Atlas Journal

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

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 11, Number 1, Jan-Mar 2007 Previous Issue / Next Issue Genes

ERG (21q22).

Liat Rainis-Ganon, Shai Izraeli.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 1-7. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/ERGID53ch21q22.html

ARHGAP20 (11q23).

Claudia Kalla.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 8-12. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/ARHGAP20ID42979ch11q23.html

PSAP (10q22).

Shahriar Koochekpour.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 13-25. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/PSAPID42980ch10q22.html

CASC5 (15q14).

Masato Takimoto.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 26-29. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/AF15q14ID318.html

BRWD3 (Xq21).

Claudia Kalla.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 30-34. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/BRWD3ID42978chXq21.html

TFPT (19q13).

Enrica Privitera.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 35-38. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/TFPTID495ch19q13.html

KLF5 (13q21).

Ceshi Chen, Yinfa Zhou, Jin-Tang Dong.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 39-44. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/KLF5ID41074ch13q21.html Leukaemias

t(X;11)(q21;q23).

Claudia Kalla.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 45-47. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0X11q21q23ID1430.html

t(6;12)(p21;p13) in lymphoid malignancies.

Maria D Odero.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 48-49. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0612p21p13ID1424.html

Essential Thrombocythemia.

Antonio Cuneo, Francesco Cavazzini.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 50-000. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/JAK98.html

Myelofibrosis with Myeloid Metaplasia . Antonio Cuneo, Francesco Cavazzini.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 53-56. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/Myelofib.html

t(8;9)(p22;p24).

Andreas Reiter, Christoph Walz.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 57-59. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0809p22p24ID1329.html

der(9;18)(p10;q10).

Ulrike Bacher, Claudia Haferlach.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 60-61. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/der918p10q10ID1418.html

+9 or trisomy 9.

Ulrike Bacher, Claudia Haferlach.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 62-65. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/tri9ID1020.html

+13,+13 or tetrasomy 13.

Catherine Roche-Lestienne.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 66-67. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/Tetra13ID1260.html Solid Tumours

Oral squamous cell carcinoma.

Yuesheng Jin , Charlotte Jin.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 68-75. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/OralSquamCellID5368.html

Laryngeal squamous cell carcinoma.

Charlotte Jin, Yuesheng Jin.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 76-83. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/LarynSquamCellID5367.html

Nephroblastoma (Wilms tumor).

Ayse Elif Erson, Elizabeth M Petty.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 84-90. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/WilmsID5034.html

Soft tissue chondroma with t(3;12)(q27;q15).

Anna Collin.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 91-94. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/Chondromat0312ID5428.html Cancer Prone Diseases

Schwannomatosis.

Lan Kluwe.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 ( ): 95-96. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/SchwannomatID1012.html

Hereditary Desmoid Disease.

Rodney J Scott.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 97-99. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/HereditDesmoidID10119.html Deep Insights

Mechanisms of hepatocarcinogenesis.

Raphaël Saffroy, Antoinette Lemoine, Brigitte Debuire.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 100-107. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Deep/HepatocarcinogenesisID20055.html Case Reports Isolated trisomy 2 is non-random and may be found in myelodysplastic syndrome and in acute myeloblastic leukaemia. Case 1. Catherine Roche-Lestienne, Agnès Charpentier, Sandrine Geffroy, Joris Andrieux, Jean-Loup Demory, Jean-Luc Laï. Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 108-109. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/02RocheID100015.html Isolated trisomy 2 is non-random and may be found in myelodysplastic syndrome and in acute myeloblastic leukaemia. Case 2. Catherine Roche-Lestienne, Agnès Charpentier, Sandrine Geffroy, Joris Andrieux, Jean-Loup Demory, Jean-Luc Laï. Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 110-111. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/02RocheID100016.html Educational Items

DNA: molecular structure.

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (1): 112-123. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Educ/DNAEngID30001ES.html

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

ERG (v-ets erythroblastosis virus E26 oncogene like (avian)) Identity Hugo ERG Location 21q22.2 DNA/RNA

Top : Schematic representation of the ERG gene locus. Exons are depicted as black boxes. Bottom : Structure of alternative transcripts encoded by the ERG gene. Coding exons are shown in grey, 5' UTRs in white and 3' UTRs in black (Adapted from Owczarek et. al., Gene 2004 (324) : 65-77)..

Description 17 exons, 300kb DNA. Transcription There are five isoforms created by alternative splicing and alternative initiation of translation. Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -1-

The different ERG isoforms (Adapted from Duterque-Coquillaud et. al., Oncogene 1993 (8) : 1865-1873)..

Description 5 different isoforms, 38-55 kDa, all contain the ETS DNA binding domain. Expression ERG-3 is expressed in hematopoietic stem cells and in endothelial cells. In the GNF SymAtlas database, the major ERG expression was found to be in CD34+ cells (that include both hematopoietic stem cells and endothelial cells). ERG was also reported to be expressed in during early T and B cell development, and to be down-regulated in later stages of B and T cell differentiation. Furthemore, ERG was found to be expressed in platelets, megakaryoblastic cell lines and in primary megakaryoblastic leukemia (AMKL or M7-AML) from Down syndrome patients. Localisation Nuclear Function Transcription factor Homology A member of the ETS transcription factors, most homologous to FLI1:. Mutations Note No known mutations. Implicated in Entity Ewing Sarcoma Hybrid/Mutated -ERG HYBRID_IMAGE Gene Abnormal The EWS gene fuses with the carboxy terminal of ERG containing the ets DNA Protein binding domain of ERG. Oncogenesis In a transgenic mouse model expression of the EWS-ERG in lymphoid progenitors induced T-cell leukemia.

Entity Prostate cancer Hybrid/Mutated Fusion of the the 5' untranslated region of an androgen regulated gene TMPRSS2and Gene all the coding region of the ERG protein. Abnormal This translocation results in androgen dependent overexpression of ERG. Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -2- Entity Acute myeloid leukemia (AML) and Ewing Sarcoma Prognosis Poorer prognosis Hybrid/Mutated The FUS gene fuses with the carboxy terminal of ERG containing the ets DNA binding Gene domain of ERG.

Entity Childhood ALL with either TEL-AML1 (ETV6-RUNX1) translocation or extra copies of chromosome 21 (where ERG is located); AML with complex karyotype and AML with t(X;21)(q25-26;q22) translocation. Note Overexpression of ERG Prognosis Overexpression of ERG was reported to predict a worse outcome in acute myeloid leukemia with normal karyotype. Oncogenesis Overexpression of ERG in the different leukemias and in prostate cancer suggests that overexpression of the full-length ERG may be oncogenic.

Entity AMKL: Association of ERG expression with normal and malignant megakaryocytic differentiation. Oncogenesis ERG was found to be expressed megakaryoblastic leukemic cell lines and in primary leukemic cells from DS patients.

Entity ERG involvement in endothelial development. Note ERG has been reported to regulate genes involved in chondrogenesis and angiogenesis and functions as a modulator of endothelial cell differentiation.

Entity ERG involvement in lymphoid development. Note ERG was reported to be expressed in during early T and B cell development, and to be down-regulated in later stages of B and T cell differentiation.

External links Nomenclature Hugo ERG GDB ERG Entrez_Gene ERG 2078 v-ets erythroblastosis virus E26 oncogene homolog (avian) Cards Atlas ERGID53ch21q22 GeneCards ERG Ensembl ERG Genatlas ERG GeneLynx ERG eGenome ERG euGene 2078 Genomic and cartography GoldenPath ERG - 21q22.2 chr21:38675671-38955488 - 21q22.2 (hg18-Mar_2006) Ensembl ERG - 21q22.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -3- HomoloGene ERG Gene and transcription Genbank AF015313 [ ENTREZ ] Genbank AY204740 [ ENTREZ ] Genbank AY204741 [ ENTREZ ] Genbank AY204742 [ ENTREZ ] Genbank AY204743 [ ENTREZ ] RefSeq NM_004449 [ SRS ] NM_004449 [ ENTREZ ] RefSeq NM_182918 [ SRS ] NM_182918 [ ENTREZ ] RefSeq AC_000064 [ SRS ] AC_000064 [ ENTREZ ] RefSeq NC_000021 [ SRS ] NC_000021 [ ENTREZ ] RefSeq NT_011512 [ SRS ] NT_011512 [ ENTREZ ] RefSeq NW_927384 [ SRS ] NW_927384 [ ENTREZ ] AceView ERG AceView - NCBI TRASER ERG Traser - Stanford Unigene Hs.473819 [ SRS ] Hs.473819 [ NCBI ] HS473819 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P11308 [ SRS] P11308 [ EXPASY ] P11308 [ INTERPRO ] Prosite PS00345 ETS_DOMAIN_1 [ SRS ] PS00345 ETS_DOMAIN_1 [ Expasy ] Prosite PS00346 ETS_DOMAIN_2 [ SRS ] PS00346 ETS_DOMAIN_2 [ Expasy ] Prosite PS50061 ETS_DOMAIN_3 [ SRS ] PS50061 ETS_DOMAIN_3 [ Expasy ] Interpro IPR000418 Ets [ SRS ] IPR000418 Ets [ EBI ] Interpro IPR002341 HSF_ETS_DNA_bd [ SRS ] IPR002341 HSF_ETS_DNA_bd [ EBI ] Interpro IPR010993 SAM_homology [ SRS ] IPR010993 SAM_homology [ EBI ] Interpro IPR003118 SAM_PNT [ SRS ] IPR003118 SAM_PNT [ EBI ] Interpro IPR011991 Wing_hlx_DNA_bd [ SRS ] IPR011991 Wing_hlx_DNA_bd [ EBI ] CluSTr P11308 Pfam PF00178 Ets [ SRS ] PF00178 Ets [ Sanger ] pfam00178 [ NCBI-CDD ] Pfam PF02198 SAM_PNT [ SRS ] PF02198 SAM_PNT [ Sanger ] pfam02198 [ NCBI-CDD ] Smart SM00413 ETS [EMBL] Smart SM00251 SAM_PNT [EMBL] Blocks P11308 PDB 1SXE [ SRS ] 1SXE [ PdbSum ], 1SXE [ IMB ] 1SXE [ RSDB ] HPRD P11308 Protein Interaction databases DIP P11308 IntAct P11308 Polymorphism : SNP, mutations, diseases OMIM 165080 [ map ] GENECLINICS 165080 SNP ERG [dbSNP-NCBI] SNP NM_004449 [SNP-NCI] SNP NM_182918 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -4- SNP ERG [GeneSNPs - Utah] ERG] [HGBASE - SRS] HAPMAP ERG [HAPMAP] General knowledge Family ERG [UCSC Family Browser] Browser SOURCE NM_004449 SOURCE NM_182918 SMD Hs.473819 SAGE Hs.473819 GO transcription factor activity [Amigo] transcription factor activity GO signal transducer activity [Amigo] signal transducer activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO protein amino acid phosphorylation [Amigo] protein amino acid phosphorylation GO signal transduction [Amigo] signal transduction GO development [Amigo] development GO cell proliferation [Amigo] cell proliferation GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding PubGene ERG Other databases Probes Probe ERG Related clones (RZPD - Berlin) PubMed PubMed 26 Pubmed reference(s) in LocusLink Bibliography New human erg isoforms generated by alternative splicing are transcriptional activators. Duterque-Coquillaud M, Niel C, Plaza S, Stehelin D. Oncogene 1993; 8:1865-1873. Medline 8510931

EWS-erg and EWS-Fli1 fusion transcripts in Ewing's sarcoma and primitive neuroectodermal tumors with variant translocations. Giovannini M, Biegel JA, Serra M, Wang JY, Wei YH, Nycum L, Emanuel BS and Evans GA. J Clin Invest 1994; 94:489-496. Medline 8040301

Consistent Detection of TLS/FUS-ERG Chimeric Transcripts in Acute Myeloid Leukemia With t(16; 21)(p11; q22) and Identification of a Novel Transcript. Kong XT, Ida K, Ichikawa H, Shimizu K, Ohki M, Maseki N, Kaneko Y, Sako M, Kobayashi Y, Tojou A, Miura I, Kakuda H, Funabiki T, Horibe K, Hamaguchi H, Akiyama Y, Bessho F, Yanagisawa M and Hayashi Y. Blood 1997; 90:1192-1199. Medline 9242552

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -5-

Selective expression of erg isoforms in human endothelial cells. Hewett PW, Nishi K, Daft EL and Clifford Murray J. Int J Biochem Cell Biol 2001; 33:347-355. Medline 11312105

The role of ERG (ets related gene) in cartilage development. Iwamoto M, Higuchi Y, Enomoto-Iwamoto M, Kurisu K, Koyama E, Yeh H, Rosenbloom J and Pacifici M. Osteoarthritis Cartilage 2001; 9 Suppl A: S41-S47. Medline 11680687

Combined genomic and antisense analysis reveals that the transcription factor Erg is implicated in endothelial cell differentiation. McLaughlin F, Ludbrook VJ, Cox J, von Carlowitz I, Brown S and Randi AM. Blood 2001; 98:3332-3339. Medline 11719371

Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L and Downing JR. Cancer Cell 2002; 1: 133-143. Medline 12086872

Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes. Baldus CD, Liyanarachchi S, Mrozek K, Auer H, Tanner SM, Guimond M, Ruppert AS, Mohamed N, Davuluri RV, Caligiuri MA, Bloomfield CD, and de la Chapelle A. Proc Natl Acad Sci USA 2004; 101: 3915-3920. Medline 15007164

Detailed mapping of the ERG-ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16. Owczarek CM, Portbury KJ, Hardy MP, O'Leary DA, Kudoh J, Shibuya K, Shimizu N, Kola I and Hertzog PJ. Gene 2004; 324: 65-77. Medline 14693372

Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. Marcucci G, Baldus CD, Ruppert AS, Radmacher MD, Mrozek K, Whitman SP, Kolitz JE, Edwards CG, Vardiman JW, Powell BL, Baer MR, Moore JO, Perrotti D, Caligiuri MA, Carroll AJ, Larson RA, de la Chapelle A and Bloomfield CD. J Clin Oncol 2005; 23: 9234-9242. Medline 16275934

The proto-oncogene ERG in megakaryoblastic leukemias. Rainis L, Toki T, Pimanda JE, Rosenthal E, Machol K, Strehl S, Gottgens B, Ito E and Izraeli S. Cancer Res 2005; 65: 7596-7602. Medline 16140924

Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X,

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -6- Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA and Chinnaiyan AM. Science 2005; 310: 644-648. Medline 16254181

Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression. van Zelm MC, van der Burg M, de Ridder D, Barendregt BH, de Haas EF, Reinders MJ, Lankester AC, Revesz T, Staal FJ and van Dongen JJ. J Immunol 2005; 175: 5912-5922. Medline 16237084

At the crossroads: diverse roles of early thymocyte transcriptional regulators. Anderson MK. Immunol Rev 2006; 209: 191-211. Medline 16448544

ELF4 is fused to ERG in a case of acute myeloid leukemia with a t(X;21)(q25-26;q22). Moore SD, Offor O, Ferry JA, Amrein PC, Morton CC and Dal Cin P. Leuk Res 2006; 30: 1037-1042. Medline 16303180

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed BiblioGene - INIST Contributor(s) Written 08-2006 Liat Rainis-Ganon, Shai Izraeli Citation This paper should be referenced as such : Rainis-Ganon L, Izraeli S . ERG (v-ets erythroblastosis virus E26 oncogene like (avian)). Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Genes/ERGID53ch21q22.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -7- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ARHGAP20 (Rho GTPase activating protein 20) Identity Other names KIAA1391 RARHOGAP Hugo ARHGAP20 Location 11q23.1 Local_order telomeric to ATM DNA/RNA

Genomic organization (A) and transcript variants (B) of ARHGAP20. (A) Gene structure (drawn to scale): black boxes represent exons. (B) Transcripts (drawn to scale): boxes, exons; UTR, untranslated region; light shaded box, coding region; shaded and dark shaded boxes, nucleotide sequences coding for protein domains (PH: pleckstrin homology domain, RA: ras association domain; RhoGAP: RhoGAP domain).

