, Binelli G, Acquati F, Taramelli R. Cancer Genet Cytogenet 2003; 146: 145-153. Medline 14553949

Platelet-derived endothelial cell growth factor predicts of progression and recurrence in primary epithelial ovarian cancer. Watanabe Y, Nakai H, Ueda H, Nozaki K, Hoshiai H, Noda K. Cancer Lett 2003; 200: 173-176. Medline 14568172

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 12- Lisa Lee-Jones 2003

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -301- Citation This paper should be referenced as such : Lee-Jones L . Ovary: Epithelial tumors. Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/OvaryEpithTumID5230.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -302- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Lung: Non-small cell carcinoma

Identity Note See also the overview on lung tumors Classification Non-small cell carcinomas are divided into three main categories according to the predominant morphology of the tumour cells as determined by light microscopy. Although it is possible to distinguish different histological sub-groups in this way, or by using gene expression profiling, treatment is currently decided on the basis of tumour staging, age and performance status and is independent of tumour histology. In the future, this may change as new drugs are developed and as more information is gathered on the predictive power of such expression profiles. Clinics and Pathology Pathology Squamous cell carcinoma: Approximately 30% of lung tumours are classified as squamous cell carcinomas (SCC). Whilst this was the most common sub-type seen in the past, the incidence of SCC appears to be decreasing relative to adenocarcinoma, probably as a consequence of historical changes in the way that cigarettes are smoked (lower tar and filter tips promoting deeper inhalation). SCC cells are large, flattened and stratified with a high cytoplasm to nucleus ratio. Key diagnostic features include the presence of intracytoplasmic keratin which may be linked to the presence of intercellular bridges and squamous pearl formation. Most SCC arise centrally within the main, lobar, segmental or subsegmental bronchi but some occur more peripherally. The tumour mass generally extends into the lumen of the airway with invasion into the underlying wall.

Adenocarcinoma: A further 30-50% of tumours are defined as adenocarcinomas (ADC). This tumour type is the most common in non-smokers and women and it is more frequently associated with pleural effusions and distant metastases. ADC may be further sub-classified into:

acinar (gland forming), papillary, bronchioalveolar (BAC), solid with mucin and

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -303- mixed. As most ADC are histologically heterogeneous, they generally fall into the mixed category. The tumours usually arise in the smaller peripheral airways (as distinct from the cartilage bearing bronchi) but they can be found more centrally. The key diagnostic features of ADC include gland formation - where the tumour cells are arranged around a central lumen - and/or mucin production. ADC is the tumour type most commonly found associated with fibrotic scars, which are thought to be caused in some way by the tumour. BAC, which represents 2-6% of total lung cancer is distinct from other sub-types both in terms of its growth pattern, which is lepidic (typically arising beyond the terminal bronchioloes, where it spreads along the alveolar septa causing minimal structural damage) and by the fact that it is non-invasive. Large cell carcinoma: Approximately 10% of NSCLC are defined as large cell carcinomas (LCC). This is a diagnosis of exclusion. Where a poorly differentiated tumour has none of the defining features of SCLC, SCC or ADC it may be classified as LCC: that is, where the cells of the lesion are not-columnar in shape, do not contain mucous, do not show squamous differentiation, and do not have neuroendocrine properties or small cell characteristics. Tumours tend to consist of large cells with abundant cytoplasm, large nuclei and prominent nucleoli and they may occur peripherally or centrally. Variants of LCC include clear cell carcinoma, giant cell carcinoma and large cell neuroendocrine carcinoma (LCNEC). Pre-invasive lesions The bronchial epithelium of the larger airways is a pseudo- stratified epidermal layer. The most frequent cell types present are ciliated columnar cells, interspersed mucous-producing goblet cells and, lying closely against the basement membrane, multi-potent basal epithelial cells. The basal (or reserve) cell has a repair capacity in that it is able to differentiate, as required, into the other mature cells of the larger conducting airways. In the smaller terminal and respiratory bronchioles, basal cells are not present. The reserve cells of these epithelia are the cuboidal, non-ciliated Clara cells. It has been suggested that the multipotent basal cell or a stem cell precursor of such cells may represent a common lung cancer progenitor. In chronic smokers, the cells of the tracheo-bronchial tree are repeatedly exposed to a range of carcinogenic compounds. Consequently, histologically-recognisable reactive and pre- neoplastic changes can generally be seen scattered throughout the airways of long-time smokers. In situ (pre-invasive) carcinoma (CIS: full thickness cytological atypia, increased nuclear to cytoplasmic ratio) is a recognised precursor of squamous cell carcinoma. This is the end of a spectrum of pre- neoplastic transformation that ranges from squamous metaplasia (change in appearance of cuboidal cells towards squamous morphology) through mild to severe dysplasia (loss of polarity,

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -304- increasing disorder) to CIS. A second pre-neoplastic state is represented by Atypical Adenomatous Hyperplasia (AAH). This is a bronchioalveolar proliferation of slightly atypical cuboidal cells that falls short of the criteria for BAC: it is a recognised precursor to adenocarcinoma. Cytogenetics Note Lung carcinomas represent the end-stage of the neoplastic transformation of a stem (or stem-cell like) cell that has been repeatedly exposed over many years to high levels of multiple carcinogens. It is therefore not surprising that the genetic and epigenetic lesions seen in lung cancer cells are complex. Correspondingly, frequent numerical and structural chromosomal alterations are reported in NSCLC. Whilst many changes are common, some perhaps occurring more often in one histological class over another, few if any have been shown to be exclusive to particular sub-types of disease or prognostic groupings. At the molecular level, highly complex patterns of allelic imbalance (LOH) have been observed in primary tumours. Again, few if any of these have been strongly related to diagnosis or prognosis. No balanced chromosomal translocations have yet been associated characteristically with NSCLC. Cytogenetics The generally low mitotic index of lung carcinomas makes karyotypic Morphological analysis difficult. However, common numerical changes observed include the losses of chromosomes 9 and 13 and trisomy for chromosome 7. Unbalanced rearrangements have been reported to occur frequently within chromosomes 1, 3, 5, 6, 7, 8, 9, 11, 13, 14, 15, 17 and 19 and it is thought that the loss of genetic material due to such events might encompass, to some lesser extent, all chromosome arms. Arms which frequently show clear loss include; 9p, 3p,6q, 8p, 9q, 13q, 17p, 18q, 19p, 21q, and 22q with those often associated with gains being 7p, 7q, 1q, 3q, 5p, 11q and 12q. Cytogenetics Comparative genomic hybridisation (CGH) has been used to extend Molecular conventional karyotypic analysis in NSCLC. Prominent imbalances seen in several studies include losses of 3p, 8p, 9p, 13q and 17p and gain of chromosome arms 1q, 3q, 5p and 8q. Regional amplification has been reported for 3q26, 8q24, 3q13, 3q28-qter, 7q11.2, 8p11-12, 12p12 and 19q13.1-13.2. Minimally localised under-represented regions include 3p14-21, 8p21-23 and 17p12-13. CGH analysis has also suggested that some alterations are more commonly seen in particular NSCLC sub-types with gain of 3q24-qter more common in SCC than ADC and gain of 1q22-32 more common in ADC than SCC. Genes involved and Proteins Note Consistent somatic mutation of coding sequence in primary tumours is strong evidence that a particular gene has been or is involved in the development of a neoplastic phenotype. In common with a range of tumours, particular genes are therefore clearly associated with NSCLC

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -305- initiation or progression. These include TP53 (17p13.1), CDKN2A encoding p16 and p14 (9p21.3) and KRAS2 (12p12.1). Each of these genes lies within a region identified cytogenetically as implicated in NSCLC.

The amplification of chromosomal regions containing genes implicated in cell growth has also been reported in primary NSCLC, albeit at a relatively low frequency. Such data are suggestive of the involvement of these sequences in neoplasia but they are weaker than direct mutational evidence given that the amplified regions generally contain a number of distinct genes, the relative contributions of each of which to the tumour phenotype is usually unknown. Genes reported as amplified in primary lesions include CCND1, encoding cyclin D1 (11q13.3), TP73L, encoding p63 (3q28), KRAS2 (12p12), MYC (8q24.21) and EGFR (7p11.2).

A number of genes that are encoded from within chromosomal regions which show LOH or homozygous deletion in certain lesions have been identified. Such sequences may show a lack of expression in primary tumour cells compared to at least most of the cells in normal lung tissue. This lack of expression may in turn be correlated with hypermethylation of the relevant promoter sequence. Examples of such genes include RASSF1A (3p21) and CDKN2A (9p21.3). It is tempting to speculate that genes which show high levels of promoter methylation in tumour over normal tissue have been somatically inactivated by such methylation and are therefore likely to represent causally involved tumour suppressors. Whilst this may well be true in specific instances, especially where the gene in question is mutationally inactivated in a separate fraction of lesions (CDKN2), it may not be so generally, as the methylation level seen in the tumour may be completely appropriate for the cell type of origin of the particular lesion.

Whilst the data suggesting the involvement of an individual gene in a tumour type might not be compelling, when pathways or control points are considered, the evidence often becomes much stronger. The best example of this is perhaps damage to the genetic system controlling progression through the G1 restriction point of the cell cycle, beyond which the cell is committed to divide. Proteins intimately involved in this key decision point, cyclin D1, p16, and pRB are frequent targets of NSCLC miss-regulation and may be involved at the earliest stages of pre-neoplastic development.

Microarray analyses: Recent microarray analyses have shown that gene expression profiling can be used to sub-divide tumours into existing histological classes. Perhaps more importantly, analyses of adenocarcinoma series have demonstrated that sub-groups of stage 1 lesions with better or worse survival can be identified from their expression patterns. Such data suggest that tumour behaviour may be, at least to some point, fixed very early in the disease process. From a different perspective, many genes have been shown to be commonly

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -306- differentially expressed (over-represented) in NSCLC compared to normal lung, to some extent at least, irrespective of general histology. Such genes are potential diagnostic targets. More importantly, the study of their function, normal expression patterns and mechanisms of expression control may shed considerable light on the biology of lung cancer and the characteristics of the cell type(s) of origin. Preliminary analyses of genomics and/or proteomics highlighted sequences (S100A2, encoding maspin and TP73L, encoding p63) in lung tumours and pre-neoplastic lesions supports such hypotheses and raise the possibility that some measure of tumour gene expression may result from a failure to appropriately inactivate particular sequences involved in the self-renewal phenotype of stem-cell (like) progenitors. It is anticipated that in the future, further detailed molecular investigations of gene expression in disease and normal tissues will lead to new prognostic, predictive, diagnostic, therapeutic and preventative tools.

COMPLEMENTATION_GROUPS

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REVIEW articles automatic search in PubMed Last year automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -308- publications Contributor(s) Written 02- Jim Heighway, Daniel C Betticher 2004 Citation This paper should be referenced as such : Heighway J, Betticher DC . Lung: Non-small cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. February 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/LungNonSmallCellID5141.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -309- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Lung tumors: an overview

Identity Note The overwhelming majority of lung tumours are carcinomas. Most commonly, they arise from the pseudo-stratified epithelial lining of the bronchial airways but they can also arise from the epithelia of the smaller terminal airways and alveoli. Worldwide, lung cancer is the most common cause of cancer-related death. Classification Note Lung cancer diagnosis and classification are currently based primarily on light microscopy, occasionally supplemented by immunohistochemical assays. The use of microarray generated data in the future is likely to radically improve disease sub-classification. Lung tumours are divided into two broad categories of small cell carcinoma (SCLC 20-25% of cases) and non-small cell lung cancer (NSCLC 70-80% of cases) based on clinical behaviour and histological appearance. Other rarer tumour types include carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant and spindle cell carcinomas.

NSCLC is further divided histologically into three main disease subtypes of:

squamous cell carcinoma, adenocarcinoma and large cell carcinoma.

Whilst in certain countries, adenocarcinoma is now the most common disease subtype seen, in other countries, whilst the relative frequency of adenocarcinoma is rising, squamous cell carcinoma still predominates. Clinics and Pathology Etiology The smoking of tobacco is the primary cause of lung cancer and patterns of occurrence are largely determined by historical exposure. In general, the contribution of genetic or other environmental factors to lung cancer risk is thought to be small but some may synergise with smoking. Such additional environmental factors include exposure to

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -310- radon gas (an indoor environmental pollutant), workplace exposures to inorganic fibres (asbestos) or toxic chemical entities, air pollution and ionising radiation. As for many cancers, poor diet appears to be associated with increased disease risk. Epidemiology Smoking increases the risk of all histological subtypes but is most strongly associated with squamous cell and small cell disease. Adenocarcinoma is more common in women than in men and more common in non-smokers with disease than smokers. The number of cases attributable to tobacco smoking varies between countries and regions depending on the historical levels of smoking for those regions. A recent estimate for Europe suggested that 90% of male and 60% of female lung cancers were caused by exposure to cigarette smoke.

The observation that perhaps only 1-2 of every 10 smokers develops clinical lung cancer during their lifetime has been used as an argument to suggest that some level of genetic predisposition modifies disease risk. Whilst this argument is perhaps not compelling, it is not unreasonable and indeed a small number of genetic polymorphisms have been associated with modest increases in lung cancer risk. As lung cancer is usually caused by a chronic exposure of the bronchial epithelium to multiple procarcinogenic (and carcinogenic) agents, it is not surprising that many of these polymorphisms lie in genes associated with the activation (cytochrome P450s) or deactivation (Glutathione S-transferases) of such entities or the repair of subsequently induced damage (TP53). In general, epidemiological analysis has not suggested the existence of highly-penetrant, strongly- predisposing lung cancer associated genetic variants. Clinics In the early stages of disease, lung cancer tends to be asymptomatic. Consequently, at the time of diagnosis, most tumours are overtly (stage IIIB, IV) or covertly metastatic. Resectable, localised, disease (stages I-IIIA) is identified in approximately 20% of patients. Generally advanced stage at diagnosis and the relative resistance of the disease to currently available anti-cancer drugs leads to a high mortality rate, with 5-year survival typically between 10 and 15%. The potential benefits and costs of CT screening for the detection of early, asymptomatic lung cancer are currently being evaluated in large randomised trials in several countries. Pathology Tumours are classified primarily on their cytological appearance. The relative frequency of subtypes varies in different regions and the figures cited therefore represent broad approximations. Clinically, the most important division is between SCLC and NSCLC. Small cell tumours metastasise very early in the course of the disease but are relatively responsive to chemotherapeutic drugs: they are therefore managed in a different way to non-small cell lesions. Lung cancers are generally heterogeneous, consisting frequently of cells of different histological subtypes. Pathological classifications therefore emphasise the major cell type present in the tissue analysed and may note significant minor components. When components are roughly equal,

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -311- designations such as adenosquamous carcinoma may be used. This common intra-tumour heterogeneity has led to the suggestion that lung carcinomas arise from a multipotent stem cell-like (or stem cell) component of the bronchial epithelium. Whilst microarray analyses have shown that gene expression can be used effectively to subdivide disease into existing or novel subtypes, it has also highlighted the similarity that lies between these subtypes at the level of gene expression. Such observations are consistent with a common stem cell progenitor.

NSCLC

Squamous cell lung carcinoma comprises approximately 30% of lung cancers. These tumours generally arise centrally within the lungs inside a large bronchus although they may sometimes be peripheral; Adenocarcinomas, representing perhaps 30% of invasive lesions, tend to occur in more peripheral locations arising from the smaller airways but they can be found centrally in a main bronchus; Large cell carcinomas, 10% of lung cancers, are undifferentiated tumours which lack the diagnostic features of the other subtypes. This is therefore to some extent a default classification, made when other specific histology has been excluded.