Description 19 exons spanning 136.1 kb genomic DNA. Transcription 5.9-6.2 kb mRNA, coding sequence: 3.5-3.6 kb Alternative splicing of the first 5 exons results in the expression of 5 transcript variants (ARHGAP20-1e, ARHGAP20-1d, ARHGAP20-1ad, ARHGAP20-1be, ARHGAP20-1c). Pseudogene None. Protein

Schematic representation of ARHGAP20 protein variants as deduced from the transcripts. Hatched box, amino-terminal extension of unknown function; PH: pleckstrin homology domain, RA: ras association domain; RhoGAP: RhoGAP domain.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -8- Description The amino-terminal region shows significant homology to a pleckstrin homology (PH) domain commonly found in eukaryotic signaling proteins. Adjacent to the PH domain a Ras association (RA) domain is postulated, which is found in proteins involved in GTPase-mediated signaling processes. The central section of the protein contains a RhoGAP domain, which is crucial for the regulation of Rho-like GTPases by Rho GTPase-activating proteins in the course of transmitting diverse intracellular signals. Expression Predominantly expressed in brain, but transcripts were also detected in peripheral blood lymphocytes. Localisation Cytoplasm Function The presence of a RhoGAP domain in combination with PH and RA modules indicates that ARHGAP20 is involved in the regulation of Rho-family GTPases. ARHGAP20 was shown to be activated by Rap1 and to induce inactivation of Rho, resulting in the neurite outgrowth. Homology Mouse: RarhoGAP (RhoGAP having the RA domain), Arhgap20. Rat: RahoGAP (RhoGAP having the RA domain), Arhgap20. Mutations Note Single nucleotide polymorphism 1785T/C (transcript variant ARHGAP20-1ad, AY496263). Germinal None detected. Somatic In the tumour cells of one case of B-cell chronic lymphocytic leukemia, the missense mutation 2995T>G (S999A; transcript variant ARHGAP20-1ad, AY496263) was found. Implicated in Entity B-cell chronic lymphocytic leukemia (B-CLL). Note In the tumour cells of two B-CLL cases, ARHGAP20 was found affected by translocations that rearranged the gene with BRWD3 (Xq21) and a novel gene on 13q14 (unpublished data), respectively. No fusion transcripts were generated. ARHGAP20 transcript expression is significantly upregulated in B-CLL lymphocytes vs. CD19+ control B cells.

Entity t(X;11)(q21;q23) Disease B-cell chronic lymphocytic leukemia (B-CLL). Cytogenetics t(X;11)(q21;q23) Hybrid/Mutated ARHGAP20 - BRWD3 Gene Abnormal None detected. Protein

Entity t(11;13)(q23;q14) Disease B-cell chronic lymphocytic leukemia (B-CLL). Cytogenetics t(11;13)(q23;14) Hybrid/Mutated ARHGAP20 - novel gene on 13q14 (unpublished data) Gene Abnormal None detected. Protein

External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -9- Hugo ARHGAP20 GDB ARHGAP20 Entrez_Gene ARHGAP20 57569 Rho GTPase activating protein 20 Cards Atlas ARHGAP20ID42979ch11q23 GeneCards ARHGAP20 Ensembl ARHGAP20 Genatlas ARHGAP20 GeneLynx ARHGAP20 eGenome ARHGAP20 euGene 57569 Genomic and cartography GoldenPath ARHGAP20 - 11q23.1 chr11:109952976-110088661 - 11q22.3 (hg18-Mar_2006) Ensembl ARHGAP20 - 11q22.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

HomoloGene ARHGAP20 Gene and transcription Genbank AB037812 [ ENTREZ ] Genbank AI936560 [ ENTREZ ] Genbank AY496263 [ ENTREZ ] Genbank AY496264 [ ENTREZ ] Genbank AY496265 [ ENTREZ ] RefSeq NM_020809 [ SRS ] NM_020809 [ ENTREZ ] RefSeq AC_000054 [ SRS ] AC_000054 [ ENTREZ ] RefSeq NC_000011 [ SRS ] NC_000011 [ ENTREZ ] RefSeq NT_033899 [ SRS ] NT_033899 [ ENTREZ ] RefSeq NW_925173 [ SRS ] NW_925173 [ ENTREZ ] AceView ARHGAP20 AceView - NCBI TRASER ARHGAP20 Traser - Stanford Unigene Hs.6136 [ SRS ] Hs.6136 [ NCBI ] HS6136 [ spliceNest ] Protein : pattern, domain, 3D structure Prosite PS50238 RHOGAP [ SRS ] PS50238 RHOGAP [ Expasy ] Interpro IPR008936 Rho_GAP [ SRS ] IPR008936 Rho_GAP [ EBI ] Interpro IPR000198 RhoGAP [ SRS ] IPR000198 RhoGAP [ EBI ] Pfam PF00620 RhoGAP [ SRS ] PF00620 RhoGAP [ Sanger ] pfam00620 [ NCBI-CDD ] Protein Interaction databases Polymorphism : SNP, mutations, diseases OMIM 609568 [ map ] GENECLINICS 609568 SNP ARHGAP20 [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -10- SNP NM_020809 [SNP-NCI] SNP ARHGAP20 [GeneSNPs - Utah] ARHGAP20] [HGBASE - SRS] HAPMAP ARHGAP20 [HAPMAP] General knowledge Family ARHGAP20 [UCSC Family Browser] Browser SOURCE NM_020809 SMD Hs.6136 SAGE Hs.6136 PubGene ARHGAP20 Other databases Probes Probe ARHGAP20 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O DNA Res 2000; 7: 65-73. Medline 10718198

Identification and characterization of human KIAA1391 and mouse Kiaa1391 genes encoding novel RhoGAP family proteins with RA domain and ANXL repeats. Katoh M, Katoh M Int J Oncol 2003; 23: 1471-1476. Medline 14532992

Identification of RARhoGAP, a novel putative RhoGAP gene expressed in male germ cells. Curry BJ, Su H, Law EG, McLaughlin EA, Nixon B, Aitken RJ Genomics 2004; 84: 406-418. Medline 15234003

Translocation t(X;11)(q13;q23) in B-cell chronic lymphocytic leukemia disrupts two novel genes. Kalla C, Nentwich H, Schlotter M, Mertens D, Wildenberger K, D_hner H, Stilgenbauer S, Lichter P Genes Chromosomes Cancer 2005; 42: 128-143. Medline 15543602

RA-RhoGAP, Rap-activated Rho GTPase-activating protein implicated in neurite outgrowth through Rho. Yamada T, Sakisaka T, Hisata S, Baba T, Takai Y J Biol. Chem 2005; 280: 33026-33034. Medline 16014623

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed BiblioGene - INIST Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -11- Written 08-2006 Claudia Kalla Citation This paper should be referenced as such : Kalla C . ARHGAP20 (Rho GTPase activating protein 20). Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Genes/ARHGAP20ID42979ch11q23.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -12- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PSAP (Prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)) Identity Other names FLJ00245 GLBA MGC110993 SAP1 Hugo PSAP Location 10q22.1 Between CDH23 (cadherin-like 23; centromeric) and Carbohydrate (chondroitin 6) Local_order sulfotransferase 3 (CST3; telomeric). DNA/RNA

Schematic diagram of the human PSAP gene (A) and cDNA (B). Open squares are exons 2-15 and shaded boxes correspond to untranslated 5' and 3' regions. The signal sequence is located adjacent to ATG and will be removed during transit in the edoplasmic reticulum. Exon 8 of the saposin B domain of prosaposin contain a 9-bp alternate splicing site that might generate three different cDNAs: a) a complete exon 8 (CAG GAT CAG; 3 amino acids), b) no exon 8, and c) exon 8 with downstream 6 bases (GAT CAG; 2 amino acids).

Description The human PSAP-precursor gene spans approximately 20 kb in length of the long arm of chromosome 10 and consists at least 15 exons. The size of exons range from 57 to 1200 bp and the size of the introns vary from 91 to more than 3800 bp in length. The PSAP gene can be cateogorized as a polycistronic gene. Further analysis of PSAP intronic positions has indicated that it may be evolved from an ancestral gene subjected to two duplication and at least one gene rearrangement. Transcription Due to the presence of an alternative splice site in exon 8, PSAP gene could be transcribed into three mRNA isoforms: one with complete exon 8 (9 bases), one without exon 8, and one with downstream 6 bases of exon 8. While all three PSAP mRNAs could be detected in human, mice, and rat, differential expression of PSAP mRNA isoforms has been reported in human and mouse tissues or cell lines.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -13- However, in chicken, there are only two mRNA isoforms (+/- exon 8). The exact biological significances of different nucleotide sequences of saposin B domain in prosaposin precursor are not known. However, it has been shown that the stability of functionally mature saposin B is not significantly affected by the presence or absence of 6 or 9 base pairs (+3 or +2 amino acids) of exon 8. In addition, mutations in the PSAP gene leading to lack or disruption of saposin B protein in patients showed similar metabolic phenotypes. Taking into consideration that neurotrophic activity of PSAP has been attributed to saposin C domain of the molecule, alternative splicing is not expected to modulate this effect. Pseudogene No pseudogen is identified for PSAP. Protein

Structure of human PSAP, saposins, and sequence alignment of a known neurotrophic fragment of human saposin C. (A) Organization of human PSAP protein. Individual saposin domains and signal peptide are indicated; lightning bolts represent proteolytic cleavage sites in the intersaposin sequences; glycosylation sites and exon-intron boundaries are shown by 8-point stars and vertical lines, respectively. (B) Amino acid sequence of human saposin A-D. Potential N-Glycosylation type carbohydrate side chain linked to asparagine are indicated with capital letter "N". As indicated, each saposin molecule also contains 6 cystein residues positioned at almost similar location. Neurotrophic sequence of saposin C is double-underlined. (C) Alignment and comparison of neurotrophic sequence of human saposin C with other vertebrates and known viruses. All sequences presented are linear. Each plus sign indicates the presence of a non-fit amino acid. DESCRIPTION Prosaposin is a highly conserved glycoprotein (with approximate molecular weight of 65-72 kDa), and the precursor of 4 small lysosomal proteins (saposin A-D; of 8-13 kDa) which are required for intracellular degradation of certain sphingolipids. Proteolytic cleavage of PSAP precursor mediated by lysosomal cysteine protease-cathepsin D, leads to individual mature saposin proteins (acidic glycoproteins).PSAP is secreted as a full- length protein. However, individual saposin proteins also exist as extracellular mature proteins (e.g., in tissue culture supernatant, serum, prostatic secretions, malignant pleural effusion). Although the origin of mature saposin proteins in the extracellular fluids is not known, it is likely that circulating serum enzymes may participate in

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -14- proteolytic cleavage of secreted PSAP. Each saposin domain presents with near identical localization of glycosylation sites and cysteine residues. The presence of high percentage homology in amino acid sequences between saposin A and C further indicates that they have originated from a single ancestroral gene at least via duplication and/or gene rearrangement.

Description Prosaposin is the saposin precursor protein with 524 amino acids including a 16 amino acids signal peptide. The full-length precursor molecule contains complex oligosaccharides chains which is probably the result of cotranslational glycosylation of the 53-kDa polypeptide and its later modification within the Golgi system that yield the 70-72 kDa precursor protein. After transport to the lysosome, cathepsin D participates in its proteolytic processing to intermediate molecular forms with 35 to 53 kDa and then to 13-kDa glycoprotein and finally to the mature 8-11 kDa less or partially glycosylated forms of individual saposin molecules. It is noteworthy that western analysis (using different anti-PSAP monoclonal and polyclonal antibodies) of human seminal fluid and whole cell lysates prepared from a number of malignant prostatic cells and other malignant cell types (e.g., breast, lung) show the presence of multiple bands with approximate molecular weight of 12-, 24-, and 36-kDa. These bands are most probably represent mono-, di-, and tri-saposins and are the result of sequential cleavage of the precursor molecule. Saposins are highly homologous molecules, each with approximately 80 amino acids containing six cysteine residues (forming 3 disulfide bonds and hair-pin structure) and N-glycosylated carbohydrate chains that are highly conserved. PSAP amino acid sequence among various species (e.g., human, rat, mouse, chicken, Zebrafish) reveals evolutionary conservation in terms of saposin domains and the homologus positioning of terminally-situated cysteine residues and an N-linked glycosylated site. Expression Prosaposin and individual saposin proteins are expressed by a wide variety of cells types originating from ectodermal, mesodermal, and endodermal germ layers including but not limited to lung, skin, fibroblast, stromal cells, bone, smooth muscle, skeletal muscle, cardiac muscle, placenta, red and white blood cells, pancreas, placenta, lymphoreticular system (spleen, thymus, liver), micro and macrovascular system, genitourinary system (e.g., prostate, testes, seminal vesicle), central and peripheral nervous system, etc. Interestingly, comparative protein expression analysis on normal human adult and fetal tissues has shown elevated levels of PSAP expression in the adult liver and decreased amounts in fetal skeletal muscle. Prosaposin and saposins also present as soluble proteins in extracellular space/fluid including pleural fluid, cerebrospinal fluid, seminal fluid, milk, and serum. PSAP and saposins are predominantly expressed in cells of hematopoietic origin (e.g., red- and white-blood cells) and neuroglial-derived tissues as compared to all other normal cell types in the mammalian system. In malignant cells, compared to their normal cellular counterparts, prosaposin is overexpressed in breast adenocarcinoma cell lines, non small-cell lung adenocarcinoma, neuroblastoma, and schwannoma cell lines. In addition, similar PSAP-overexpression is also detected in glioma cell lines, adult and pediatric brain tumors (e.g., medulloblastoma-, astrocytoma-, glioblastoma multiforme-cell lines), fibrosarcoma, osteosarcoma, and prostate cancer cell lines. In addition, immunoblotting of total protein array derived from different types of tumors (brain, colon, lung, pancreas, rectum, ovary, parotid, skin, bladder, small intestine, thymus, and uterus) with mouse monoclonal antibodies against PSAP and GAPDH followed by densitometric analysis demonstrated 1.6 to 5-fold increase in PSAP expression in malignant tissues compared to their corresponding normal tissues (Table 1). Most noticeably, PSAP is overexpressed and/or amplified in human prostate cancer tissues, xenografts, and cell lines. Quantitative SNP array hybridization in conjunction with southern hybridization and quantitative real-time PCR demonstrated a frequency of 20.6% for PSAP amplification (4 out of 25 prostate cancer xenografts and metastatic tissues and three out of nine prostate cancer cell lines). Expression of PSAP protein and mRNA in malignant prostate cancer cells is exclusively higher than normal prostate epithelial and stromal cells. Immunoblotting of conditioned media derived from prostate cancer cells shows the presence of PSAP-immunoreactive bands with

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -15- approximate molecular size of 72-kDa, 140-kDa, and 220-kDa. It is not clear whether or not the 140- and 220-kDa bands represent the dimeric or trimeric form of PSAP. In addition, PSAP mRNA and protein expression is higher in several androgen- independent than the androgen-dependent prostate cancer cell lines. This finding suggests that PSAP expression might be under androgenic, steroid hormone regulation, or feedback control mediated by the hypothalamus-pituitary-gonadal neuroendocrine axis. The involvement of pertussis toxin-sensitive GPCR-dependent mechanism for in vitro biological activities of PSAP (or its active molecular derivatives such as saposin C, TX14A) has been demonstrated in a number of cell lines. In addition, using human and mouse fibroblasts and in vivo studies, it has been demonstrated that PSAP entry into the cells is also possible via at least three other independent receptor system including the mannose receptor, mannose-6-phosphate (M-6-P) receptor, and low density lipoprotein receptor-related protein (LRP). Cell type-specific distribution of any of the above receptor systems, their relative abundance, their involvement in various biological activities of soluble PSAP and/or saposin C (e.g., cell signaling, sphingolipid transport), or post-receptor occupancy events require additional studies.