SCLC

Small cell carcinomas account for 20% of lung cancers. They mostly arise centrally in a large bronchus and are highly invasive and highly metastatic. Treatment Before the appropriate treatment can be defined a careful staging of the disease must be made. The principles of therapy of NSCLC and SCLC are different. SCLC is very seldom surgically resectable, usually widespread at presentation and is generally both more chemosensitive and radiosensitive.

NSCLC: Treatment is based on the stage of the disease at presentation (which may be assessed by thoracic CT, PET scan, brain MRI). Stage I-II are usually resected (adjuvant chemotherapy can be discussed with the patient) and locally advanced stages (III) are treated by combined modality treatments (neoadjuvant chemotherapy, resection if stage IIIA or radiotherapy). If overt distant metastases are detected, therapy is palliative and chemotherapy has been shown to improve median survival and quality of life.

SCLC: If the tumour is confined to one hemithorax (limited disease), a combined modality therapy (chemo- and radiotherapy) is indicated: in more advanced disease (overt distant metastases in brain, liver, bones, surrenal glands or other organs) chemotherapy will be palliative though an excellent remission might be obtained in more than half of

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -312- the patients.

New therapies based on an improved understanding of the molecular basis of the disease are currently in use or are under development. For example, Gefitinib, a tyrosine kinase inhibitor, is one such example that has been launched on the market in different countries for patients with relapsed or refractory NSCLC after chemotherapy. Further drugs with other defined molecular targets are anticipated. Prognosis Once a diagnosis of lung cancer has been made (biopsy, cytology) the disease is staged (I - IV) according to established international criteria. NSCLC patients are divided into different groups based on the TNM classification system. This is a combined grading incorporating tumour size and location (T), lymph node involvement (N) and presence of distant metastasis (M). In general, higher stage (both overall and within each category) correlates with a poorer prognosis with a 5-year survival of 60-70% for T1-2, N0, M0 (stage I) disease and <1% for TX, NX, M1 (stage IV) disease. SCLC is classified as limited (to one hemithorax) or extensive (with distant metastasis) disease with 3-year survival being 5-10% and <1%, respectively. Cytogenetics Note Lung tumours generally show complex karyotypic changes which involve multiple chromosomes. However, one of the most consistent alterations seen in both SCLC (approaching 100%) and NSCLC (approaching 90%) is a loss of coding potential from the short arm of chromosome 3. Loss of chromosome 3 sequence appears to occur frequently at the very earliest stages of neoplastic transformation, when epithelial cells may show no evidence of morphological alteration. Genes involved and Proteins Note The loss of p53 function, generally through mutation of the coding sequence is seen in the majority of lung carcinomas. Less dramatically, mutation of KRAS2 occurs in approximately 20% of NSCLC lesions and may indicate a poor prognosis when it is detected in small adenocarcinomas.

Microarray analyses have shown that many other genes show dramatic differences in expression between lung tumours and normal lung tissue. These differences may be driven by tumour gene amplification, deletion, control region mutation or chromosomal translocation (all apparently relatively rare in primary disease) or perhaps more commonly, may be associated with changes in various types of epigenetic modification of the DNA sequence. The differential expressions may be disease-related in the sense that they are induced directly by DNA damage events in the tumour cell, or they may be only indirectly linked to the disease, in the sense that they are typical of the gene expression patterns of progenitor cells and atypical for the majority of normally differentiated lung cells.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -313-

Bibliography Lung cancer and cigarette smoking in Europe: an update of risk estimates and an assessment of inter-country heterogeneity. Simonato L, Agudo A, Ahrens W et al. Int J Cancer 2001; 91: 876-887. Medline 11275995

Cancer burden in the year 2000. The global picture. Parkin DM, Bray FI, Devesa SS. Eur J Cancer 2001; 37: S4-S66. Medline 11602373

Lung cancer in Europe in 2000: epidemiology, prevention, and early detection. Tyczynski JE, Bray F, Parkin DM. Lancet Oncol 2003; 4: 45-55. Medline 12517539

Lung Cancer: Principles and Practice. Pass HI, Mitchell JB, Johnson DH. Lippincott Williams & Wilkins, Philadelphia (pubs); 2000: 453-517.

Pathology of the Lung: second edition. Thurlbeck WM and Churg AM (Eds). Thieme Medical Publishers, Inc. NY; 1995: 437-551.

Diversity of gene expression in adenocarcinoma of the lung. Garber ME, Troyanskaya OG, Schluens K et al. Proc Natl Acad Sci U S A 2001; 98: 13784-13789. Medline 11707590

Expression profiling of primary non-small cell lung cancer for target identification. Heighway J, Knapp T, Boyce L. Oncogene 2002; 21: 7749-7763. Medline 12400018

Genetic polymorphisms and lung cancer susceptibility: a review.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -314- Kiyohara C, Otsu A, Shirakawa T, Fukuda S, Hopkin JM. Lung Cancer 2002; 37: 241-256. Medline 12234692

Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hwang SJ, Cheng LS, Lozano G et al. Hum Genet 2003; 113: 238-243. Medline 12802680

Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. Borczuk AC, Gorenstein L, Walter KL et al. Am J Pathol 2003; 163: 1949-1960. Medline 14578194

Cytogenetics and molecular genetics of lung cancer. Mitsuuchi Y, Testa JR. Am J Med Genet 2002; 115: 183-188. Medline 12407699

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Zabarovsky ER, Lerman MI, Minna JD. Oncogene 2002; 21: 6915-6935. Medline 12362274

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 02- Jim Heighway, Daniel C Betticher 2004 Citation This paper should be referenced as such : Heighway J, Betticher DC . Lung tumors: an overview. Atlas Genet Cytogenet Oncol Haematol. February 2004 . URL : http://AtlasGeneticsOncology.org/Tumors/LungTumOverviewID5030.html

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Contributor(s) Written 01-2005 Eric Engel Citation This paper should be referenced as such : Engel E . Some vagaries of non-traditional mendelian recessive inheritance in uniparental disomy: AA x Aa = aa !. Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Deep/UniparentDisomy2005ID20049.html

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Transcription factors

* I Introduction

II Initiation of transcription

III Transcription factors family pdf version

III.1 Helix-Turn-Helix proteins

III.2 Zinc finger proteins

III.3 Leucine zipper proteins

III.4 Helix-Loop-Helix proteins *

I Introduction

In eukaryotic cells, there are three different RNA polymerases (RNA Pol). Each RNA Pol is responsible for a different class of transcription : PolI transcribes rRNA (ribosomal RNA), PolII mRNA (messenger RNA), and PolII tRNA (transfer RNA) and other small RNAs. Any protein that is needed for the initiation of transcription is defined as a transcription factor. Many transciption factors act by recognizing cis- acting sites that are parts of promoters or enhancers. However, binding to DNA is not the only means of action for a transcription factor. A factor may recognize another factor, or may recognize RNA Polymerases. In Eukaryotes, transcription factors, rather than the enzymes themselves, are principally responsible for recognizing the promoter. Transcription factors are able to bind to specific sets of short conserved sequences contained in each promoter. Some of these elements and factors are common, and are found in a variety of promoters and used constitutively; others are specific and their use is regulated. The factors that assists RNA polII can be divided into 3 general groups:

• The general factors, which are required for the initiation of RNA synthesis at all class II promoters (coding genes). With RNA PolII, they form a complex

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -329- surrounding the transcription startpoint, and they determine the site of initiation ; this complex constitute the basal transcription apparatus.

• The upstream factors, which are DNA-binding proteins that recognize specific short consensus elements located upstream the transcription startpoint (e.g. Sp1, which binds the GC box). These factors are ubiquitous and act upon any promoter that contain the appropriate binding site on DNA. They increase the efficiency of initiation.

• The inducible factors, which function in the same general way as the upstream factors, but have a regulatory role. They are synthesized or activated at specific times and in specific tissues. The sequences that they bind are called response elements.