Localisation Prosaposin exists as a lysosomal, integral membrane, and an intracellular protein. In addition, prosaposin also exist as an integral membrane protein. The relative abundance of prosaposin is believed to be the highest as a secretory (soluble) protein and the lowest as an integral protein. However, it is not clear whether there is a tissue or cell type-specificity (e.g., benign versus malignant cells, epithelial versus stromal cells) for PSAP distribution. Function Prosaposin is a dual function molecule; as the precursor of intracellular lysosomal saposin proteins involved in sphingolipid hydrolysis activity and as a secreted soluble protein with neurotrophic activities, including growth, development, and maintenance of the peripheral and central nervous system, nerve regeneration and plasticity, stimulation of neurite outgrowth, stimulation of neuroblastoma cells proliferation, protection from cell-death or apoptosis, and activation of MAPK- and PI3K/Akt- signaling pathways. Column chromatography data indicated the formation of stable complexes between PSAP/saposins and several gangliosides. It has been suggested that PSAP functions as a sphingolipid binding protein and on the cell surface, complex formation between PSAP and gangliosides may suggests a role for this molecule in ganglioside function. Whether or not there is a link between the function of secreted soluble form as a trophic factor and its role as a ganglioside-binding or -career protein remain to be understood. Saposins function as coprotein for intracellular degradation of sphingolipids. Saposin A and C is involved in hydrlysis of glucosylceramide and galactosylceramide. saposin B stimulates galacto-cerebroside sulfate hydrolysis, GM1 ganglioside, and globotriaosylceramide. Saposin C is the activator of sphingomyelin phosphodiesterase. While several members of CD1 proteins are involved in lipid presentation to T cells, prosaposin-deficient mice exhibit certain defects in CD1d- mediated antigenic presentation suggesting that saposins are involved in mobilization of lipid monomers from the lysosomal membrane and their association with CD1d. In addition, prosaposin-deficient fibroblasts transfected with another member of CD1 family (CD1b) also failed to activate lipid-specific T lymphocytes. Upon reconstitution of fibroblasts with saposin C, T-cells response was restored. These findings might be suggestive of potential implications for saposin C or perhaps PSAP in recognition of tumor antigens. Several reports have identified a number of linear 5-22 amino acid segments called prosaptides (e.g., D5, TX14A) that demonstrate in vitro and/or in vivo neurotrophic activities. These bioactive sequences are located at the downstream region of saposin C domain of PSAP. Prosaptides, saposin C, or PSAP exert their effect at least partially, by binding to a single high-affinity G protein-coupled receptor. This receptor has been partially characterized but not cloned. In malignant cells and tissues, several classic reports have indicated a pluripotent regulatory role for saposin C and PSAP in prostate cancer with potential involvement in prostate carcinogenesis or progression toward metastatic or androgen-independent state.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -16- Immunohistochemical staining on benign and malignant prostate tissues revealed an intense cytosolic and anti-prosaposin immunoreactivity in tumor cells, stromal, endothelial, and inflammatory mononuclear cells and the intensity of staining was proportional to the overall Gleason s score. PSAP-immunoreactivity was also noticeable as extracellular deposition in hypercellular regions in high-grade prostatic tumors. In addition, PSAP and/or its active molecular derivatives (saposin C or TX14A) stimulate prostate cancer cells growth, motility, and invasion, upregulates uPA/uPAR expression, activates the p42/44 MAPK (Raf-MEK-ERK-RSK-Elk-1 signaling cascade), p38 MAPK, and SAPK/JNK family members of the MAPK superfamily and PI3K/Akt signaling pathways, and protects cells from apoptotic cell-death induction by etoposide via modulation of caspase-3, -7, and -9 expression/activity and/or the PI3K/Akt signaling pathway activation.

Homology The four saposin A-D proteins share a great deal of homology (~50% ) in their amino acids sequences. In addition to these, saposins also contain 6 highly conserved cysteines. Considering all these structural similarities, they differ from each other for their specificity of intracellular or potential extracellular functions. Among fopur saposins, cross-species analysis of saposin sequences, show evolutionary conservation for saposin A, B, and D. However, with the exception to the neurotrophic sequence, saposin C sequence appear to be more species-specific. For example, from the linear human saposin C-neurotrophic sequence (LIDNNKTEKEILD): (1) LID-NK and TEKEIL is shared with RNA polymerase subunit of sheep Pox virus; (2) LIÐNK and TEKEL is shared with Lumpy skin disease virus; (3) NNK and EKEIL is shared with the Hemagglutinin influenza A virus; (4) NNTEK-IL is shared with HIV-I envelop glycoprotein; (5) DN---EKEI is shared with Bacillus anthracis; or (6) LIDN-KT-KEI is shared with flagellar filament outer layer protein precursor (sheet protein) of Lyme disease spirochete. Although these linearly ordered sequence homologies appear to be remote and partial, but due to the observed profound biological activities of the neurotrophic sequence- derived peptides (in in vitro and in vivo studies) and their relative hydrophilic nature, their presence in pathogenic agents (e.g., HIV virus, anthrax) might have some potential clinical application or might be useful in understanding the mechanism underlying their pathogenicity (with respect to eukaryotic cells). Mutations Note Mutation in PSAP gene in human was reported for the first time in 1990 and so far there are 10 recorded mutations. Seven cases are identified with nucleotide substitutions in the form of missence or nonsense mutation. Among this three patients with non-sense mutations that led to prosaposin deficiency, 3 cases developed metachromatic leukodystrophy (MLD)phenotype, and one case showed the atypical Gaucher disease. Two cases of PSAP mutation were in the form of nucleotide substitution (splicing type) and both showed clinical characteristics of MLD. In one patient, deletional mutation occurred in the saposin B domain (c.803delG) and led to premature stop codon and total prosaposin deficiency. Interestingly, mutant cDNA was detected in the heterozygous parents who were the careers for the same single base deletion (c.803delG)in exon 9. Implicated in Entity Metachromatic Leukodystrophy (MLD), Gaucher Disease, Combined SAP deficiency Disease The clinical features in patients with total PSAP deficiency (combined SAP deficiency) are reported to be similar to those in Gaucher disease type 2, which present with acute infantile neuronopathic symptoms, abnormally large size of visceral organs, deteriorating general physical condition, and death in the first two years of life. Saposin A deficiency as a disease entity has not been reported. However, mice with mutation in saposin A demonstrated a phenotype similar to late-onset Krabbe disease. Patients with saposin B deficiency show similar clinical finding to those with MLD. There are three main types of MLD; Late infantile MLD, Juvenile MLD, and adult MLD. Depending on the patient s age, their clinical signs and symptoms may vary. Saposin

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -17- C deficient patients present with clinical findings similar to Gaucher disease type 3. Saposin D mutation in a mouse model has shown progressive polyuria and ataxia and accumulation of ceramide in the brain and kidney. Accumulation of saposins (up to 80-fold) are detected in spleen, liver, and brain of individuals affected with lysosomal storage diseases (LSD) such as Gaucher disease, Niemann-Pick disease (type 1), fucosidosis, Tay-Sachs disease, and Sandhoff disease. Analysis of plasma levels of saposins in patients with LSD disorders has revealed an increase of 59%, 25%, 61%, and 57% above the 95 percentile of control population for saposin A, saposin B, saposin C, and saposin D, respectively.

Total prosaposin deficiency leads to a lethal phenotype in both man and mice. Mice with homozygous inactivation of prosaposin gene showed similar clinicopathologic pictures to the human patient with total PSAP deficiency. Among these features was intrauterine or early neonatal death in PSAP-/- mice. In other mice, severe developmental abnormalities in the nervous system and male reproductive system was detected. Neuroembryological developmental abnormalities presented as muscular weakness, trembling or shakiness of head, and ataxia of the limb and progressed to severe weakness and shaking of head and trunk and after 4 weeks they developed seizures and persistant tonic epilepsy and finally died at the age of 35 days. Evidence of lysosomal storage disease was detected by abnormal accumulation of ceramide in brain, liver, and kidney, and storage of gangliosides and ceramide and hypomyelination of the brain. Gross pathological features were also detected in the male reproductive organ including atrophy of prostate gland, testes, epididymis, seminal vesicle, and reduced spermatogenesis. Microscopic examination of the involuted prostate, seminal vesicles, and epididymis revealed the presence of rudimentary undifferentiated epithelial cells. In spite of these abnormal findings, the testosterone level was normal or even elevated.

Table 1: PSAP overexpression in Human tumor tissues (; Koochekpour et al. unpublished observation). Oncogenesis Overall the expression and biofunctional significances of prosaposin and saposins in cancer are largly unknown. The observation of PSAP overexpression in squamous cell carcinoma of lung, melanoma of skin, ovarian carcinoma, transitional cell carcinoma of the bladder, leiomyoma or non-hodgkinís lymphoma of the small intestine, malignant thymoma, glioblastoma multiforme, and adenocarcinoma of the colon, pancreas, parotid, and endometrium is a strong indication of the potential involvement of PSAP at least in human carcinogenesis (Table 1). Most convincingly, available in vitro data indicate its potential significance and involvement in prostate carcinogenesis and its progression toward metastatic and/or androgen-independent status. Probably the most

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -18- important finding was the genomic amplification and/or overexpression of PSAP in androgen-independent prostate cancer cell lines and punch biopsy samples of xenografts and lymph node metastases obtained from patients with hormone- refractory androgen-dependent or •independent prostate cancer. Immunohistochemical staining has demonstrated the relative abundance of immunoreactive-PSAP in high Gleason grade tumors as compared to the low-grade tumors or benign prostatic hyperplasia. Although PSAP appears to function as a protooncogene in prostate cancer cells, direct experimental evidence is not available at this time.

External links Nomenclature Hugo PSAP GDB PSAP PSAP 5660 prosaposin (variant Gaucher disease and variant metachromatic Entrez_Gene leukodystrophy) Cards Atlas PSAPID42980ch10q22 GeneCards PSAP Ensembl PSAP Genatlas PSAP GeneLynx PSAP eGenome PSAP euGene 5660 Genomic and cartography GoldenPath PSAP - 10q22.1 chr10:73246062-73281088 - 10q22.1 (hg18-Mar_2006) Ensembl PSAP - 10q22.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PSAP Gene and transcription Genbank AB209776 [ ENTREZ ] Genbank AK057878 [ ENTREZ ] Genbank AK129790 [ ENTREZ ] Genbank AK223290 [ ENTREZ ] Genbank BC001503 [ ENTREZ ] RefSeq NM_001042465 [ SRS ] NM_001042465 [ ENTREZ ] RefSeq NM_001042466 [ SRS ] NM_001042466 [ ENTREZ ] RefSeq NM_002778 [ SRS ] NM_002778 [ ENTREZ ] RefSeq AC_000053 [ SRS ] AC_000053 [ ENTREZ ] RefSeq NC_000010 [ SRS ] NC_000010 [ ENTREZ ] RefSeq NT_008583 [ SRS ] NT_008583 [ ENTREZ ] RefSeq NW_924796 [ SRS ] NW_924796 [ ENTREZ ] AceView PSAP AceView - NCBI TRASER PSAP Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -19- Unigene Hs.523004 [ SRS ] Hs.523004 [ NCBI ] HS523004 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q6IBQ6 [ SRS] Q6IBQ6 [ EXPASY ] Q6IBQ6 [ INTERPRO ] CluSTr Q6IBQ6 Blocks Q6IBQ6 HPRD Q6IBQ6 Protein Interaction databases DIP Q6IBQ6 IntAct Q6IBQ6 Polymorphism : SNP, mutations, diseases OMIM 176801 [ map ] GENECLINICS 176801 SNP PSAP [dbSNP-NCBI] SNP NM_001042465 [SNP-NCI] SNP NM_001042466 [SNP-NCI] SNP NM_002778 [SNP-NCI] SNP PSAP [GeneSNPs - Utah] PSAP] [HGBASE - SRS] HAPMAP PSAP [HAPMAP] General knowledge Family PSAP [UCSC Family Browser] Browser SOURCE NM_001042465 SOURCE NM_001042466 SOURCE NM_002778 SMD Hs.523004 SAGE Hs.523004 GO cerebroside-sulfatase activity [Amigo] cerebroside-sulfatase activity GO galactosylceramidase activity [Amigo] galactosylceramidase activity GO glucosylceramidase activity [Amigo] glucosylceramidase activity GO alpha-galactosidase activity [Amigo] alpha-galactosidase activity GO beta-galactosidase activity [Amigo] beta-galactosidase activity sphingomyelin phosphodiesterase activity [Amigo] sphingomyelin phosphodiesterase GO activity GO extracellular space [Amigo] extracellular space GO lysosome [Amigo] lysosome GO lipid metabolism [Amigo] lipid metabolism GO sphingolipid metabolism [Amigo] sphingolipid metabolism GO glycosphingolipid metabolism [Amigo] glycosphingolipid metabolism GO lipid transport [Amigo] lipid transport lysosome organization and biogenesis [Amigo] lysosome organization and GO biogenesis GO enzyme activator activity [Amigo] enzyme activator activity GO lipid binding [Amigo] lipid binding GO integral to membrane [Amigo] integral to membrane

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -20- PubGene PSAP Other databases Probes Probe PSAP Related clones (RZPD - Berlin) PubMed PubMed 47 Pubmed reference(s) in LocusLink Bibliography Concentrations of an activator protein for sphingolipid hydrolysis in liver and brain samples from patients with lysosomal storage diseases. Inui K, Wenger DA. J Clin Invest 1983; 72(5):1622-1628. Medline 6415115

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Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene. Schnabel D, Schroder M, Furst W, Klein A, Hurwitz R, Zenk T, Weber J, Harzer K, Paton BC, Poulos A, et al. J Biol Chem 1992; 267(5): 3312-3315. Medline 1371116

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Identification of the neurotrophic factor sequence of prosaposin. O'Brien JS, Carson GS, Seo HC, Hiraiwa M, Weiler S, Tomich JM, Barranger JA, Kahn M, Azuma N, Kishimoto Y. FASEB J 1995; 9(8): 681-685. Medline 7768361

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Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids. Fujita N, Suzuki K, Vanier MT, Popko B, Maeda N, Klein A, Henseler M, Sandhoff K, Nakayasu H, Suzuki K. Hum Mol Genet 1996 Jun; 5(6): 711-725. Medline 8776585

Expression of the three alternative forms of the sphingolipid activator protein precursor in baby hamster kidney cells and functional assays in a cell culture system. Henseler M, Klein A, Glombitza GJ, Suziki K, Sandhoff K. J Biol Chem 1996; 271(14): 8416-8423. Medline 8626540

A hydrophilic peptide comprising 18 amino acid residues of the prosaposin sequence has neurotrophic activity in vitro and in vivo. Kotani Y, Matsuda S, Wen TC, Sakanaka M, Tanaka J, Maeda N, Kondoh K, Ueno S, Sano A. J Neurochem 1996; 66(5): 2197-2200. Medline 8780053

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Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides. Hiraiwa M, Taylor EM, Campana WM, Darin SJ, O'Brien JS. Proc Natl Acad Sci U S A 1997; 94(9): 4778-4781. Medline 9114068

Prosaptide activates the MAPK pathway by a G-protein-dependent mechanism essential for enhanced sulfatide synthesis by Schwann cells. Campana WM, Hiraiwa M, O'Brien JS. FASEB J 1998; 12(3): 307-314. Medline 9506474

Cellular uptake of saposin (SAP) precursor and lysosomal delivery by the low density

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -22- lipoprotein receptor-related protein (LRP). Hiesberger T, Huttler S, Rohlmann A, Schneider W, Sandhoff K, Herz J. EMBO J 1998; 17(16): 4617-4625. Medline 9707421

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Secretion of prosaposin, a multifunctional protein, by breast cancer cells. Campana WM, O'Brien JS, Hiraiwa M, Patton S. Biochim Biophys Acta 1999; 1427(3): 392-400. Medline 10350655

Phosphatidylinositol 3-kinase and Akt protein kinase mediate IGF-I- and prosaptide-induced survival in Schwann cells. Campana WM, Darin SJ, O'Brien JS. J Neurosci Res 1999; 57(3): 332-341. Medline 10412024

Saposins A, B, C, and D in plasma of patients with lysosomal storage disorders. Chang MH, Bindloss CA, Grabowski GA, Qi X, Winchester B, Hopwood JJ, Meikle PJ. Clin Chem 2000; 46(2): 167-174. Medline 10657372

Physiology and pathophysiology of sphingolipid metabolism and signaling. Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K. Biochim Biophys Acta 2000; 1485(2-3): 63-99. Review. Medline 10832090

Targeted disruption of the mouse prosaposin gene affects the development of the prostate gland and other male reproductive organs. Morales CR, Zhao Q, El-Alfy M, Suzuki K. J Androl 2000; 21(6): 765-775. Medline 11105903

A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hulkova H, Cervenkova M, Ledvinova J, Tochackova M, Hrebicek M, Poupetova H, Befekadu A, Berna L, Paton BC, Harzer K, Boor A, Smid F, Elleder M. Hum Mol Genet 2001; 10(9): 927-940. Medline 11309366

Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase. Misasi R, Sorice M, Di Marzio L, Campana WM, Molinari S, Cifone MG, Pavan A, Pontieri GM, O'Brien JS. FASEB J 2001; 15(2): 467-474. Medline 11156962

Differential membrane interactions of saposins A and C: implications for the functional specificity.