II Initiation of transcription

RNA pol II enzyme cannot initiate transcription itself, but is absolutely dependent on auxiliary transcription factors (called TFIIX, where "X" is a letter that identifies the individual factor). The enzyme together with these factors constitutes the basal (or minimal) transcriptional apparatus that is needed to transcribe any class II promoter. The efficiency and specificity with which a promoter is recognized depend upon short sequences, farther upstream the TATA box, which are recognized by upstream and inducible factors. Examples of these sequences are the CAAT box, which plays a strong role in determining the efficiency of the promoter, and is recognized in different promoters by different factors, such as factors of the CTF family, the factors CP1 and CP2, and the factors C/EBP and ACF, and the GC box, which is recognized by the factor Sp1. These factors have the ability to interact with one another by protein- protein interactions. The main purpose of the elements is to bring the factors they bind into the vicinity of the initiation complex, where protein-protein interactions determine the efficiency of the initiation reaction.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -330- Figure 1: Schematic model for the assembly of the basal transcriptional apparatus

III Transcription factors family

Common types of motifs that are responsible for binding to DNA can be found in different transcription factors. There are several groups of proteins that regulate transcription by using particular motifs to bind DNA :

III.1 Helix-turn-helix proteins

The helix-turn-helix motif was originally identified as the DNA-binding domain of phage repressors; one -helix lies in the wide groove of DNA, the other lies at an angle across DNA. A related form of the motif is present in the homeodomain, a sequence first characterized in several proteins encoded by genes concerned with developmental regulation in Drososphila ; it is also present in genes coding for mammalian transcription factors. The homeobox is a sequence that codes for a domain of 60 amino-acids. The homeodomain is responsible for binding to DNA; the specificity of DNA recognition lies within the homeodomain. Its C-ter region shows homology with the helix-turn-helix motif of procaryotic repressors.

III.2 Zinc finger proteins

The zinc-finger motif comprises a DNA-binding domain. It was originally found in the factor TFIIIA, which is required for RNA PoIIII to transcribe 5S rRNA genes. These proteins take their name from their structure, in which a small group of conserved aminoacids binds a zinc ion. Two types of DNA-binding proteins have structures of this type: the classic " zinc finger " proteins, and the steroid receptors. A " finger protein " typically has a series of zinc fingers; the consensus sequence of a single finger is: Cys-X2-4-Cys-X3-Phe-X3-Leu-X2-His-X3-His The motif takes its name from the loop of aminoacids that protrudes from the zinc- binding site and is described as the Cys2/His2 finger. The fingers are usually organized as a single series of tandem repeats ; the stretch of fingers ranges from 9 repeats that occupy almost the entire protein (as in TFIIIA), to providing just one small domain consisting on 2 fingers ; the general transcription factor Sp1 has a DNA-binding domain that consists of 3 zinc fingers. The C-terminal part of each finger forms -helices that bind DNA ; the N-terminal part form -sheets. The non-conseved aminoacids in the C-terminal side of each finger are responsible for recognizing specific target sites.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -331- Steroid receptors, which are activated by binding a particular steroid (e.g. glucocorticoids, thyroid hormone, retinoic acid), and some other proteins, have another type of finger. The structure is based on a sequence with the zinc-binding consensus : Cys-X2-Cys-X13-Cys-X2-Cys These are called Cys2/Cys2 fingers. Proteins with Cys2/Cys2 fingers often have non- repetitive fingers, in contrast with the tandem repetition of the Cys2/His2 type. Binding sites on DNA are usually short and palindromic. The glucocorticoid and estrogen receptors each have 2 fingers, that form -helices that fold together to form a large globular domain.

III. 3 Leucine zipper proteins

The leucine zipper is a stretch of aminoacids rich in leucine residues that provide a dimerization motif. Dimerization allows the juxtaposition of the DNA-binding regions of each subunit. A leucine zipper forms an amphipathic helix in which the leucines of the zipper on one protein could protrude from the -helix and interdigitate with the leucines of the zipper of another protein in parallel to form a coiled coil domain. The region adjacent to the leucine repeats is highly basic in each of the zipper proteins, and could comprise a DNA-binding site. The 2 leucine zippers in effect form a Y- shaped structure, in which the zippers comprise the stem, and the 2 basic regions bifurcate simmetrically to form the arms that bind to DNA. This is known as the bZIP structural motif. It explains why the target sequences for such proteins are inverted repeats with no separation. Zippers may be used to sponsor the formation of homodimers or heterodimers. There are 4 repeats in the protein C/EBP (a factor that binds as a dimer to both the CAAT box and the SV40 core enhancer), and 5 repeats in the factors and (which form the heterodimeric transcription factor AP1).

III.4 Helix-loop-helix proteins

The amphipathic helix-loop-helix (HLH) motif has been identified in some developmental regulators and in genes coding for eukaryotic DNA-binding proteins. The proteins that have this motif have both the ability to bind DNA and to dimerize. They share a common type of sequence motif: a stretch of 40-50 aminoacids contains 2 amphipathic -helices separated by a linker region (the loop) of varying length. The proteins in this group form both homodimers and heterodimers by means of interactions between the hydrophobic residues on the corresponding faces of the 2 helices. The ability to form dimers resides with these amphipathic helices, and is common to all HLH proteins. Most HLH proteins contain a region adjacent to the HLH motif itself that is highly basic, and which is needed for binding to DNA. Members of the group with such a region are called bHLH proteins. A dimer in which both subunits have the basic region can bind to DNA. The bHLH proteins fall into 2 general groups. Class A consists of proteins that are ubiquitously expressed, including mammalian E12/E47. Class B consists of proteins that are expressed in a tissue-specific manner, including mammalian MyoD, Myf5, myogenin and MRF4 (a group of transcription factors that are involved in myogenesis, called myogenic regulatory factors, MRFs). A common modus operandi for a tissue-specific bHLH protein may be to form a heterodimer with

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -332- a ubiquitous partner. There is also a group of gene products that specify development of the nervous system in Drosophila melanogaster (where Ac-S is the tissue-specific component, and da is the ubiquitous component). The proteins form a separate class of bHLH proteins.

Contributor(s) Written 03-2004 Valentina GUASCONI, Hakima YAHI, Slimane AIT-SI-ALI Citation This paper should be referenced as such : Guasconi V, Yahi H, Ait-Si-Ali S . Transcription factors. Atlas Genet Cytogenet Oncol Haematol. March 2004 . URL : http://AtlasGeneticsOncology.org/Deep/TranscripFactorsID20043.html

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Microdeletions and Molecular Genetics

By Annick VOGELS and Jean-Pierre FRYNS. Center for Human, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium

* ABSTRACT Long version INTRODUCTION

THE VELOCARDIOFACIAL SYNDROME

THE PRADER-WILLI SYNDROME AND THE ANGELMAN SYNDROME

NEUROFIBROMATOSIS

THE WILLIAMS SYNDROME

THE SMITH MAGENIS SYNDROME

THE 8P DELETION SYNDROME

CONCLUSION

REFERENCES *

ABSTRACT

Microdeletions are often characterised by a complex clinical and behavioural phenotype resulting from the imbalance of normal dosage of genes located in that particular chromosomal segment. In this review we include the present state of art and a delineation of the future approach to study the candidate genes in the microdeletion syndromes resulting from unequal homologous recombination at meiosis between duplicons: Velocardiofacial syndrome, Prader-Willi syndrome, Angelman syndrome, Neurofibromatosis type 1, Williams syndrome, Smith-Magenis syndrome and distal 8p deletion.