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Molecular and cell biology of acid beta-glucosidase and prosaposin. Qi X, Grabowski GA. Prog Nucleic Acid Res Mol Biol 2001; 66: 203-239. Review Medline 11051765

Large-scale genotyping of complex DNA. Kennedy GC, Matsuzaki H, Dong S, Liu WM, Huang J, Liu G, Su X, Cao M, Chen W, Zhang J, Liu W, Yang G, Di X, Ryder T, He Z, Surti U, Phillips MS, Boyce-Jacino MT, Fodor SP, Jones KW. Nat Biotechnol 2003;(10): 1233-1237. Medline 12960966

Prosaposin ablation inactivates the MAPK and Akt signaling pathways and interferes with the development of the prostate gland. Morales CR, Badran H. Asian J Androl 2003; 5(1): 57-63. Review. Medline 12647005

Biosynthesis and degradation of mammalian glycosphingolipids. Sandhoff K, Kolter T. Philos Trans R Soc Lond B Biol Sci 2003; 358(1433): 847-861. Review. Medline 12803917

Analyses of temporal regulatory elements of the prosaposin gene in transgenic mice. Sun Y, Witte DP, Jin P, Grabowski GA. Biochem J 2003; 370(Pt 2): 557-566. Medline 12467496

Conservation of expression and alternative splicing in the prosaposin gene. Cohen T, Ravid L, Altman N, Madar-Shapiro L, Fein A, Weil M, Horowitz M. Res Mol Brain Res 2004; 129(1-2): 8-19. Medline 15469878

Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells. Kang SJ, Cresswell P. Nat Immunol 2004; 5(2): 175-181. Medline 14716312

Prosaptide TX14A stimulates growth, migration, and invasion and activates the Raf-MEK-ERK- RSK-Elk-1 signaling pathway in prostate cancer cells. Koochekpour S, Sartor O, Lee TJ, Zieske A, Patten DY, Hiraiwa M, Sandhoff K, Remmel N, Minokadeh A. Prostate 2004; 61(2): 114-123. Medline 15305334

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed BiblioGene - INIST Contributor(s) Written 03-2006 Shahriar Koochekpour

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -24- Updated 09-2006 Shahriar Koochekpour Citation This paper should be referenced as such : Koochekpour S . PSAP (Prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)). Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PSAPID42980ch10q22.html Koochekpour S . PSAP (Prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)). Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PSAPID42980ch10q22.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -25- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CASC5 (Cancer Sensitibity Candidate 5) Identity Other names AF15q14 (ALL1 fused gene from 15q14) KIAA1570 D40 Hugo CASC5 Location 15q14 DNA/RNA Note Whole genomic size is not determined, but consists of at least 10 Exons. Transcription D40/CASC5 mRNA expression is dominant in normal human testis and slight expression are observed in other organs, such as placenta. At least two alternative isoforms of cDNA were identified. Northern blotting analysis on testis shows two bands with size of approximately 6 and 8.5 kb which are probably derived from the two isoforms. Analysis on cancer cell lines, such as HeLa, gave single band with 8.5 kb. There is another alternative splicing site at the 5¹ side of this gene that generates a short exon with 78 bp in cDNA. There are potential other alternative splicing at cancer cell lines. Protein

Description Encodes 1833 amino acids and 2342 amino acids. Expression In human testis D40/CASC5 protein expression with molecular weight of approximately 300 kDa and 250 kdDa are observed in germ cell. The significant high expressions are observed in nucleus of spermatocytes and Pre-acrosome of spermatids. As D40/CASC5 protein has no hydrophobic signal peptide in its amino terminal. Localisation It localizes outer surface of Pre-acrosome membrane. Kitnetochore proteins in C. elegans and yeast have sequence homology to D40 and it was shown that D40 is localized in kinetochore in a human cancer cell line. Implicated in Entity t(11;15)(q23;q14) < ID: 1199 >/acute non lymphocytic leukemia (ANLL) -->MLL- CASC5 Note It is reported that MLL gene and D40 (AF15q14) gene are translocated each other in three cases of leukemias.

Entity lung cancer Note In primary lung cancer, clinicopathological findings correlates with D40 expression. D40 mRNA expression is more frequent in the tumors with low differentiation than the ones with moderate and high differentiation. Further, the tumors derived from smoker express higher incidence of D40 mRNA than the ones from non-smoker. D40 is a member of cancer/testis gene family.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -26- External links Nomenclature Hugo CASC5 GDB CASC5 Entrez_Gene CASC5 57082 cancer susceptibility candidate 5 Cards Atlas AF15q14ID318 GeneCards CASC5 Ensembl CASC5 Genatlas CASC5 GeneLynx CASC5 eGenome CASC5 euGene 57082 Genomic and cartography GoldenPath CASC5 - 15q14 chr15:38673739-38743829 + 15q15.1 (hg18-Mar_2006) Ensembl CASC5 - 15q15.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CASC5 Gene and transcription Genbank AB022190 [ ENTREZ ] Genbank AB046790 [ ENTREZ ] Genbank AF173994 [ ENTREZ ] Genbank AF248041 [ ENTREZ ] Genbank AF461041 [ ENTREZ ] RefSeq NM_144508 [ SRS ] NM_144508 [ ENTREZ ] RefSeq NM_170589 [ SRS ] NM_170589 [ ENTREZ ] RefSeq AC_000058 [ SRS ] AC_000058 [ ENTREZ ] RefSeq NC_000015 [ SRS ] NC_000015 [ ENTREZ ] RefSeq NT_010194 [ SRS ] NT_010194 [ ENTREZ ] RefSeq NW_925840 [ SRS ] NW_925840 [ ENTREZ ] AceView CASC5 AceView - NCBI TRASER CASC5 Traser - Stanford Unigene Hs.181855 [ SRS ] Hs.181855 [ NCBI ] HS181855 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q8NG31 [ SRS] Q8NG31 [ EXPASY ] Q8NG31 [ INTERPRO ] CluSTr Q8NG31 Blocks Q8NG31 HPRD Q8NG31 Protein Interaction databases DIP Q8NG31 IntAct Q8NG31

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -27- Polymorphism : SNP, mutations, diseases OMIM 609173 [ map ] GENECLINICS 609173 SNP CASC5 [dbSNP-NCBI] SNP NM_144508 [SNP-NCI] SNP NM_170589 [SNP-NCI] SNP CASC5 [GeneSNPs - Utah] CASC5] [HGBASE - SRS] HAPMAP CASC5 [HAPMAP] General knowledge Family CASC5 [UCSC Family Browser] Browser SOURCE NM_144508 SOURCE NM_170589 SMD Hs.181855 SAGE Hs.181855 GO acrosome [Amigo] acrosome GO acrosome formation [Amigo] acrosome formation GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus PubGene CASC5 Other databases Probes Probe CASC5 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography Chromosomal assignment of a novel human gene D40. Wei G., Takimoto M, Yoshida I, Mao PZ, Miura T, Kuzumaki N. Nucleic Acids Symp Ser 1999; (42): 71-72. Medline 10780384

AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14). Hayette S, Tiqaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Delage G, Magaud JP, Rimokh R. Oncogene 2000; 19(38): 4446-4450. Medline 10980622

Frequent expression of new cancer/testis gene D40/AF15q14 in lung cancers of smokers. Takimoto M, Wei G, Dosaka-Akita H, Mao P, Kondo S, Sakuragi N, Chiba I, Miura T, Itoh N, Sasao T, Koya RC, Tsukamoto T, Fujimoto S, Katoh H, Kuzumaki N. Br J Cancer 2002; 86(11): 1757-1762. Medline 12087463

A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15. Chinwalla V, Chien A, Odero M, Neilly MB, Zeleznik-Le NJ, Rowley JD.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -28- Oncogene 2003; 22(9): 1400-1410. Medline 12618766

Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14). Kuefer MU, Chinwalla V, Zeleznik-Le NJ, Behm FG, Naeve CW, Rakestraw KM, Mukatira ST, Raimondi SC, Morris SW. Oncogene 2003; 22(9): 1418-1424. Medline 12618768

A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Cheeseman IM, Niesen S, Anderson S, Hyndman F, Yates JR 3rd, Oegema K, Desai A. Genes Dev 2004; 18(18): 2255-2268. Medline 15371340

A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1. Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M. Nat Cell Biol 2004; 6(11): 1135-1141. Medline 15502821

The protein encoded by cancer/testis gene D40/AF15q14 is localized in spermatocytes, acrosomes of spermatids and ejaculated spermatozoa. Sasao T, Itoh N, Takano H, Watanabe S, Wei G, Tsukamoto T, Kuzumaki N, Takimoto M. Reproduction 2004; 128(6): 709-716. Medline 15579588

Cancer/testis antigens, gametogenesis and cancer. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Nat Rev Cancer 2005; 5(8): 615-625. Medline 16034368

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed BiblioGene - INIST Contributor(s) Written 03-2000 Jean-Loup Huret, Christiane Charrin Updated 09-2006 Masato Takimoto Citation This paper should be referenced as such : Huret JL, Charrin C . CASC5 (Cancer Sensitibity Candidate 5). Atlas Genet Cytogenet Oncol Haematol. March 2000 . URL : http://AtlasGeneticsOncology.org/Genes/AF15q14ID318.html Takimoto M . CASC5 (Cancer Sensitibity Candidate 5). Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Genes/AF15q14ID318.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -29- Atlas of Genetics and Cytogenetics in Oncology and Haematology

BRWD3 (bromodomain and WD repeat domain containing 3) Identity Other names BRODL FLJ38568 Hugo BRWD3 Location Xq21.1 DNA/RNA

Genomic organization (A) and transcript variants (B) of BRWD3. (A) Gene structure (drawn to scale): black boxes represent exons. (B) Transcripts (drawn to scale): boxes, exons; UTR, untranslated region; light shaded box, coding region; shaded and dark shaded boxes, nucleotide sequences coding for protein domains (WD40: WD40 tandem repeats; BROMO: bromodomain). For transcript variants BRWD3-C to BRWD3-P only the largest possible coding regions are indicated, though translation of different short proteins by using the start sites of BRWD3-A and BRWD3-B might also be possible.

Description 44 exons spanning 132.7 kb genomic DNA Transcription 5.6-6.2 kb mRNA, coding sequence: 4.2-5.4 kb Alternative splicing results in the expression of at least 15 transcript variants (BRWD3-A to BRWD3-P): The two most abundant transcript variants A and B are the result of alternative splicing of the first four exons (BRWD3-A contains exons 1 to 4, whereas BRWD3-B starts with an extended version of exon 4). BRWD3-C to BRWD3-P represent alternatively spliced variants of A and B, which contain additional exons 6a, 6b, and/or 12a and lack exons 3, 5, 6, 7, 8, and/or 9.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -30- Pseudogene None. Protein

Schematic representation of protein variants BRWD3-A and BRWD3-B as deduced from the transcripts. WD40: WD40 tandem repeats; BROMO: bromodomain. Translation initiation in exons 11 and 13 of transcripts BRWD3-C to BRWD3-P produces proteins, which retain four and three of the eight WD40 repeats, respectively.

Description The amino-terminal region consists of eight tandem WD40 repeats, which had been identified as the structural determinant of the beta -subunit of the G-proteins that mediateting transmembrane signal transduction. The carboxy terminus is predicted to contain two bromodomains with the potential to mediate protein-protein interactions in DNA-binding proteins. BRWD3-C to BRWD3-P are amino-terminally truncated versions of BRWD3-A and BRWD3-B, which retain three or four of the eight WD40 repeats and both bromodomains. Expression Expressed in a variety of adult tissues (lymphocytes, brain, heart, kidney, placenta) and in fetal liver. Function By performing a systematic genomewide survey for genes required for JAK/STAT pathway activity (involved in cell proliferation and haematopoiesis), the Drosophila homologon of BRWD3 was isolated as a member of the JAK/STAT signalling cascade acting downstream of JAK. In vivo analysis demonstrated that disrupted Drosophila BRWD3 functions as a suppressor of leukemia-like blood cell tumors. Homology Drosophila melanogaster: BRWD3 Mouse: Brwd3 Pan troglodytes: BRWD3 Implicated in Entity t(X;11)(q21;q23) Note In the tumour cells of one case of B-cell chronic lymphocytic leukemia (B-CLL), BRWD3 was affected by a translocation that rearranged the gene with ARHGAP20 (11q23). No fusion transcripts were generated. BRWD3 transcript expression is downregulated in B-CLL lymphocytes vs. CD19+ control B cells. Disease B-cell chronic lymphocytic leukemia Cytogenetics t(X;11)(q21;q23) Hybrid/Mutated ARHGAP20 - BRWD3 Gene Abnormal None detected. Protein

External links Nomenclature Hugo BRWD3 GDB BRWD3 Entrez_Gene BRWD3 254065 bromodomain and WD repeat domain containing 3 Cards

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -31- GeneCards BRWD3 Ensembl BRWD3 Genatlas BRWD3 GeneLynx BRWD3 eGenome BRWD3 euGene 254065 Genomic and cartography GoldenPath BRWD3 - Xq21.1 chrX:79818351-79951889 - Xq21.1 (hg18-Mar_2006) Ensembl BRWD3 - Xq21.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BRWD3 Gene and transcription Genbank AK095887 [ ENTREZ ] Genbank AY497046 [ ENTREZ ] Genbank AY497047 [ ENTREZ ] Genbank AY497048 [ ENTREZ ] Genbank AY497049 [ ENTREZ ] RefSeq NM_153252 [ SRS ] NM_153252 [ ENTREZ ] RefSeq AC_000066 [ SRS ] AC_000066 [ ENTREZ ] RefSeq NC_000023 [ SRS ] NC_000023 [ ENTREZ ] RefSeq NT_011651 [ SRS ] NT_011651 [ ENTREZ ] RefSeq NW_927713 [ SRS ] NW_927713 [ ENTREZ ] AceView BRWD3 AceView - NCBI TRASER BRWD3 Traser - Stanford Unigene Hs.170667 [ SRS ] Hs.170667 [ NCBI ] HS170667 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q2T9J6 [ SRS] Q2T9J6 [ EXPASY ] Q2T9J6 [ INTERPRO ] Prosite PS50014 BROMODOMAIN_2 [ SRS ] PS50014 BROMODOMAIN_2 [ Expasy ] Prosite PS00678 WD_REPEATS_1 [ SRS ] PS00678 WD_REPEATS_1 [ Expasy ] Prosite PS50082 WD_REPEATS_2 [ SRS ] PS50082 WD_REPEATS_2 [ Expasy ] Prosite PS50294 WD_REPEATS_REGION [ SRS ] PS50294 WD_REPEATS_REGION [ Expasy ] Interpro IPR001487 Bromodomain [ SRS ] IPR001487 Bromodomain [ EBI ] Interpro IPR011048 Cyt_cd1_haem_C [ SRS ] IPR011048 Cyt_cd1_haem_C [ EBI ] Interpro IPR011045 N2O_reductase_N [ SRS ] IPR011045 N2O_reductase_N [ EBI ] Interpro IPR011047 Quino_alc_DH [ SRS ] IPR011047 Quino_alc_DH [ EBI ] Interpro IPR001680 WD40 [ SRS ] IPR001680 WD40 [ EBI ] CluSTr Q2T9J6 Pfam PF00439 Bromodomain [ SRS ] PF00439 Bromodomain [ Sanger ] pfam00439 [ NCBI- CDD ] Pfam PF00400 WD40 [ SRS ] PF00400 WD40 [ Sanger ] pfam00400 [ NCBI-CDD ] Smart SM00297 BROMO [EMBL] Smart SM00320 WD40 [EMBL]

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -32- Prodom PD000018 WD40[INRA-Toulouse] Prodom Q2T9J6 Q2T9J6_HUMAN [ Domain structure ] Q2T9J6 Q2T9J6_HUMAN [ sequences sharing at least 1 domain ] Blocks Q2T9J6 HPRD Q2T9J6 Protein Interaction databases DIP Q2T9J6 IntAct Q2T9J6 Polymorphism : SNP, mutations, diseases OMIM 300553 [ map ] GENECLINICS 300553 SNP BRWD3 [dbSNP-NCBI] SNP NM_153252 [SNP-NCI] SNP BRWD3 [GeneSNPs - Utah] BRWD3] [HGBASE - SRS] HAPMAP BRWD3 [HAPMAP] General knowledge Family BRWD3 [UCSC Family Browser] Browser SOURCE NM_153252 SMD Hs.170667 SAGE Hs.170667 PubGene BRWD3 Other databases Probes Probe BRWD3 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Translocation t(X;11)(q13;q23) in B-cell chronic lymphocytic leukemia disrupts two novel genes. Kalla C, Nentwich H, Schlotter M, Mertens D, Wildenberger K, D_hner H, Stilgenbauer S, Lichter P Genes Chromosomes Cancer 2005; 42: 128-143. Medline 15543602

Identification of JAK/STAT signalling components by genome-wide RNA interference. Müller P, Kuttenkeuler D, Gesellchen V, Zeidler MP, Boutros M Nature 2005; 436: 871-875. Medline 16094372

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed BiblioGene - INIST Contributor(s) Written 09-2006 Claudia Kalla Citation

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -33- This paper should be referenced as such : Kalla C . BRWD3 (bromodomain and WD repeat domain containing 3). Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Genes/BRWD3ID42978chXq21.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -34- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TFPT (TCF3/E2A fusion partner) Identity Other names FB1 Hugo TFPT Location 19q13.4 DNA/RNA Description Genomic structure of six exons and five introns spanning about 10kb Transcription Two transcripts of 1.1kb and 1.2kb, expressed mainly in brain and in hemopoietic cell lines. The rat ortholog, Amida, was found highly expressed also in rat testis. TATA less promoter, that can be transactivated in vitro by PU.1 and Ikaros 2. Orientation, minus strand. Protein

Description Conserved protein of 253 amino acids (in man) with two nuclear localization signals (NLS) (n.68-75 and n.190-194) and a DNA binding domain located between the two NLSs. Expression constitutive Localisation nuclear Function Over expression of TFPT/Amida in cultured cells induces arrest in G2-M. Biochemical studies indicate that TFPT/Amida interacts with Cdc2/CDK1 in mitosis and its over expression results in a decrease of Cdc2/CDK1 activity. It is also suggested that the TFPT/Amida DNA binding activity is necessary for cell cycle inhibition and that Amida phophorylation by Cdc2/CDK1, detected in vitro, might decrease this DNA binding activity. Up-regulation of TFPT promotes caspase 9-dependent, p53-independent apoptosis. The pro-apoptotic role of TFPT appears modulated by interaction with specific factors, like Arc and Par-4, which might provide an explanation for the different susceptibility of different cell types to TFPT induced apoptosis. Homology Very high homology with mouse and rat orthologs. Mutations Somatic Involved in chromosome rearrangement in leukaemia. Implicated in Entity Childhood pre-B ALL Note We detected 8 cases out of 200 : incidence about 4% of childhood pre-B ALL Cytogenetics Following the position of the two involved genes, E2A on 19p13 and FB1 on 19q13 an inv(19)(p13q13) appears more likely but a translocation t(19;19)(p13;q13) cannot be yet ruled out. Still pending. Hybrid/Mutated E2A-FB1 Gene Abnormal Since the chimeric transcripts so far analyzed contain the FB1 sequence fused out of Protein frame to E2A and no truncated E2A protein was detected by Western blot, we suggest that no fusion protein is produced.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -35- Breakpoints Note We detected different joining points in the transcripts of the different analyzed cases indicating different breakpoints in a genomic region spanning exons 15-17 on TCF3 and exons 5-6 on TFPT. External links Nomenclature Hugo TFPT GDB TFPT Entrez_Gene TFPT 29844 TCF3 (E2A) fusion partner (in childhood Leukemia) Cards Atlas TFPTID495ch19q13 GeneCards TFPT Ensembl TFPT Genatlas TFPT GeneLynx TFPT eGenome TFPT euGene 29844 Genomic and cartography GoldenPath TFPT - 19q13.4 chr19:59302142-59310848 - 19q13.42 (hg18-Mar_2006) Ensembl TFPT - 19q13.42 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TFPT Gene and transcription Genbank AF052052 [ ENTREZ ] Genbank BC001728 [ ENTREZ ] Genbank BC004281 [ ENTREZ ] Genbank BC007776 [ ENTREZ ] Genbank CR590072 [ ENTREZ ] RefSeq NM_013342 [ SRS ] NM_013342 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011109 [ SRS ] NT_011109 [ ENTREZ ] RefSeq NW_927284 [ SRS ] NW_927284 [ ENTREZ ] AceView TFPT AceView - NCBI TRASER TFPT Traser - Stanford Unigene Hs.590939 [ SRS ] Hs.590939 [ NCBI ] HS590939 [ spliceNest ] Protein : pattern, domain, 3D structure Protein Interaction databases Polymorphism : SNP, mutations, diseases OMIM 609519 [ map ] GENECLINICS 609519

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -36- SNP TFPT [dbSNP-NCBI] SNP NM_013342 [SNP-NCI] SNP TFPT [GeneSNPs - Utah] TFPT] [HGBASE - SRS] HAPMAP TFPT [HAPMAP] General knowledge Family TFPT [UCSC Family Browser] Browser SOURCE NM_013342 SMD Hs.590939 SAGE Hs.590939 PubGene TFPT Other databases Probes Probe TFPT Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Identification of a novel molecular partner of the E2A gene in childhood leukemia. Brambillasca F, Mosna G, Colombo M, Rivolta A, Caslini C, Minuzzo M, Giudici G, Mizzi L, Biondi A, Privitera E. Leukemia 1999; 13: 369-375. Medline 10086727

Molecular cloning and characterization of Amida, a novel protein which interacts with a neuron specific immediate early gene product Arc, contains novel nuclear localization signals and causes cell death in cultured cells. Irie Y, Yamagata K, Gan Y, Miyamoto K, Do E, Kuo C-H, Taira E, Miki N. J Biol Chem 2000; 275: 2647-2653. Medline 10644725

Promoter analysis of TFPT(FB1), a molecular partner of TCF3 (E2A) in childhood acute lymphoblastic leukemia. Brambillasca F, Mosna G, Ballabio E, Biondi A, Boulukos KE, Privitera E. Biochemical Biophysical Research Communications 2001; 288: 1250-1257. Medline 11700047

Heterozygous targeted disruption of E2A gene by an Inv(19)(p13;q13). Roettgers S, Brambillasca F, Giudici G, Harbott J, Privitera E, Biondi A. The American Society of Hematology 44th Annual Meeting, Philadelphia, 2002

Arrest of cell cycle by Amida which is phosphorilated by Cdc2 kinase. Gan Y, Taira E, Irie Y, Fujimoto T, Miki N. Molec Cell Biochem 2003; 246: 179-185. Medline 12841360

Apoptosis promoted by up-regulation of TFPT (TCF3 fusion partner) appears p53 independent, cell type restricted and cell density influenced. Franchini C., Fontana F, Minuzzo M, Babbio F, Privitera E. Apoptosis 2006; Epub aheah of print

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -37- Medline 17041757

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed BiblioGene - INIST Contributor(s) Written 01-2005 Enrica Privitera, Andrea Biondi Updated 10-2006 Enrica Privitera Citation This paper should be referenced as such : Privitera E, Biondi A . TFPT (TCF3/E2A fusion partner). Atlas Genet Cytogenet Oncol Haematol. January 2005 . URL : http://AtlasGeneticsOncology.org/Genes/TFPTID495ch19q13.html Privitera E . TFPT (TCF3/E2A fusion partner). Atlas Genet Cytogenet Oncol Haematol. October 2006 . URL : http://AtlasGeneticsOncology.org/Genes/TFPTID495ch19q13.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -38- Atlas of Genetics and Cytogenetics in Oncology and Haematology

KLF5 : Kruppel-like factor 5 (intestinal) Identity Other names IKLF BTEB2 Hugo KLF5 Location 13q21.3

Note FISH study in PC-3 prostate cancer cell line using BAC 505F3 as a probe DNA/RNA

Black box: Exon

Description KLF5 gene encompasses 4 exons which span about 18.7 kb of DNA. BAC clone RPCI- 505F3 contains the complete KLF5 genome sequence. Transcription about 3.4 Kb mRNA, 1374 bp open reading frame Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -39-

TAD: transactivation domain, PY: PPPSY sequence

Description 457 amino acids; about 55 kDa protein; KLF5 protein undergoes numerous post translational modifications: phosphorylation, acetylation, and ubiquitination. The major transactivation domain is proline rich and contains a PY motif (324-328), which can bind to E3 ubiquitin ligase WWP1. Three zinc finger domains at C-terminus can bind to GC rich DNA sequence. Expression widely expressed in intestine, prostate, breast, lung, bladder, pancreas, placenta, uterus, skin, and skeletal muscle. Localisation nucleus Function KLF5 is a transcription factor. Many KLF5 target genes, such as PDGFa, PPARg, NFkB, cyclinD1, KLF4, and TCR, have been identified in different cell models. KLF5 regulates cell proliferation, cell cycle, apoptosis, and differentiation. KLF5 is an important transcription factor for cardiovascular remodeling and tumor angiogenesis. KLF5 is essential for mouse embryo development. Additionally, KLF5 may play an important role in several tumor types including breast, prostate, bladder, colon, esophagus, and skin. Homology KLF5 gene is highly-conserved among species (from human to Drosophila). KLF5 belongs to the SP1/KLF transcription factor family Mutations Somatic The KLF5 gene is rarely mutated in human prostate cancer. One point mutation (A --> G), which change Met294 to Val, has been found in the breast cancer cell line MDA- MB-231. Implicated in Entity Breast cancer Disease The KLF5 gene is deleted in about 43% breast cancer cell lines. Consistently, KLF5 mRNA is down-regulated in these cell lines. In 9 breast cancer cell lines without KLF5 mRNA loss, KLF5 protein is excessively degraded through ubiquitin-proteasome pathway. Forced expression of KLF5 inhibits T-47D cancer cell growth in vitro. In contrast, KLF5 expression is upregulated in clinical breast tumor samples (see below) Prognosis Recently, high level of KLF5 mRNA expression is found to be associated with shorter survival for breast cancer patients. Using tissue microarray, we performed immunohistochemical staining with the anti-KLF5 Ab. The results suggest that KLF5 protein is generally weak in normal breast epithelial cells but strongly positive in breast tumors. Therefore, KLF5 expression is probably a good prognosis marker for breast cancer.

Entity Prostate cancer Disease The KLF5 gene is deleted in about 33% prostate cancer cell lines/xenografts. Consistently, KLF5 mRNA is down-regulated in these samples compared to three immortalized prostate epithelial cell lines. In PC-3 prostate cancer cell line in which KLF5 mRNA is at normal high level, KLF5 protein is excessively degraded by over-expression of WWP1. KLF5 protein is highly expressed in normal prostate epithelial cells (Figure 5).

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -40- Forced expression of KLF5 inhibits DU145 and 22Rv1 prostate cancer cell growth in vitro. In contrast, KLF5 knock-down decreases RWPE1 immortalized prostate epithelial cell growth in vitro. These results suggest that KLF5 may play a context dependent role in prostate cancer.

Entity Bladder cancer Disease KLF5 mRNA is down-regulated in several bladder cancer cell lines. In TSu-Pr1 cell line, KLF5 over-expression promotes tumorigenesis in SCID mice. Consistently, KLF5 promotes cell cycle progression from G1 to S phase. Interestingly, KLF5 appears to promote tumor angiogenesis. Microarray analysis identified a number of angiogenic factors that are potentially regulated by KLF5, including HBP17, TGFa, and PDGFa. These findings suggest that the KLF5 transcription factor may play an oncogenic role in bladder cancer.

Entity Intestinal and colon cancer Disease Down-regulation of KLF5 may be an early event in intestinal tumorigenesis. Expression of KLF5 in non-transformed intestinal epithelial cells enhances cell growth; however,

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -41- KLF5 inhibits cell growth in colon cancer cell lines. Another group found that all-trans retinoic acid inhibits intestinal epithelial cell growth in vitro through inhibiting KLF5 expression. At the same time, lipopolysaccharide (LPS) induces proinflammatory response in intestinal epithelial cells through inducing KLF5 expression. These findings suggest that KLF5 may play an important but yet to be identified role in intestinal and colon cancer.

Entity Esophagus cancer Disease KLF5 is expressed in proliferating cells of the gastrointestinal tract, including the esophagus. Expression of KLF5 in a poorly differentiated esophageal squamous cancer cell line TE2 inhibits proliferation and invasion, decreases viability after treatment with hydrogen peroxide and UV irradiation, and increases anoikis. KLF5 upregulates the cdk inhibitor p21(waf1/cip1) and pro-apoptotic protein BAX following UV irradiation.

Entity Skin cancer Disease KLF5 is expressed predominantly in the basal layers of the developing epidermis, in the basal layers of cells of the inner root sheath, and in matrix cells of adult human hair follicles. In a transgenic mouse model, KLF5 over-expression in the basal layers of the epidermis causes abnormal epidermal development and differentiation. KLF5 overexpression may decrease the proliferation of stem cell populations of bulge keratinocytes.

Entity Cardiovascular remodeling Disease KLF5 hemizygous knock-out mice reduce cardiac hypertrophy and interstitial fibrosis upon infusion of angiotensin II. Additionally, KLF5 may play a role in antherosclerosis and restenosis through regulating vascular smooth muscle cells.

External links Nomenclature Hugo KLF5 GDB KLF5 Entrez_Gene KLF5 688 Kruppel-like factor 5 (intestinal) Cards Atlas KLF5ID41074ch13q21 GeneCards KLF5 Ensembl KLF5 Genatlas KLF5 GeneLynx KLF5 eGenome KLF5 euGene 688 Genomic and cartography GoldenPath KLF5 - 13q21.3 chr13:72531143-72549676 + 13q22.1 (hg18-Mar_2006) Ensembl KLF5 - 13q22.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene KLF5 Gene and transcription

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -42- Genbank AB030824 [ ENTREZ ] Genbank AF132818 [ ENTREZ ] Genbank AF287272 [ ENTREZ ] Genbank AK131397 [ ENTREZ ] Genbank BC007695 [ ENTREZ ] RefSeq NM_001730 [ SRS ] NM_001730 [ ENTREZ ] RefSeq AC_000056 [ SRS ] AC_000056 [ ENTREZ ] RefSeq NC_000013 [ SRS ] NC_000013 [ ENTREZ ] RefSeq NT_024524 [ SRS ] NT_024524 [ ENTREZ ] RefSeq NW_925506 [ SRS ] NW_925506 [ ENTREZ ] AceView KLF5 AceView - NCBI TRASER KLF5 Traser - Stanford Unigene Hs.508234 [ SRS ] Hs.508234 [ NCBI ] HS508234 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q13887 [ SRS] Q13887 [ EXPASY ] Q13887 [ INTERPRO ] Prosite PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 ZINC_FINGER_C2H2_1 [ Expasy ] Prosite PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 ZINC_FINGER_C2H2_2 [ Expasy ] Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr Q13887 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ] Smart SM00355 ZnF_C2H2 [EMBL] Prodom PD000003 Znf_C2H2[INRA-Toulouse] Prodom Q13887 KLF5_HUMAN [ Domain structure ] Q13887 KLF5_HUMAN [ sequences sharing at least 1 domain ] Blocks Q13887 HPRD Q13887 Protein Interaction databases DIP Q13887 IntAct Q13887 Polymorphism : SNP, mutations, diseases OMIM 602903 [ map ] GENECLINICS 602903 SNP KLF5 [dbSNP-NCBI] SNP NM_001730 [SNP-NCI] SNP KLF5 [GeneSNPs - Utah] KLF5] [HGBASE - SRS] HAPMAP KLF5 [HAPMAP] General knowledge Family KLF5 [UCSC Family Browser] Browser SOURCE NM_001730 SMD Hs.508234 SAGE Hs.508234 GO DNA binding [Amigo] DNA binding

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -43- RNA polymerase II transcription factor activity [Amigo] RNA polymerase II GO transcription factor activity GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent transcription from RNA polymerase II promoter [Amigo] transcription from RNA GO polymerase II promoter GO zinc ion binding [Amigo] zinc ion binding GO metal ion binding [Amigo] metal ion binding PubGene KLF5 Other databases Probes Probe KLF5 Related clones (RZPD - Berlin) PubMed PubMed 28 Pubmed reference(s) in LocusLink REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed BiblioGene - INIST Contributor(s) Written 10-2006 Ceshi Chen, Yinfa Zhou, Jin-Tang Dong Citation This paper should be referenced as such : Chen C, Zhou Y, Dong JT . KLF5 : Kruppel-like factor 5 (intestinal). Atlas Genet Cytogenet Oncol Haematol. October 2006 . URL : http://AtlasGeneticsOncology.org/Genes/KLF5ID41074ch13q21.html

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t(X;11)(q21;q23) Identity Originally, this translocation had been published as t(X;11)(q13;23), before BRWD3 Other names was re-mapped to Xq21.1. Clinics and Pathology Disease B-cell chronic lymphocytic leukemia (B-CLL) Epidemiology Only one case reported to date. In a second B-CLL case, a variant translocation t(11;13)(q23;q14) rearranged the same gene on 11q23 with another partner. Cytogenetics

Dual-color interphase FISH analysis of the 11q23 and Xq21 breakpoints with BAC clones. (A) FISH analysis with 11q23 specific BACs: RP11-468P24 (red signals) and RP11- 206G12 (green signals). Three red signals indicate translocation within the genomic region represented by RP11-468P24. (B) FISH analysis with the 11q23 specific BAC RP11-264L21 (green signals) and the Xq21 BAC RP11-325E14 (red signals). In the right cell, colocalization of one red and one of the three green signals indicates transfer of 11q23 sequences to Xq21 (white arrow).