INTRODUCTION

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -334- Microdeletion syndromes are defined as a group of clinically recognisable disorders characterised by a small (< 5Mb) deletion of a chromosomal segment spanning multiple disease genes, each potentially contributing to the phenotype independently [1]. The genetic changes of microdeletions are often not detectable by the current band resolution using routine or high resolution karyotyping (2-5 Mb) but require the application of molecular cytogenetic techniques such as Fluorescence In Situ Hybridisation (FISH). FISH has now become the standard diagnostic approach for the commonly known microdeletions. The phenotype is the result of haploinsufficiency for specific genes in the critical interval. Clinically well described syndromes, for which the involvement of multiple disease genes has been established or is strongly suspected include Velocardiofacial syndrome (22q11 microdeletion), Williams syndrome (7q11 microdeletion), Neurofibromatosis type 1 (17q11 microdeletion), Smith-Magenis Syndrome (17p microdeletion) and 8p microdeletion syndrome. Correlations between chromosomal rearrangements and clinical manifestations, or genotype/ phenotype correlations, can provide essential information for the discovery of the causes of developmental effects [2]. However, progress towards the identification of these developmental genes has been slow.

• The first step in the search for genotype/phenotype correlation is identifying the deletion size also called “the typically deleted region” (TDR) of the syndrome. It was found that each microdeletion syndrome has same-sized deletions in the majority of the patients. It was then suggested that there might be sequences at the breakpoints that are particularly prone to rearrangements. • The second step in identifying genes in these microdeletions syndromes is to compare deletions sizes from different patients with the same microdeletion syndrome in order to establish the shortest region of deletion overlap (SRDO). Although more tractable than the larger size of the typical deleted region, these SRDO’s commonly encompass multiple genes and identifying the disease genes is still a surprisingly difficult task. • A third common strategy to identify the essential genes that are involved in a particular syndrome, is traditional positional-cloning in patients with unusual deletions or rare translocations.

In this chapter we will review the microdeletion syndromes resulting from unequal homologous recombination at meiosis between duplicons that had a well described physical and behavioural phenotype before the discovery of their genetic aetiology. : Velocardiofacial syndrome, Prader-Willi syndrome, Angelman Syndrome, Neurofibromatosis type 1, Williams syndrome, Smith-Magenis syndrome and distal 8p deletion.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -335- THE VELOCARDIOFACIAL SYNDROME

Clinical and behavioural phenotype

Velocardiofacial syndrome is the most frequent known interstitial deletion found in man with an incidence of 1 in 4000 live births [12]. Most deletions are the result of a de novo event, although probably 5- 10% are inherited [11]. Several diagnostic labels have been used for this syndrome including Di George syndrome (DGS) [13], Conotruncal anomaly face syndrome or Takao syndrome [14]. Shprintzen syndrome [15] and 22q11deletion syndrome [16].

The structures primarily affected in VCFS include the thymus, parathyroid gland, aortic arch, branchial arch arteries and face. These key clinical features are due to abnormal development of the third and fourth pharyngeal pouches during embryogenesis and are therefore classified as “the pharyngeal phenotype”. The other key clinical traits include learning difficulties, cognitive deficits, attention deficit disorders and psychiatric disorders [10] and are classified as “the neurobehavioral phenotype”. There is incomplete penetrance and therefore a marked variability in clinical expression between the different patients, making early diagnosis difficult [16]. The physical phenotype is characterised by facial dysmorphism, palatal abnormalities, hypocalcemia, T-cell immunodeficiency and learning disabilities. Heart defects are present in 50-75% of the patients and are usually diagnosed in early infancy. Minor manifestations are usually associated including a history of polyhydramnios, signs of velopharyngeal insufficiency, minor facial anomalies, slender appearance of the fingers, constipation and hypotonia. Speech and language delay is one of the most consistent manifestations of VCFS in part related to the velopharyngeal insufficiency. Recurrent upper-airway and ear infections are common during infancy and early childhood. In adolescence there is a high risk for development of obesity and scoliosis (10%) [17].

Recent studies of the cognitive and psychoeducational profiles of children with 22q11deletion confirm a wide variation in intelligence, ranging from moderate mental retardation to average intelligence, with a mean full-scale IQ of about 70 [18,19]. Severe mental retardation is rare. The mean full-scale IQ in familial cases is lower compared to those with de novo cases [19,20], a finding which can be explained at least in part by the multifaceted origin of intelligence and by assortative mating. A possible relationship between 22q11deletion and a nonverbal learning disorder was suggested [21,22]. Common behavioural and temperamental characteristics include impulsiveness, disinhibition, shyness and withdrawal [19]. A wide variety of child psychiatric disorders has been reported including attentions deficit disorder and rapidly cycling bipolar disorder in late childhood and adolescence [23], childhood schizophrenia [24,25] and mood disorders [26]. Current estimates are that +/- 35 % of patients develop psychiatric disorders in

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -336- adolescence or adulthood [27]. There is a higher than expected rate of psychotic disorder, specifically schizophrenia, schizoaffective disorder and bipolar disorder, among adult persons diagnosed with VCFS [23,28].

Molecular genetics

Genes within the deletion

Numerous genes have been identified within the most commonly deleted region of 22q11.2. In their search for genes, investigators have also sought for genes that might have a role in branchial arch or neural crest development [11]. Several candidate genes have received particular attention (IDD/SEZI/LAN, GSCL, HIRA, UFD1L) but all proved to be negative for mutations in VCFS patients without a 22q11 microdeletion. COMT, the gene encoding for catechol-O-methyl transferase, has a crucial role in the metabolism of the neurotransmitter dopamine. Abnormal function of the dopaminergic pathways is considered to play a major role in schizophrenia [44]. As the gene coding for COMT maps to 22q11, the COMT gene is considered a prime candidate gene for the etiology of schizophrenia in VCFS. It was therefore suggested that the common functional genetic polymorphism in the COMT gene, which results in a 3-to4-fold difference in COMT activity [45] may contribute to the etiology of psychiatric disorders. Two studies reported that in a population of patients with VCFS, there is an apparent association between the low- activity allele, COMT158met, on the non-deleted chromosome and the development of a bipolar spectrum disorder and, in particular, a rapid cycling form [45-47].

THE PRADER-WILLI SYNDROME AND THE ANGELMAN SYNDROME

Clinical and behavioural phenotype of the Prader-Willi syndrome

The Prader-Willi syndrome (PWS) is a complex multisystem disorder characterised by a variety of clinical features [62]. The clinical phenotype is characterised by hyperphagia, childhood-onset- obesity, severe muscle hypotonia, a typical facies, hypogonadism with absence of a pubertal growth spurt, short stature, small hands and feet and delayed developmental milestones. The typical facial features include a small forehead, almond shaped eyes, micrognathia, a thin upper lip and down-turned corners of the mouth [63]. The syndrome is now

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -337- considered as a multistage disorder characterised by three different phases [64].

• The first, “the hypotonic phase”, is characterised by varying degrees of hypotonia during the neonatal period and early infancy, a weak cry, hypothermia, hypogenitalism and a poor suck reflex usually necessitating gavage feeding [65]. During the first year, PWS children are defined as friendly, easy going and affectionate [66]. • The second phase, “the hyperphagic phase”, which usually starts between the ages of one and two, is characterised by a voracious appetite, hyperphagia, foraging for food, early onset of childhood obesity, physical inactivity, decreased pain sensitivity, disturbed thermoregulation, psychomotor retardation, speech articulation difficulties and cognitive dysfunction. Simultaneously, with the change in eating pattern, PWS individuals show significant maladaptive behavioural and emotional characteristics including temper tantrums, inappropriate social behaviour, automutilation (skin picking), stubbornness, mood lability, impulsivity, argumentativeness, anxiety and obsessive compulsive symptoms [67,68]. • The third phase ‘“adolescence and adulthood” is dominated by health problems secondary to obesity. These include scoliosis, dental problems, diabetes mellitus, hypertension, hypercholesterolemia, osteoporosis [69]. About 10% of the adolescents and adults develop major psychiatric problems ranging from severe and agitated depression to psychotic episodes [70,71]. The psychotic episodes in PWS patients have many features in common including an acute onset, a polymorphous and fluctuating symptomatology with anxieties, agitation, abnormal beliefs and auditory hallucinations. These episodes are classified as acute cycloid psychosis [72].

Dysfunction of the hypothalamus may be the basis of a number of symptoms in the Prader-Willi syndrome. The fetal hypothalamus plays a major role in labour and hypothalamic dysfunction may explain the high proportion of children born prematurely or postmaturely. Abnormal LSH- releasing hormones are thought to be responsible for the decreased levels of sex hormones resulting in non-descended testes, undersized sex organs, amenorrhoea and insufficient growth during puberty. Growth hormone deficiency due to hypothalamic dysregulation contributes to the abnormal growth pattern, excess of body fat and deficit of lean body mass with consequent reduced energy expenditure. Hypothalamic disturbances cause aberrant control of body temperature and daytime hypersomnolence. The insatiable hunger and hyperphagia is probably a consequence of the decreased number of oxytocine neurones- the putative satiety neurones in the hypothalamic paraventricular nucleus [73].

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -338- Clinical and behavioural phenotype of the Angelman Syndrome

The typical facial features in Angelman syndrome (AS) include brachycephaly, microcephaly, a large mouth with widely spaced teeth, mandibular prognatism, midfacial hypoplasia, deep-set and blue eyes and hypopigmentation. This facial gestalt becomes apparent between the age of one and four years and there is a facial coarsening with increasing age. AS patients show truncal ataxia and hypotonia with hypertonia of the limbs and have a high risk for developing scoliosis. All patients have severe mental retardation with little or no development of active language. Jerky movements including tongue thrusting, mouthing and flapping when walking become apparent in the first years of life. The gait is slow, ataxic and stiff-legged with the characteristic posture of raised arms with flexed wrists and elbows. Paroxysms of easily provoked, prolonged laughter may start as early as 10 weeks. Hyperactivity and sleep disorders are common in childhood. AS individuals are fascinated by water, mirrors and plastic. Epileptic seizures occur in 80% of the patients with an onset varying between one month and 5 years. A diversity of seizures can be observed, ranging from atypical absence seizures, tonic-clonic seizures, myoclonic seizures, and tonic seizures to status epilepticus. They are difficult to control. The EEG patterns seen in AS are very characteristic and are seen in patients with and without seizures and may play an important diagnostic role in the appropriate clinical context [74]. Neuroimaging studies are normal. Cerebral atrophy and ventricular dilatation are seen in a minority of the patients.

Molecular genetics of the Angelman and the Prader-Willi syndrome

PWS and AS result from loss of paternal or maternal expression, respectively, of genes located on the human chromosome 15q11-13 region [75]. Different molecular mechanisms leading to this loss of expression have been identified, including microdeletions, intragenic mutations, uniparental disomy and imprinting defects:

A. Microdeletions in PWS and AS 75% of the PWS patients and 70% of the AS patients have large chromosomal deletions of +/- 4 Mb of the same chromosomal 15q11-13 region, the typically deleted region (TDR). In PWS there is a deletion on the paternally inherited chromosome, while in Angelman there is a deletion on the maternally inherited chromosome.

B. Single gene mutations in PWS and AS There are no known PWS patients with a single gene mutation, suggesting that PWS is a continuous gene syndrome. In 4 % of the cases, Angelman is caused by mutations in the Ubiquitin ligase gene, UBE3A [76,77].

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -339- C. Uniparental disomy in PWS and AS Uniparental disomy occurs in 24% of the PWS patients (maternal disomy) and in 3-5% of AS patients (paternal disomy). The most likely explanation is trisomy 15 rescue, suggested by the observation of trisomy 15 mosaicism in patients with unusual PWS manifestations [78- 80]

D. Imprinting defects in PWS and AS The imprinting centre (IC) regulates the erasure, establishment and maintenance of paternal and maternal imprinted genes. It has been mapped to the SNURF-SNRPN locus and presents with a bipartite structure overlapping the SNRPN promotor. The exon alpha SNRPN promotor is found within a CpG island that is completely methylated on the maternal chromosome and completely unmethylated on the paternal chromosome. IC defects are found in 2 % of the AS cases and in less than 1 % of the PWS cases.

Genes within the deletion for PWS

In PWS patients, the typically deleted region on the paternal chromosome is 4Mb and the PWS-SRO (smallest region of overlap) is 4,3 kb .The common deletion includes a large cluster of imprinted genes (2-3Mb) and a non-imprinted domain (1-2Mb) [89,97]. A cluster of paternally expressed genes has been mapped to the PWS region: SNURF-SNRPN (small ribonucleoprotein N upstream reading frame- small ribonucleoprotein N), MKRN3 (makorin ring finger protein), IPW (imprinted gene in the PWS region gene), MAGEL2 (melanoma antigen-like gene2), and NDN (necdin) [75,98]. It is not clear if PWS is caused by the loss of expression of a single imprinted gene or multiple genes. Two strong candidates for PWS are NDN and MAGEL2. The human NDN is a good candidate due to its expression in the nervous system and the observation that it is absent in PWS patients [99]. MAGEL2 is expressed predominantly in the brain and in several foetal tissues.

Genes within the deletion for AS

In AS patients, the common deletion on the maternal chromosome also spans a 4 Mb interval and includes a cluster of imprinted and a non- imprinted domain [101]. The UBE3A gene (ubiquitin ligase 3) was mapped to the AS critical region in 1994 and its role in AS was corroborated by the observation that point mutations in UBE3A are present in a small (4-6%) fraction of the AS patients [76,77,102-104].

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -340- Genotype/phenotype correlation

Genotypic / phenotypic correlations with these different genetic causes were identified. Individuals with a deletion show the classic signs of AS [119]. A milder phenotype is found among the cases with paternal UPD. These AS individuals have better growth, less hypopigmentation, more subtle facial changes, walk at earlier ages, have less severe or frequent seizure disorders, less ataxia and a greater facility with rudimentary communication such as signing and gesturing [120,121]. AS patients with imprinting mutations have a less severe seizure disorder, show milder microcephaly and less hypopigmentation. Milder epilepsy is noted in AS with UBE3A mutations [122]. Further refinement of the phenotype/ genotype correlation will progressively improve the gene- behaviour understanding [123]. A correlation between psychiatric disorders in PWS and uniparental disomy has recently been reported [124]. If this finding is confirmed, imprinted genes outside the typically deleted region on the paternal or the maternal chromosome may contribute to the psychiatric phenotype.

NEUROFIBROMATOSIS

Introduction

The neurofibromatoses (NF) are a heterogeneous group of hereditary neurocutaneous disorders clinically characterised by abnormalities in tissues that are predominantly derived from the neural crest [128]. In the past few years, clinical and genetic studies have led to the identification of two separate entities as the major NF forms: neurofibromatosis type 1 (NF 1) and neurofibromatosis type 2 (NF 2). Final confirmation that NF 1 and NF 2 are different disorders has been achieved by the identification of the two responsible genes, the NF1 gene located on chromosome 17q11.2 [129] and the NF2 gene located on chromosome 22q12.2 [130]. NF1 is usually caused by a mutation in the NF1 gene, but in an estimated 5-10% of cases NF1 is the result of a microdeletion in the 17q11.2 region.

Clinical and behavioural phenotype

Café-au-lait spots are the most typical skin abnormality in Neurofibromatosis 1 (NF1). They usually appear during the first year of life and are present in all affected children by the age of five [131]. Freckling, especially skin fold freckling in the axillar and inguinal regions, appear later in age. Neurofibromas often make their appearance just before or during adolescence. They tend to increase

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -341- with age and during pregnancy suggesting that their presence may be hormone responsive [132].