Probes BAC clones covering the Xq21 breakpoint region: RP11-325E14, RP11-625B7. BAC clones covering the 11q23 breakpoint region: RP11-468P24, RP11-264L21, RP11-285P16. Variants t(11;13)(q23;q14) is a variant translocation that rearranged ARHGAP20 with a novel gene on 13q14 (unpublished data). Genes involved and Proteins Gene Name BRWD3 Location Xq21.1 Note BRWD3 had been originally mapped to Xq13.3 5' telomeric --> 3' centromeric orientation; 44 exons spanning 132.7 kb genomic DNA; Dna / Rna mRNA coding sequence: 4.2-5.4 kb Protein Contains eight tandem WD40 repeats and two bromodomains; involved in the JAK/STAT signalling cascade.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -45- Gene Name ARHGAP20 Location 11q23.1 5' telomeric --> 3' centromeric orientation; 19 exons spanning 136.1 kb genomic DNA; Dna / Rna mRNA coding sequence: 3.5-3.6 kb. Protein Contains a RhoGAP domain in combination with PH and RA modules; involved in the regulation of Rho-family GTPases (e.g. regulating the neurite outhgrowth); cytoplasmic localisation. Result of the chromosomal anomaly Hybrid gene

Schematic representation of the ARHGAP20-BRWD3 gene rearrangement. Black ovals represent the centromeres. The gene loci and orientation of ARHGAP20 and BRWD3 and their promoter regions are indicated by red and green arrows and boxes, respectively. Black arrows and the dashed line indicate the position of the breakpoints.

Description der(11): 5' BRWD3 (exons 1-22) - 3' ARHGAP20 (exons 1e-15); der(X): 5' ARHGAP20 (promoter-part of exon 1e) - 3' BRWD3 (exons 23-41); BRWD3 and ARHGAP20 are in the same transcriptional directions, fusion transcripts, however, were not detected.

Fusion Protein Note No fusion transcript expressed.

External links Other t(X;11)(q21;q23) Mitelman database (CGAP - NCBI) database Other t(X;11)(q21;q23) CancerChromosomes (NCBI) database To be noted

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -46- Both t(X;11)(q21;q23) and the variant translocation t(11;13)(q23;q14) affect ARHGAP20, which resides within the critical 11q22-q23 deletion region in B-CLL. Deletion of this genomic region is associated with an aggressive course of B-CLL. 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 Translocation t(X;11)(q13;q23) in B-cell chronic lymphocytic leukemia disrupts two novel genes. Kalla C, Nentwich H, Schlotter M, Mertens D, Wildenberger K, Döhner H, Stilgenbauer S, Lichter P. Genes Chromosomes Cancer 2005; 42: 128-143. Medline 15543602

Contributor(s) Written 08-2006 Claudia Kalla. Citation This paper should be referenced as such : Kalla C. . t(X;11)(q21;q23). Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0X11q21q23ID1430.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -47- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(6;12)(p21;p13) in lymphoid malignancies Identity

t(6;12)(p21;p13) G-banding

Clinics and Pathology Disease t(6;12)(p21;p13) has been described in only 6 cases: chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma; (AML), NOS; myelodysplastic syndrome (MDS), RAEB-2; and breast adenocarcinoma. Phenotype / cell stem B lineage. origin Prognosis No prognosis value established. Cytogenetics Cytogenetics May be not easy to detect. Morphological Cytogenetics In CLL, the translocation was detected by FISH with ETV6 probes. The ETV6 gene is Molecular rearranged, and the breakpoint is between exon 1 and exon 2. Additional -9 and der(16)t(9;16)(q21;q24) in CLL; and del(7)(p13p22) in ALL. anomalies Variants No variants in CLL and ALL. Genes involved and Proteins Gene Name ETV6 Location 12p13 Note The gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. Dna / Rna 9 exons; alternate splicing. Protein The gene encodes an ETS family transcription factor; the product of this gene contains a N-terminal pointed (PNT) domain that is involved in the protein-protein interactions, and a C-terminal ETS DNA-binding domain; wide expression; nuclear localization. Gene Name CCND3 (cyclin D3) Location 6p21 Note Could be the putative gene involved on 6p21. No molecular studies on 6p21 are

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -48- described in cases with t(6;12). In t(6;14)(p21;q32), the breakpoint is centromeric to the CCND3 gene, causing dysregulation and overexpression of CCND3. Dna / Rna . Protein . Result of the chromosomal anomaly Fusion Protein Description In CLL the ETV6 gene is rearranged; the breakpoint in ETV6 is between exon 1 and exon 2.

External links Other t(6;12)(p21;p13) in lymphoid malignancies Mitelman database (CGAP - NCBI) database Other t(6;12)(p21;p13) in lymphoid malignancies 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 Immunophenotype-karyotype associations in human acute lymphoblastic leukemia. Uckun FM, Gajl-Peczalska KJ, Provisor AJ, Heerema NA. Blood 1989; 73: 271-280. Medline 2910365

Identification of new translocations involving ETV6 in hematologic malignancies by fluorescence in situ hybridization and spectral karyotyping. Odero MD, Carlson K, Calasanz MJ, Lahortiga I, Chinwalla V, Rowley JD. Cancer 2001; 31: 134-142 Medline 11319801

Contributor(s) Written 08-2006 Maria D Odero Citation This paper should be referenced as such : Odero MD . t(6;12)(p21;p13) in lymphoid malignancies. Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0612p21p13ID1424.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -49- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Essential Thrombocythemia (ET) Clinics and Pathology Disease chronic myeloproliferative syndrome Phenotype / The disease is a chronic myeloproliferative disorder originating from a mutated cell stem pluripotent stem cell capable of producing red blood cells, granulocytes and origin megakaryocytes. In some cases, B-lymphocyte involvement by the clonal proliferation was documented. T-lymphocytes are not involved by the malignant process and nonclonally derived granulocytes may coexist with clonal cells in patients with ET. Epidemiology ET has an annual incidence of 1.5 to 2.4 patients /100,000. The disease incidence may show a peak around 30 years in females, with a second peak in the elderly with a 1:1 male-to-female ratio. The average age at diagnosis is 50-60 years. Clinics The disease is diagnosed in the presence of a sustained increase of the platelet count (>600 X 109/L) over at least 1 month without an obvious explanation. In the majority of patients the disease remains asymptomatic for many years. The disease symptoms are usually related to arterial thrombosis and, less frequently, deep venous thrombosis, which are more frequent in the untreated patient. Death may occur following major ischemic events or leukemic transformation. Cytology The peripheral blood smear shows thrombocytosis without obvious morphologic abnormalities of the white blood cells and erythrocytes. Megathrombocytes may be seen. The bone marrow is hypercellular with enlarged megakaryocytes, which may tend to aggregate in small clusters. At diagnosis a moderate increase of reticulin fibers may be observed, whereas the presence of marked fibrosis is a diagnostic exclusion criteria. Treatment Treatment should be considered for patients at risk of thrombosis (age > 60 years, previous ischemic events, platelet > 1500 X 109/L). Low-dose aspirin or other anti- platelet agents are used. Hydroxyurea is effective in reducing the platelet count and the incidence of thrombotic events. Interferon or anagrelide may be used in young patients. Evolution Leukemic transformation may occur in 3-10% of the cases. Transformation into a stage indistinguishable form idiopathic myelofibrosis was documented in 5% of the cases. Prognosis The large majority of the patients survive >10 years. No significant difference between life expectancy of ET patients and age-matched subjects was observed in a study. Cytogenetics Cytogenetics Less than 10% of the patients show a clonal chromosome defect at diagnosis. Morphological Recurrent abnormalities include total/partial trisomy 1q, trisomy 8 and trisomy 9, del(13q) and del(20q). Rearrangements of Chromosome 17, leading to 17p deletion can be frequently associated with Leukemic transformation. Cytogenetics a) Fluorescence in situ hybridization (FISH) and molecular studies : Molecular FISH may be more sensitive than conventional karyotyping for the detection of chromosome deletions b) Janus Kinase JAK2 mutation : A valine to phenylalanine substitution at position 617 (JAK2 V617F mutation) is present in 50-75% of the patients leading to constitutive kinase activity. Unlike polycythemia vera, mutated homozygous cells are not found in ET. In 1% of the

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -50- patients a gain-of-function mutation of the thrombopoietin receptor (MPL) gene can be found, determining activation of the JAK-STAT pathway Bibliography Evidence for the involvement of B lymphoid cells in polycythemia vera and essential thrombocythemia. Raskind WH, Jacobson R, Murphy S, Adamson JW, Fialkow PJ. J Clin Invest 1985; 75:1388-1390. Medline 3921571

Cytogenetic analysis in essential thrombocythemia at diagnosis and at transformation. A 12- year study. Sessarego M, Defferrari R, Dejana AM, Rebuttato AM, Fugazza G, Salvidio E, Ajmar F. Cancer Genet Cytogenet. 1989; 43: 57-65. Medline 2790773

Life expectancy of patients with chronic non leukemic myeloproliferative disorders. Rozman C, Giralt M, Feliu E, Rubio D, Cortes MT. Cancer 1991; 67: 2658-2663. Medline 2015567

Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets. el-Kassar N, Hetet G, Briere J, Grandchamp B. Blood 1997; 89: 128-134. Medline 8978285

Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Sterkers Y, Preudhomme C, Lai JL, Demory JL, Caulier MT, Wattel E, Bordessoule D, Bauters F, Fenaux P. Blood 1998; 91: 616-622. Medline 9427717

Cytogenetic and molecular genetic aspects of essential thrombocythemia. Steensma DP, Tefferi A. Acta Haematol. 2002; 108: 55-65. Medline 12187022

Incidence of trisomy 8 and 9, deletion of D13S319 and D20S108 loci and BCR/ABL translocation in non-treated essential thrombocythemia patients: an analysis of bone marrow cells using interphase fluorescence in situ hybridization. Zamora L, Espinet B, Florensa L, Besses C, Salido M, Sole F. Haematologica 2003; 88: 110-111. Medline 12551834

Management of Polycythemia Vera and Essential Thrombocythemia. Campbell PJ, Green AR. ASH Educational Book 2005; 201-208.

Essential thrombocythemia. Fruchtman SM, Hoffman R. IN: Hematology. Basic Principles and practice. Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silbertsein LE, McGlave P (Eds). Elsevier, Philadelphia, Pennsylvania, 2005; 1277-1296

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MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, Steensma DP, Elliott MA, Wolanskyj AP, Hogan WJ, McClure RF, Litzow MR, Gilliland DG, Tefferi A. Blood 2006; 25 : [Epub ahead of print]. Medline 16868251

Progenitors homozygous for the V617F JAK2 mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Scott LM, Scott MA, Campbell PJ, Green AR. Blood 2006; [Epub ahead of print].

Contributor(s) Written 08-1997 Jean-Loup Huret Updated 02-1998 Jean-Loup Huret Updated 08-2006 Antonio Cuneo, Francesco Cavazzini Citation This paper should be referenced as such : Huret JL . Essential Thrombocythemia (ET). Atlas Genet Cytogenet Oncol Haematol. August 1997 . URL : http://AtlasGeneticsOncology.org/Anomalies/ET.html Huret JL . Essential Thrombocythemia (ET). Atlas Genet Cytogenet Oncol Haematol. February 1998 . URL : http://AtlasGeneticsOncology.org/Anomalies/ET.html Cuneo A, Cavazzini F . Essential Thrombocythemia (ET). Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/ET.html

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Myelofibrosis with Myeloid Metaplasia (MMM) Idiopathic myelofibrosis Agnogenic myeloid metaplasia Clinics and Pathology Disease Chronic myeloproliferative disorder Phenotype / The disease is a chronic myeloproliferative disorder originating from a mutated cell stem pluripotent stem cell capable of producing red blood cells, granulocytes, origin megakaryocytes and lymphoid cells. Fibrosis of the marrow is the hallmark of the disease, however fibroblasts are not part of the malignant process and fibrosis represents a reaction of marrow stromal cells. Epidemiology MMM has an incidence of 0.3 to 1.5 new cases per year in 100.000 persons. Male predominance was observed in some studies and not confirmed in others. The average age at diagnosis is 60 years. Exposure to radiation and to organic solvents increases the risk of developing MMM. Clinics MMM usually presents with fatigue, weight loss, splenomegaly with or without symptoms. Anemia and various alterations of the white blood cell and/or platelet count are frequently seen at diagnosis. Thrombocytopenia-related bleeding may occur. MMM must be distinguished from myelodysplasia with fibrosis, from acute megakayoblastic leukemia and . CLINICS As the disease progresses, increased marrow fibrosis with severe symptomatic peripheral cytopenias and extramedullary hemopoiesis predominate, with consequent massive splenomegaly, hepatomegaly with portal hypertension, pulmonary hypertension. Leukemic transformation may represent the terminal event in 5-20% of the cases. Cytology Teardrop poikilocytosis and leukoerythroblastosis are present in the peripheral blood (PB) smear. Platelet are increased in size. The bone marrow is usually hypercellular at presentation with remarkably increased megakaryocytes and, to a lesser degree, granulocytes. Reticulin fibrosis is always present. Hemopoietic cellularity is patchy, with some areas showing hypercellularity and other being depleted of hemopoietic cells. The spleen histology shows extramedullary hemopoiesis involving predominantly the sinusoids. Treatment The treatment depends on the patient¹s general condition and symptoms. Supportive treatment is required for anemia and profound thrombocytopenia. Cytoreductive treatment with busulphan, hydroxyurea, thioguanine, low-dose melphalan or chlorambucil, interferon-a may be useful to control progressive splenomegaly. Irradiation of the spleen may be also employed. Danazol or low-dose dexamethasone can be used to ameliorate anemia. Allogeneic bone marrow transplantation should be considered for patients aged 60 years or less. Prognosis The median survival is approximately 5 years. Causes of death include infection, leukemic transformation, bleeding, hepatic failure with portal hypertension due to myeloid metaplasia, heart failure. Cytogenetics Cytogenetics a) Chromosome lesions: Morphological The absence of the t(9;22)/BCR-ABL fusion is an absolute diagnostic requirement. Approximately 40-50% of the patients analyzed at diagnosis show a clonal defect. The proportion of cytogenetically abnormal cases increases at disease transformation into acute leukemia, were up to 90% of the cases carry a clonal defect. Non-random

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -53- chromosome aberrations are del(13q), del(20q) and gain of 1q. These abnormalities represented 65% of abnormal cases in a study. Other recurrent chromosome aberrations include trisomy 8 and del(12p) , monosomy 7/del(7q) , der(6)t(1;6)(q21- 23;p21.3). The latter abnormality leads to trisomy 1q21-23 to 1qter and to loss of 6p21 to 6pter. FISH on deparaffinized bone biopsies showed a 56% incidence of cytogenetic lesions in a study using probes for 7q31, 12p, 13q14, 17p13, 20q13, 21q22, cen7, cen8, cen11 and cen17. b) Prognostic significance: The presence of abnormal karyotype does not appear to be an independent prognostic factor, whereas +8, 12p deletion and -7/7q- were associated with an inferior outcome at multivariate analysis. Genes involved and Proteins Gene Name JAK2 Location 9p24 Note Janus Kinase JAK2 mutation (See also Polycythemia Vera). Protein A valine to phenylalanine substitution at position 617 (JAK2 V617F mutation) is present in approximately 50-55% of the patients leading to constitutive kinase activity. The mutated JAK2 protein binds to the cytoplasmic domain of Epo-R and promotes signalling independent of Epo stimulation. The JAK2 protein is coded for by a gene mapping at 9p and it is activated upon erythropoietin binding to the receptor. JAK2 signalling involves the phosphorylation of several Y residues at the Epo receptor with activation of STAT, MAP kinase PI-3-kinase and AKT. These events lead to survival and proliferation of erythroid progenitors. JAK2 is involved in intracellular signalling following stimulation by IL3, TPO and GM-CSF, and erythroid progenitors in PV are hypersensitive to stimulation by these cytokines. Patients with JAK2 V617F mutation showed high white blood cell counts, required less transfusions and had an inferior outcome in a study. In 5-9% of the patients a gain-of-function mutation of the thrombopoietin receptor (MPL) gene can be found, determining activation of the JAK-STAT pathway. Bibliography Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases. Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM, Jones N, Watmore A, Potter A. Br J Haematol 1997;98:96-102. Medline 9233570

Cytogenetic findings and their clinical relevance in myelofibrosis with myeloid metaplasia. Tefferi A, Mesa RA, Schroeder G, Hanson CA, Li CY, Dewald GW. Br J Haematol. 2001;113:763-771. Medline 11380468

Conventional cytogenetics of myeloproliferative diseases other than CML contribute valid information. Bacher U, Haferlach T, Kern W, Hiddemann W, Schnittger S, Schoch C. Ann Hematol. 2005; 84:250-257. Medline 15692838

Cancer Genome Project. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR. Lancet. 2005;365:1054-1061.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -54- Medline 15781101

Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia. Dingli D, Grand FH, Mahaffey V, Spurbeck J, Ross FM, Watmore AE, Reilly JT, Cross NC, Dewald GW, Tefferi A. Br J Haematol. 2005;130:229-232. Medline 16029451

Idiopathic myelofibrosis. Hoffman R, Ravandi-Kashani F, IN: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silbertsein LE, McGlave P (Eds). Hematology. Basic Principles and practice. Elsevier, Philadelphia, Pennsylvania, 2005 pp 1255-1275.

Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Blood. 2005;105:973-977. Medline 15388582

Chromosome 7 deletions are associated with unfavorable prognosis in myelofibrosis with myeloid metaplasia. Strasser-Weippl K, Steurer M, Kees M, Augustin F, Tzankov A, Dirnhofer S, Fiegl M, Gisslinger H, Zojer N, Ludwig H. Blood. 2005;105:4146. Medline 15867421

A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases. Vainchenker W. Constantinescu SN. ASH Educational Book 2005:195-200. Medline 16304380.

V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Campbell PJ, Griesshammer M, Dohner K, Dohner H, Kusec R, Hasselbalch HC, Larsen TS, Pallisgaard N, Giraudier S, Le Bousse-Kerdiles MC, Desterke C, Guerton B, Dupriez B, Bordessoule D, Fenaux P, Kiladjian JJ, Viallard JF, Briere J, Harrison CN, Green AR, Reilly JT. Blood. 2006;107:2098-2100. Medline 16293597

MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, Cuker A, Wernig G, Moore S, Galinsky I, Deangelo DJ, Clark JJ, Lee SJ, Golub TR, Wadleigh M, Gilliland DG, Levine RL. PLoS Med. 2006;3:e270 [Epub ahead of print]. Medline 16834459

Contributor(s) Written 08-1997 Jean-Loup Huret

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -55- Updated 01-1998 Jean-Loup Huret Updated 08-2006 Antonio Cuneo, Francesco Cavazzini Citation This paper should be referenced as such : Huret JL . Myelofibrosis with Myeloid Metaplasia (MMM),Idiopathic myelofibrosis,Agnogenic myeloid metaplasia. Atlas Genet Cytogenet Oncol Haematol. August 1997 . URL : http://AtlasGeneticsOncology.org/Anomalies/Myelofib.html Huret JL . Myelofibrosis with Myeloid Metaplasia (MMM),Idiopathic myelofibrosis,Agnogenic myeloid metaplasia. Atlas Genet Cytogenet Oncol Haematol. January 1998 . URL : http://AtlasGeneticsOncology.org/Anomalies/Myelofib.html Cuneo A, Cavazzini F . Myelofibrosis with Myeloid Metaplasia (MMM),Idiopathic myelofibrosis,Agnogenic myeloid metaplasia. Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/Myelofib.html

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t(8;9)(p22;p24) Clinics and Pathology Disease The PCM1-JAK2 resulting from a t(8;9)(p22;p24) fusion gene occurs in both myeloid and lymphoid malignancies: CML-like chronic phase disease with associated eosinophilia and marrow fibrosis and possible evolvement to secondary AML and B- ALL ('blast crisis'), de novo B-ALL and T-ALL/T-NHL. Striking male predominance. Phenotype / Atypical chronic myeloid leukemia; chronic eosinophilic leukemia; pre-B-cell acute cell stem lymphoblastic leukemia; acute myeloid leukemia M6;T-cell acute lymphoid leukemia; origin myelodysplastic syndrome/myeloproliferative disease, unclassifiable; secondary acute myeloid leukemia. Epidemiology 15 published cases (plus 3 unpublished), striking male predominance, only 2 females, median age 45.5 years (range, 12-74). Clinics CML-like chronic phase disease with associated eosinophilia and marrow fibrosis and possible evolvement to secondary AML and B-ALL ('blast crisis'), de novo B-ALL and T-ALL/T-NHL. Striking male predominance, clinical course highly variable. Treatment Allogeneic stem cell transplantation; interferon; hydroxyurea; no specific JAK2 inhibitor currently available. Prognosis PCM1-JAK2 positive disease is an aggressive disease compared to patients with MPD and associated V617F JAK2 mutation. Acute leukemias (de novo and secondary) seen in approximately 50% of all cases. Cytogenetics Cytogenetics t(8;9)(p22;p24). Morphological Probes First probe: 5´ and 3´ regions of PCM1 (RP11-49F3 and RP11-3K23). Second probe: 5´ and 3´ regions of JAK2 (RP11-3H3 and RP11-28A9). Genes involved and Proteins Gene Name PCM1 (pericentriolar material 1). Location 8p22-p21.3. Dna / Rna 41 exons; alternate splicing. Protein PCM1 is involved in recruiting proteins necessary for centrosome replication and predicted to contain multiple coiled-coil motifs. Gene Name JAK2 (Janus kinase 2). Location 9p24. Dna / Rna 23 exons. Protein JAK2 is a tyrosine-protein kinase with transmembrane and tyrosine kinase domains. Result of the chromosomal anomaly Hybrid gene

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -57- Description 5' PCM1 - 3' JAK2. Transcript PCM1-JAK2 chimeric RNA constantly present; variable positions of the breakpoints within PCM1 and JAK2; reciprocal transcript may be present.

Fusion Protein

Diagrammatic representation of normal JAK2, normal PCM1 and the PCM1-JAK2 fusion protein.

Description PCM1-JAK2 mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Oncogenesis As has been found for other tyrosine kinase fusion proteins, e.g. BCR-ABL, it is likely that one or more of the coiled-coil motifs from PCM1 result in dimerization or oligomerization of the PCM1-JAK2 chimera, with consequent constitutive activation of the JAK2 kinase domain.

External links Other t(8;9)(p22;p24) Mitelman database (CGAP - NCBI) database Other t(8;9)(p22;p24) 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 The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1- JAK2 fusion gene. Bousquet M, Quelen C, De Mas V, Duchayne E, Roquefeuil B, Delsol G, Laurent G, Dastugue N, Brousset P. Oncogene 2005; 24: 7248-7252. Medline 16091753

JAK the trigger. Mahon FX.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -58- Oncogene 2005; 24: 7125-7126. Medline 16007127

PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocation. Murati A, Gelsi-Boyer V, Adelaide J, Perot C, Talmant P, Giraudier S, Lode L, Letessier A, Delaval B, Brunel V, Imbert M, Garand R, Xerri L, Birnbaum D, Mozziconacci MJ, Chaffanet M. Leukemia 2005; 19: 1692-1696. Medline 16034466

The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, Vanstraelen D, Barker HF, Taylor PC, O'Driscoll A, Benedetti F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann R, Chase A, Cross NC. Cancer Res 2005; 65: 2662-2667. Medline 15805263

A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell lymphoma. Adelaide J, Perot C, Gelsi-Boyer V, Pautas C, Murati A, Copie-Bergman C, Imbert M, Chaffanet M, Birnbaum D, Mozziconacci MJ. Leukemia 2006; 20: 536-537. Medline 16424865

Myeloproliferative disorders carrying the t(8;9) (PCM1-JAK2) translocation. Bousquet M, Brousset P. Hum Pathol 2006;37: 500. Medline 16564930

Contributor(s) Written 09-2006 Andreas Reiter, Christoph Walz Citation This paper should be referenced as such : Reiter A, Walz C . t(8;9)(p22;p24). Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0809p22p24ID1329.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -59- Atlas of Genetics and Cytogenetics in Oncology and Haematology

der(9;18)(p10;q10) Identity

+9,der(9; 18)(p10;q10) (G-banding).

Clinics and Pathology Disease BCR-ABL negative chronic myeloproliferative disorders (CMPD). Epidemiology Occasional occurrence: 5 cases of polycythemia vera (PV) and one case of therapy associated AML (t-AML) after ET were reported so far. Clinics 2/5 PV cases showed conversion of PV to post-polycythemic myelofibrosis. Prognosis Probably associated with progression or leukemic transformation of the CMPD. Cytogenetics Cytogenetics Unbalanced translocation between chromosomes 9 and 18 leading to trisomy of 9p Morphological and monosomy of 18p.

+9,der(9;18)(p10;q10) (chromosome painting, WCP#9 (red) + WCP#18 (green)).

Additional Sole abnormality in most cases; balanced translocations or complex aberrant anomalies karyotypes were reported as additional abnormalities. Genes involved and Proteins

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -60- Note Genes involved are unknown. Gain of 9p might play a role for gain of function of the JAK2 gene on 9p24 which codes for the JAK2 nonreceptor kinase.

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 Gain of 9p in the pathogenesis of polycythemia vera. Chen Z, Notohamiprodjo M, Guan XY, Paietta E, Blackwell S, Stout K, Turner A, Richkind K, Trent JM, Lamb A, Sandberg AA. Genes Chromosomes Cancer. 1998;22:321-324. Medline 9669670

Karyotypic abnormalities in myelofibrosis following polycythemia vera. Andrieux J, Demory JL, Caulier MT, Agape P, Wetterwald M, Bauters F, Lai JL. Cancer Genet Cytogenet. 2003;140:118-123. Medline 12645649

Gain of 9p due to an unbalanced rearrangement der(9;18): a recurrent clonal abnormality in chronic myeloproliferative disorders. Bacher U, Haferlach T, Schoch C. Cancer Genet Cytogenet. 2005;160:179-183. Medline 15993276

A gain-of-function mutation of JAK2 in myeloproliferative disorders. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. N Engl J Med. 2005;352:1779-1790. Medline 15858187

Contributor(s) Written 09-2006 Ulrike Bacher, Claudia Haferlach Citation This paper should be referenced as such : Bacher U, Haferlach C. . der(9;18)(p10;q10). Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/der918p10q10ID1418.html

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+9 or trisomy 9 Identity Note Occurs in a large spectrum of myeloid and lymphatic malignancies - chronic myeloproliferative disorders (CMPD), acute myeloid leukemias (AML), myelodysplastic syndromes (MDS), acute lymphoblastic leukemias (ALL) of B-lineage and of T-lineage. Strong association to the CMPD and especially to polycythemia vera (PV).

+9 (G-banding)

Clinics and Pathology Disease Chronic myeloproliferative disorders Epidemiology All CMPD: approx. 2% of all cases, approx. 10% of all chromosomal aberrant cases. PV: around 7% of all cases, around 16% of all chromosomal aberrant cases. Cytogenetics One of the most frequent anomalies (with del(20q), +8, and del(13q)) in BCR- ABL negative CMPD, especially in PV and in chronic idiopathic myelofibrosis (CIMF). Additional anomalies: PV: in 50% as sole abnormality, in 50% of all cases most frequently in combination with numerical gain of chromosome 8. Genes +9 is assumed to represent a gain-of-function mechanism with respect to the JAK2 gene on 9p24 coding for the JAK2 kinase. Additionally, a cooperation of +9 with the V617F mutation of the JAK2 gene is hypothesized. Prognosis No prognostic impact according to follow-up studies of limited sample sizes.

Disease Acute myeloid leukemia Phenotype / cell stem FAB subtypes M2, M4, M5. origin Epidemiology Frequent in combination with other chromosomal changes. Extremely rare as sole abnormality (around 0.1% of all cases). Cytogenetics Additional anomalies: In combination with other numerical gains (mainly +8) in simple karyotypes or in complex aberrant karyotypes (at least 3 chromosomal abnormalities). Genes Not known. Prognosis Intermediate prognosis as sole aberration or as +8,+9 in simple karyotypes. Complex aberrant karyotypes have an inferior prognosis.

Disease Myelodysplastic syndrome

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -62- Epidemiology Rare. Cytogenetics Additional anomalies: Occurrence as sole abnormality or within complex aberrant karyotype. Genes Not known Prognosis Intermediate prognosis as sole aberration. Complex aberrant karyotypes have an inferior prognosis.

Disease B-lineage acute lymphoblastic leukemia Epidemiology Rare in Philadelphia-positive and in Philadelphia-negative B-lineage. Cytogenetics Additional anomalies: Philadelphia-negative ALL: Occurrence in hyperdiploid karyotypes (equal or more than 47 chromosomes) mostly in combination with other numerical gains. Philadelphia-positive ALL: Rare additional change. Genes Not known. Prognosis Philadelphia-negative ALL with high hyperdiploid karyotype (equal or more than 51 chromosomes) shows a good prognosis, gain of chromosome 9 is not typical and prognostic impact of trisomy 9 in this setting unknown. In Philadelphia-positive ALL additional chromosomal anomalies probably enhance the inferior prognosis.

Disease T-lineage acute lymphoblastic leukemia. Epidemiology Rare, up to 4% in childhood T-ALL. Cytogenetics Additional anomalies: Occurs as sole or as combined anomaly. Genes Not known. Prognosis So far a prognostic impact could not be defined, which also might be due to the low analyzed case numbers. Cytogenetics

+9 (chromosome painting, WCP#9 (red))

External links Other +9 or trisomy 9 Mitelman database (CGAP - NCBI) database Bibliography Numerical chromosome aberrations in human neoplasia. Heim S, Mitelman F.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -63- Cancer Genet Cytogenet 1986;22: 99-108. Medline 3708552

Karyotypic patterns in chronic myeloproliferative disorders: report on 74 cases and review of the literature. Mertens F, Johansson B, Heim S, Kristoffersson U, Mitelman F. Leukemia 1991;5: 214-220. Medline 2013980

Prognostic significance of additional chromosome abnormalities in adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia. Rieder H, Ludwig WD, Gassmann W, Maurer J, Janssen JW, Gokbuget N, Schwartz S, Thiel E, Loffler H, Bartram CR, Hoelzer D, Fonatsch C. Br J Haematol 1996;95: 678-691. Medline 8982045

New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a pediatric oncology group report of 343 cases. Schneider NR, Carroll AJ, Shuster JJ, Pullen DJ, Link MP, Borowitz MJ, Camitta BM, Katz JA, Amylon MD. Blood 2000;96: 2543-2549. Medline 11001909

Chromosome and molecular abnormalities in myelodysplastic syndromes. Fenaux P. Int J Hematol 2001;73: 429-437. Medline 11503956

Exploring polycythaemia vera with fluorescence in situ hybridization: additional cryptic 9p is the most frequent abnormality detected. Najfeld V, Montella L, Scalise A, Fruchtman S. Br J Haematol 2002;119: 558-566. Medline 12406101

F. Cancer Cytogenetics; Chromosomal and Molecular Genetic Aberrations of Tumor Cells (ed 2nd edition, 1995): Viley; 2005. Heim SM.