• Cutaneous neurofibromas are complex benign peripheral nerve tumours consisting of a mixture of Schwann cells, perineural cells, fibroblasts and mast cells. In general, they are not painful but may become a cosmetic problem. • Spinal neurofibromas may be very painful and lead to neurological dysfunction. • Plexiform neurofibromas consist of a proliferation of cells in the nerve sheets extending across the length of nerve, and involving multiple nerve fascicles [133]. They appear at a very young age. • Lisch noduli are pigmented hamartomas of melanocytic origin located in the iris. They may vary in appearance depending on the underlying colour of the iris. Their prevalence increases with age, to 99 % in adults. • Optic pathway gliomas (OPG) and brains stem gliomas are the predominant intracranial neoplasms associated with NF 1 [134] and are classified as pilocytic astrocytomas. OPG remain asymptomatic in the majority of the cases. Possible symptoms associated with OPG are prooptosis, precocious puberty and diminished vision [135]. The greatest risk for development of OPG in NF1 is during the first 6 years of life [136].

There is an increased risk of developing NF1 related malignancies (lifetime risk 2-5%) [137,138]. These malignancies mainly include malignant peripheral nerve sheat tumours (MPNSTs), malignant CNS tumours, pheochromocytomas, rhabdomyosarcomas and juvenile myelocytic leukaemia (JCML) [139]. MPNSTs arise frequently from plexiform neurofibromas in young NF1 adults. They are particularly aggressive and often fatal. The first symptoms are neurological deficits or rapid growth enlargement or pain in an existing plexiform neurofibroma. The main first manifesting symptoms of pheochromocytoma are secondary hypertension with headaches, palpitation and flushing. Children with chronic myelotic leukaemia (JCML) have hepatosplenomegaly, leucocytosis and absence of the Philadelphia chromosome [140].

Unidentified bright objects (UBOs) are well circumscribed round to oval spots seen on T2-weighed brain MRI scans. Their clinical course is benign and they usually disappear with age [141-143]. Some studies suggest a correlation between UBOs and some aspects of cognitive functioning [144-147], but these findings are not confirmed by others [148,149]. NF1 specific osseous lesions include pseudoarthrosis of the tibia, sphenoid wing dysplasia, bowing or thinning of the cortex of the long bones with or without pseudoarthrosis [150].

The mean total intelligent quotient in children with NF1 ranges from 88 to 94 [149,151,152], whereas only 4-8 % have mental retardation defined as full-scale IQ below 70 [153]. There is no specific

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -342- characteristic profile of learning disability in NF1 [154]. The reported frequency of learning disabilities, defined as a significant discrepancy between ability and achievement, ranges between 30 and 65 % [153,154]. Evidence of Attention Deficits has been reported in one third of NF children [155], but the incidence of attention deficit hyperactivity disorder is not known and further research is needed in this area. Motor coordination is frequently impaired. Social and emotional problems including social problems, anxieties, depression, withdrawal, thought problems, somatic complaints, and aggressive behaviour are reported in children with NF1 [156]. A significant psychopathology was found in a twelve-year follow-up study of adult patients with NF1. One third of the patients was affected by a psychiatric disease, 21%by dysthymia [157]. It is not clear whether these characteristics are a primarily genetic affect or whether they are secondary to the impact of the somatic deficits on the psychological and emotional well being.

Molecular genetics of the NF1 microdeletions

Mechanisms leading to the deletion

About 80% of the NFI microdeletions are of maternal origin [158] and have a size of 1.5 Mb. Most cases have a de novo deletion [159]. The deletion breakpoints cluster in flanking duplicated sequences called 3 NF-REPs [160,161]. NF 1 microdeletions result from an unequal cross over in maternal meiosis 1, mediated by misalignment of the flanking NF1-REPs. The NF1-repeats are direct repeats that span 100-150kb and contain several pseudogenes and 4 expressed sequence tags (EST) [162]. Recently, it was demonstrated that most of the recombination events occur in a discrete 2 kb recombination hotspot within each of these flanking NF1-REPs [159]. The finding of a recombination hotspot for NFI microdeletions and the development of a deletion specific PCR assay have significant implications for future research

Genes within the deletion

The detection of the NF1 gene has preceded the discovery of the microdeletions as a cause of NF 1. Identification of translocation breakpoints in different patients permitted the construction of physical map and allowed cloning of the NF1 gene [163]. Since then, a large variety of mutations has been found. The identification of the encoded protein was the first clue to the molecular basis of NF 1. The NF 1 encoded protein, neurofibromin, is composed of 2818 aminoacids [164]. A central 360 amino acid region of the predicted protein product shows homology to members of the Ras-GTPase-activating (Ras-GAP) family of proteins. The GAP related domain (NF1-GRD) of neurofibromin

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -343- represents so far the only known functional domain of the NF1 gene. The function of the remainder of the molecule is not known.

Genotype/ phenotype correlation

Until now, it is not possible to predict the clinical presentation in individual NFI patients based on the localisation and the type of mutation. Only in NF1 patients with a NF1 gene deletion a distinct phenotype seems to emerge. In 5-10 % of NF1patients, an entire gene deletion has been described. In about 80% of the cases the deletion occurs de novo and is of maternal origin [158,185,186]. Most patients with NF1 microdeletions present a distinct phenotype characterised by the presence of a variable facial dysmorphism: coarse face, facial asymmetry, ptosis, prominent forehead, hypertelorism, thick prominent nasal tip and “Noonan-like” face. These patients have mild mental retardation, skeletal abnormalities and hypermobility of the joints. An important clinical feature present in NF1 deletion patients is the increased number of neurofibromas and their presence at a young age. An interesting hypothesis is that deletions of (an) unidentified nearby gene(s) predispose to the development of neurofibromas, (a) gene(s) that could have a tumour suppressor function. The role of a putative co- deleted gene has been difficult to asses because the number of patients with a microdeletion is relatively small and the information regarding number and age of onset of neurofibromas and deletionsize is not always evaluated or reported in the same way. The lower IQ in the group of patients with a microdeletion, compared with the total group of NF1 individuals, suggests that some dosage sensitive genes in the microdeletion region are important for cognitive functioning. An overgrowth syndrome has been reported in patients carrying the NF1 gene deletion [187]. The presence of large hands and feet has also been described in several NF1 deletion patients. NF1 microdeletions may predispose patients to develop malignant tumours [188]. In benign neurofibromas loss of heterozygosity has been observed for markers on the long arm of chromosome 17 reflecting a “second hit” of the NF1 gene [189]. In a patient with a microdeletion in the NF1 region a “second hit” affecting the normal chromosome 17 homologue could at the same time inactivate the NF1 gene and unknown tumour suppressor genes in the deleted region.

So far, most of the cases described in the literature carrying NF1 microdeletions are young patients. Several of the clinical signs are expected to appear only at puberty or later (neurofibromas and malignancies), making it difficult to draw any conclusion concerning the severity of the phenotype in several of these patients. Prospective studies will be able to better estimate the effect of a deletion on certain clinical manifestations such as early age of onset of cutaneous neurofibromas, malignancies and mental retardation.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -344-

THE WILLIAMS SYNDROME

Clinical and behavioural phenotype

The incidence of Williams syndrome (WBS) is estimated at approximately 1 per 20.000. Individuals with WBS have a distinct facial dysmorphism including periorbital fullness, stellate pattern of the irides, anteverted nares, long philtrum and prominent full lips. Cardiovascular anomalies include supravalvular aortic stenosis (SVAS), peripheral pulmonary artery stenosis and pulmonic valvular stenosis. Other symptoms include dental problems such as malocclusion, small and missing teeth, growth deficiency, hypercalcemia, vomiting, constipation, colic in infancy, impaired visual acuity, musculoskeletal abnormalities, hyperacusis and a hoarse low voice. They show an intriguing behavioural phenotype with mental retardation, a specific neuropsychological profile and a distinct socio-affective profile. Most individuals with WBS function in the mild range of mental retardation with IQ’s averaging about 60. The neuropsychological profile includes strengths in face perception and face recognition memory, affective attainment, short term auditory memory and select aspects of language. They show “cocktail party” verbal abilities, i.e. verbal abilities that are superficially quite intact but formal assessment shows overall delayed language abilities [190]. Along with the superficial strengths in language abilities, they show weaknesses in visuospatial, motor, visuomotor integration and arithmetic skills. Remarkable are the large differences in the visual perception of faces (visuofeature domain) and the visual perception of spatial material (visuospatial). This duality in functioning in “space and face” in WBS can be explained by functional segregation of visual processes in brain MRI studies [191]. A possible physiological base for the strength in language and music skills has been found in those recent MRI studies. Alteration in functions of the primary auditory cortex may explain the high rate of hyperacusis and could be related to the language and music perceptual processes. Future research will help to learn more about the function of the genes in the critical WS region and will help to delineate the relationship between genes, brain and behaviour.

Molecular Genetics

Mechanisms leading to the deletion

Most deletions in WBS patients are of a consistent size of 1.6Mb. Haplotype analysis demonstrated that unequal meiotic recombination underlie the formation of a high proportion of 7q11.23 deletions [192]. It

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -345- was found that the WS deletion is flanked by low-copy repeats [193,194].. These duplicons are approximately 400kb long and consist of blocks of nearly identical DNA occurring in the same or opposite directions. They contain transcribed genes, pseudogenes and putative telomere associated repeats. [9]. The majority of the WBS region interstitial deletions have been shown to be due to unbalanced interchromosomal recombination during meiosis, fewer are seen due to intrachromosomal recombination [34]. Recently, Osborne et al. [9] found that not only deletions but also inversions can be mediated by the repeating units flanking the interval. In at least three individuals, the inversion seems to be associated with a subset of the WBS phenotypic spectrum. Osborne et al [9] suggested that the breakpoints interrupts or affects the expression of functional genes located within the duplicon. Further research is needed to confirm this. In 4 of the 12 families with a proband carrying the WBS deletion, this inversion was found in the parent transmitting the disease related chromosome suggesting that this inversion may predispose to the formation of deletion [9].

Genes within the deletion

In 1993, Ewart et al demonstrated linkage of isolated familial supravalvular aortastenosis (SVAS) to the elastine gene (ELN) [195]. Since SVAS is also a component of WBS, they examined WBS for mutations in the ELN. The WBS patients were found to have large deletions encompassing the entire ELN gene, suggesting that WS may be due to a microdeletion of chromosomal region 7q11.23. Analysis of the region surrounding the ELN demonstrated that in more than 95% of the cases there is defined 1.5 Mb deletion. For the remaining individuals with clinical WBS, there is no detectable chromosomal rearrangement. Deletions occur with approximately equal frequency on the maternal and the paternally derived chromosome. At least 17 genes have been identified within this commonly deleted interval [196-198]. Vascular stenosis including supravalvular aorta stenosis is caused by haploinsufficiency of ELN.

Genotype/ phenotype correlation

Despite the number of genes commonly deleted none except ELN has been definitively shown to contribute to any of the clinical or behavioural symptoms and until now, the molecular base of the great variety in the clinical and behavioural phenotype in WBS remains unknown.

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -346- THE SMITH MAGENIS SYNDROME

Clinical and behavioural phenotype

Intelligence in SMS patients is varying from borderline to profound mental retardation. The degree of retardation is mostly moderate. Children with SMS show a particular pattern of behaviour that can be a useful clue to diagnosis. Infants are very sociable with appealing smiles and need to be waked for feeding [121]. The most characteristic features in children include neurobehavioral abnormalities such as aggressive and self-injurious behaviour (SIB) and significant sleep disturbances and stereotypical behaviours [207]. Behaviour problems include disobedience, hyperactivity, tantrums, attention seeking, sleep distortion, lability, property destruction, impulsivity, bed wetting and argumentative behaviour [208]. SIB is frequent and reported in 67 % to 92% of all patients and includes head banging, self-hitting and hand, finger and wrist biting, nose or ear picking, onychotillomania, polyembolokoilomania [209]. With increasing age and ability, the overall prevalence of SIB as well as the number of different types of SIB are increasing [210]. Sleeping difficulties are reported in 65% to 75% of the patients and include difficulties falling asleep, frequent awakening, shortened sleep cycles and excessive daytime sleepiness [211]. Stereotypical behaviours are an important clinical symptom in the diagnosis. Many SMS persons show self-hugging, behaviour and spasmodic upper body squeeze [210]. Autistic characteristics are also reported [207,212,213]. The disturbed sleep pattern and behaviour problems correlate with a disturbed circadian rhythm in melatonin [214,215]. The abnormalities in the circadian rhythm of melatonin could be secondary to aberrations in the production, secretion, distribution or metabolism of melatonin. It was suggested that haploinsufficiency for a circadian gene mapping to chromosome 17p11.2 may cause the inversions of the circadian rhythm of melatonin in SMS.

Molecular genetics

Mechanisms leading to the deletion [7]

Most patients have a 5 Mb common deletion of 17p11.2 [8]. The deletion in the 17p11.2 band in SMS patients occurs between two flanking repeat gene clusters [216].

Genes within the deletion

It is still unclear if the SMS phenotype is caused by the fusion of different genes from the flanking repeat gene clusters or by the loss of

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -347- one or multiple genes in the context of a contiguous gene syndrome [218].

THE 8P DELETION SYNDROME

Clinical and behavioural phenotype

The finding that most cases of 8p interstitial deletion have been published only in the recent years suggests that this condition is more frequent than previously thought. The condition is associated with heart defects, typically in the form of an AVSD [221,222]. Other major manifestations include microcephaly, intrauterine growth retardation, mental retardation and a characteristic behavioural pattern. The behaviour is described as sudden and extreme outbursts of aggressiveness accompanied by destructive behaviour, low frustration tolerance, oppositional behaviour, hyperactivity and poor concentration [223].

Molecular genetics

Mechanisms leading to the deletion

Recently, it was demonstrated that unequal crossover between two olfactory receptor (OR) gene clusters in 8p is responsible for the formation of intrachromosomal rearrangements involving 8p. The olfactory OR-gene superfamily is the largest in the mammalian genomes. Several of the human OR genes appear in clusters with >10 members located on almost all human chromosomes [224].

Different rearrangements are associated with the distal 8p region including inv dup(8p) [225], del (8p23.1) [226], small marker chromosome der(8) (p23-pter) [227] and inv(8p). The type of rearrangement is predominantly defined by the orientation of recombining duplicons and the number of crossovers [7].

Genes within the deletion

In most patients a uniform interstitial deletion of +/- 6 Mb in 8p23.1 is detected [224,226,228,229]. Devriendt et al. [226]performed genotype- phenotype correlation in nine unrelated patients with a de novo del 8p. Three patients with a small deletion and a partial phenotype not including heart defects lead to the delineation of a 8p heart-defect-

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -348- critical region (HDCR8p) spanning 10 cM [226,229]. Both authors suggested the transcription factor GATA4 as a candidate gene. Additional observations [224] excluded a major role for GATA 4 in these congenital heart defects. The same author narrowed the HDCR8p and showed that haploinsufficiency for a gene between markers WI-8327 and D8S1825 is critical for heart development

CONCLUSION

Detailed description of the physical and behavioural phenotype of microdeletion syndromes, genotype/phenotype correlation and clinical and molecular examination of patients with rare translocations or deletions enable identification of developmental genes. Further studies of the duplicons flanking these microdeletions will provide more insight in the mechanism of their formation, and their possible effect on the genes within the microdeletion. The study of animal models has become a powerful tool to explore further the molecular and etiological basis of these microdeletion disorders. Engineering small deletions and duplications can be used to find the gene responsible for a haploinsufficient phenotype and to give insight into the embryological base of the disorder. The results of these investigations are going to have a major impact on human genetics.

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Contributor(s) Written 02- Annick Vogels, Jean-Pierre Fryns 2004 Citation This paper should be referenced as such : Vogels A, Fryns JP . Microdeletions and Molecular Genetics. Atlas Genet Cytogenet Oncol Haematol. February 2004 . URL : http://AtlasGeneticsOncology.org/Educ/MicrodeletionID30059ES.html

Atlas Genet Cytogenet Oncol Haematol 2004; 2 -366-