Additional clonal abnormalities in Philadelphia-positive ALL and CML demonstrate a different cytogenetic pattern at diagnosis and follow different pathways at progression. Bacher U, Haferlach T, Hiddemann W, Schnittger S, Kern W, Schoch C. Cancer Genet Cytogenet 2005;157: 53-61 Medline 15676148

The role of the JAK2 mutations: A study in 1103 patients with CMPD and in 196 patients with AML. Schnittger S, Bacher U, Petrides P, Kern W, Haferlach T, Schoch C. Leukemia, submitted. 2006.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -64-

Contributor(s) Written 09-2006 Ulrike Bacher, Claudia Haferlach. Citation This paper should be referenced as such : Bacher U, Haferlach C. . +9 or trisomy 9. Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/tri9ID1020.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -65- Atlas of Genetics and Cytogenetics in Oncology and Haematology

+13,+13 or tetrasomy 13 Identity

GTG- banded (left) and RHG-banded (right) metaphases on blood cells showing the isolated tetrasomy 13. In the present case, the specific 13ps+ polymorphism of one of the chromosomes 13 revealed that tetrasomy resulted in the triplication of the same parental chromosome 13 rather than a double-duplication mechanism.

Clinics and Pathology Disease Acute myeloid leukaemia, poorly differenciated (AML-M0). Epidemiology Only 4 cases of primary acquired isolated tetrasomy have been described in patients with undifferentiated acute myeloid leukemia. Prognosis The possibility that isolated tetrasomy 13 may represent an independent poor prognostic factor could be suggested by the poor outcome under therapy in our patients and those reported previously. However, responses to intensive chemotherapy in older patients (under 60 year of age) are lower than with younger patients, and all described cases of isolated tetrasomy 13 occurred in elderly subjects. Genetics Two candidate genes mapped on chromosome 13 whose deregulated function might contribute to the development of transformation of undifferentiated myeloid cells are FLT1 and Rb1. However, their involvement in acute leukemia with trisomy 13 / tetrasomy 13 have to be determined, and the mechanism whereby the increased gene dose alone or in association with other additional mutation(s) confers neoplastic potential of undifferentiated phenotype is unknown. Cytogenetics Note Tetrasomy 13 can occur in different cases of acute leukemia with trisomy 13 as the primary cytogenetic abnormality, or can be associated with additional abnormalities following transformation. External links Other +13,+13 or tetrasomy 13 Mitelman database (CGAP - NCBI)

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -66- 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 Trisomy 13: a new recurring chromosome abnormality in acute leukemia. Döhner H, Arthur DC, Ball ED, Sobol RE, Davey FR, Lawrence D, Gordon L, Patil SR, Surana RB, Testa JR, Verma RS, Schiffer CA, Wurster-Hill DH, Bloomfield CD. Blood 1990; 76: 1614-1621. Medline 1698482

Trisomy/tetrasomy 13 in seven cases of acute leukemia. Sreekantaiah C, Baer MR, Morgan S, Isaacs JD, Miller KB, Sandberg AA. Leukemia 1990; 4: 781-795. Medline 2232892

Tetrasomy 13 as the sole cytogenetic abnormality in acute myeloid leukemia M1 without maturation. McGrattan P, Alexander HD, Humphreys MW, Kettle PJ. Cancer Genet Cytogenet 2002; 135: 192-195. Medline 12127406

Isolated tetrasomy 13: a fifth case report of a rare chromosome abnormality associated with poorly differentiated acute myeloid leukemia. Roche-Lestienne C, Soenen V, Richebourg S, Geffroy S, Laï JL, Andrieux J. Cancer Genet. Cytogenet. 2006; 168:181-182. Medline 16843114

Contributor(s) Written 09-2006 Catherine Roche-Lestienne. Citation This paper should be referenced as such : Roche-Lestienne C. . +13,+13 or tetrasomy 13. Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/Tetra13ID1260.html

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Oral squamous cell carcinoma Identity Note An invasive epithelial neoplasm with varying degrees of squamous differentiation that arises from the following anatomic sites: the oral cavity, particularly oral soft tissues including the gingival and alveolar mucosa, floor of the mouth, tongue, soft and hard palates, tonsils and oropharynx. Oral squamous cell carcinomas (SCC) have a propensity to early and extensive lymph node metastases. Clinics and Pathology Epidemiology Oral cancer consistently ranks as one of the top ten cancers worldwide, with broad differences in geographic distribution. They represent approximately 5% of cancers in men and 2% in women. Oral SCC often develops after the age of 50, with a highest peak in the sixth decade of life. The major risk factor for these neoplasms is chronic exposure of oral mucosa to tobacco and alcohol. Apart from these, human papilloma virus (HPV) infection, especially HPV 16 and 18, are found in a variable but small proportion of oral, and up to 50% of tonsillar and oropharyngeal SCC. It has been realized for a long time that patients with oral SCC are at risk of second tumors in the upper aerodigestive tract, reported to occur in 10-35% of case. Clinics More than 90-95% of oral cancers are SCC or one of its variants. SCC typically presents as a persistent mass, nodule, or indurate ulcer. The three most common sites of involvement are tongue, lip and floor of the mouth. They can develop from precancerous lesions, such as leukoplakia and erythroplakia, or apparently normal epithelium. Histopathologically, they can be categorized into three degrees of differentiation: Well differentiated disease shows greater than 75% keratinization. Moderately differentiated disease contributes to the bulk of SCC and is characterized by 25% to 75% keratinization. Poorly differentiated disease demonstrates less than 25% keratinization. The degree of differentiation may vary from one part of the tumor to another. Tumor stage is according to TNM classification. Prognosis Histological grade correlates poorly with patient outcome and thus has limited value for prognostication. Tumor size and nodal status are the most significant prognostic factors. At the time of diagnosis, the majority of patients with SCC present advanced disease (stage III-IV), and approximately one third of them show lymph node metastasis. After curative treatment, about 50% of the patients suffer recurrences; 80% within 2 years and the remaining within 4 years. The major cause of death is loco-regional failure. Cytogenetics Note Classical cytogenetics Clonal chromosome abnormalities have been described in about 250 oral SCC (115 of oral cavity, 81 of tongue, and 53 of oro- or hypopharynx). The great majority of these neoplasms are characterized by complex karyotypes with a clearly nonrandom pattern of losses and gains of chromosome segments. This is in line with the notion that oral SCC, like most of other epithelial malignancies, develop by the accumulation of multiple genetic aberrations. The most frequent imbalances were loss of 3p, 8p, 11q, 15p, 13p, 14p, 4p, 10p, 6q, 2q33-qter, and chromosomes Y, 21, 22, and 18, and gain of chromosomes 20 and 7, 8q and 11q13. The most common structural aberrations were i(8q), homogeneously

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -68- staining region (hsr), i(3q), i(5p), i(1q), del(16)(q22), i(13q), i(14q), del(2)(q33), and del(3)(p11). Another striking feature is that close to half of all structural rearrangements involve breakpoints in the centromeric or juxtacentromeric bands, particularly in chromosomes 8, 1, 3, 5, 13, 14 and 15. Molecular consequences of chromosomal aberrations revealed by fluorescence in situ hybridization (FISH) A number of fluorescence in situ hybridization (FISH), including multicolor FISH, studies have been undertaken in cytogenetically characterized oral SCC and SCC from other sites of head and neck region, in order to define the molecular consequence of chromosomal regions commonly involved in structural rearrangements, such as centromeric and pericentromeric rearrangements, homogeneously staining regions in chromosomal band 11q13 and other chromosome loci. From these studies, it could be concluded that the essential outcome of near- centromeric or centromeric rearrangements is genomic imbalances, i.e., loss or gain of cancer-associated genes. For instance, target regions for deletions in 1p and 8p have been identified. Characterization of hsr, a cytogenetic sign of gene amplification, has shown that hsr in these neoplasms almost always derives from 11q13 DNA sequences, that such amplicons always include the CCND1 gene, and that the amplification is often concomitant with loss of the distal part of 11q and with the overrepresentation of distal 3q.

Frequent finding of comparative genomic hybridization (CGH) and allelic imbalance studies Molecular genetic studies of oral SCC have been focused on the identification of tumor suppressor gene loci and amplified oncogenes. Earlier LOH studies focused on specific chromosome segments have pointed out the frequent loss of alleles from 3p, 8p, 9p, chromosome 13 and 17p in head and neck SCC, including oral SCC. A number of recent studies using allelotyping and comparative genomic hybridization (CGH) indicate that head and neck SCCs display massive and widespread genomic imbalances and that certain chromosome segment are lost more often than others. These studies confirmed the frequent deletion and LOH from 3p, 9p, 13q,and 17p, detected in more than 50% of the cases. Furthermore, deletions in 3q, 4p, 4q, 5q, 6p, 6q, 8p, 8q, 11q, 14q, 17q, 18q, and 20p have been shown in significant subsets.

Cytogenetics Candidate tumor suppressor genes (TSG) in frequently deleted chromosome Molecular region Chromosomal arm 3p: Loss of 3p material, in particular 3p13-p21, p21-23, and p25, is a common genetic change shared by several types of carcinomas. Several tumor suppressor genes have been mapped to these regions. Among them, two genes, i.e., FHIT in 3p14.2 and VHL in 3p25-26, were studied for the presence of inactivation mutations in oral SCC. The finding of alterations of FHIT in oral precancerous lesions and SCC supports the pathogenetic role of FHIT in oral SCC carcinogenesis. However, very little evidence for the involvement of VHL in oral SCC could be observed. Chromosome arms 4p and 4q: No TSG in these chromosomal arms has been identified in oral SCC so far. Chromosome arm 5q: APC located at 5q21 is a TSG important for familial colon cancer and sporadic colon cancer. Some studies support the involvement of APC in oral SCC, whereas others do not. Chromosome arms 6p and 6q: No TSG in these chromosomal arms has been identified in oral SCC so far. Chromosome arm 8p: 8p12 and 8p22 are frequently deleted in oral SCC. A recent study using RT-PCR showed reduced expression of FEZ1/LZTS1, a candidate tumor suppressor gene mapped to 8p22, which may contribute to the development of oral SCC. No other genes in these regions have been investigated. Chromosome arm 9p: CDKN2A (a.k.a. p16), a cell cycle regulatory gene, located at 9p21, is frequently down regulated through homozygous deletion or hypermethylation in oral SCC. Chromosome arms 11p and 11q: 11p14 and 11q14qter were reported to be lost in a

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -69- fraction of oral SCC. However, no TSG has been identified yet. Chromosome arm 13q: Some studies showed LOH of RB1, mapped to 13q14, in a fraction of oral SCC. Furthermore, lack of expression of RB1 in about half of cases has been reported in one immunohistochemistry study. Chromosome arm 17p: Loss of 17p is not very common at the cytogenetic level. However, such deletions are frequent at LOH studies. The prevalence of TP53 mutation and expression of a mutated protein has been reported in 40-60% of oral SCC. Expression of mutated TP53 in oral premalignant lesions may indicate malignant transformation. Especially, expression above the basal cell layer has been highly predictive of malignant development. A number of studies have shown that TP53 mutation is associated with increased risk of locoregional recurrence and poor outcome. Chromosome arm 18q: No target gene important for oral SCC has been reported for this chromosome arm.

Frequent amplification of oncogenes in homogeneously staining regions and amplified chromosome segments

Hsr in 11q13 and CCND1 amplification: The second most common structural rearrangement identified in oral SCC is hsr, a cytogenetic sign of gene amplification, found in about 25% of cytogenetically aberrant tumors. Approximately one half of the hsrs were found in chromosomal band 11q13. FISH studies have demonstrated that hsr in 11q13, as well as at other chromosomal loci, almost always originates from 11q13 DNA sequences and that the amplification then always includes CCND1. These findings are in agreement with extensive molecular investigations by various techniques, indicating that CCND1 is the prime target in the amplification process and important for oral SCC development. A recent study has shown that Cyclin D1 overexpression alone can induce extension of the replicate life span of normal keratinocytes, and the combination of cyclin D1 overexpression and TP53 inactivation led to their immortalization. Furthermore, several molecular studies have shown that CCND1 amplification and/or overexpression is a prognostic marker for disease free survival. Chromosome arm 3q: A number of oncogenes, such as LAZ3/BCL6, PIK3CA, DCUN1D1/SCCRO, telomerase RNA and AIS gene, map to 3q26-28, a frequently gained chromosomal segment shown by cytogenetic and CGH studies. Among them, SCCRO and PIK3CA may play a role in the pathogenesis of oral SCC through amplification at 3q26, and SCCRO appears to be a significant predictor of regional metastasis and may be a marker for tumor aggressiveness and clinical outcome. Chromosome arm 7p: Gain of part of or the entire chromosome 7 has been a common finding in oral SCC. Epidermal growth factor receptor EGFR and the insulin like growth factors IGFB1 and IGFB2 are three potentially interesting genes located in 7p13-22. EGFR has been extensively investigated in oral SCC, particularly with respect to therapeutic targeting of these neoplasms. The results of these studies suggest that amplification of the EGFR gene occurs at a relatively early stage of the development of oral SCC and a high level of EGFR gene expression probably plays an important role in the progression to invasive cancer. Chromosome arm 8q: Gain of 8q material through the formation of isochromosome i(8q) and unbalanced structural rearrangements are the most common structural change in oral SCC. Several genes of interest, such as MYC and PTK2, are localized at 8q23-24. However, as yet, no evidence for the involvement of these genes has been reported in oral SCC. Bibliography Amplification and overexpression of epidermal growth factor receptor gene in human oropharyngeal cancer. Saranath D, Panchal RG, Nair R, Mehta AR, Sanghavi VD, Deo MG. Eur J Cancer B Oral Oncol 1992; 28: 139-143. Medline 1306731

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -70- Allelotype of head and neck squamous cell carcinoma. Nawroz H, van der Riet P, Hruban RH, Koch W, Ruppert JM, Sidransky D. Cancer Res 1994; 54: 1152-1155. Medline 8118798

Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region. Van Dyke DL, Worsham MJ, Benninger MS, Krause CJ, Baker SR, Wolf GT, Drumheller T, Tilley BC, Carey TE. Genes Chromosomes Cancer 1994; 9: 192-206. Medline 7515662

Nonrandom chromosome abnormalities in short-term cultured primary squamous cell carcinomas of the head and neck. Jin Y, Mertens F, Jin C, Åkervall J, Wennerberg J, Gorunova L, Mandahl N, Heim S, Mitelman F. Cancer Res 1995; 55: 3204-3210. Medline 7606742

Overexpression of Cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E, Balm A. Cancer Res 1995; 55: 975-978. Medline 7867006

Distinct patterns of chromosomal alterations in high- and low-grade head and neck squamous cell carcinomas. Bockmühl U, Schwendel A, Dietel M, Petersen I. Cancer Res 1996; 56: 5325-5329. Medline 8968077

Centromeric brekage as a major cause of cytogenetic abnormalities in oral squamous cell carcinoma. Hermsen MA, Joenje H, Arwert F, Welters MJP, Braakhuis BJM, Bagnay M, Westerveld A, Slater R. Genes Chromosomes Cancer 1996; 15: 1-9. Medline 8824719

Chromosome 13q deletion mapping in head and neck squamous cell carcinomas: Identification of two distinct regions of preferential loss. Maestro R, Piccinin S, Doglioni C, Gasparotto D, Vukosavljevic T, Sulfaro S, Barzan L, Boiocchi M. Cancer Res 1996; 56: 1146-1150. Medline 8640775

Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Mao L, Lee JS, Fan YH, Ro JY, Batsakis JG, Lippman S, Hittelman W, Hong WK. Nat Med 1996; 2: 682-685. Medline 8640560

Allelic imbalance on chromosome 3p on oral dysplastic lesions: An early event in oral carcinogenesis. Roz L, Wu CL, Porter S, Scully C, Speight P, Read A, Sloan P, Thakker N. Cancer Res 1996; 56: 1228-1231. Medline 8640803

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -71- Amplification of cyclin D1 in Squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Åkervall J, Michalides R, Mineta H, Balm A, Borg Å, Dictor M, Jin Y, Loftus B, Mertens F, Wennerberg J. Cancer 1997; 79: 380-389. Medline 8625189

Patterns of chromosomal alterations in metastasizing and nonmetastasizing primary head and neck carcinomas. Bockmühl U, Petersen S, Schmidt S, Wolf G, Jahnke V, Dietel M, Petersen I. Cancer Res 1997; 57: 5213-5216. Medline 9393736

High frequency of p53 mutations in human oral epithelial dysplasia and primary squamous cell carcinoma detected by yeast functional assay. Kashiwazaki H, Tonoki H, Tada M, Chiba I, Shindoh M, Totsuka Y, Iggo R, Moriuchi T. Oncogene 1997; 15: 2667-2674. Medline 9400993

Cyclin D1 gene amplification is a more potent prognostic factor than its protein overexpression in human head and neck squamous cell carcinoma. Kyomoto R, Kumazawa H, Toda Y, Sakaida N, Okamura A, Iwanaga M, Shintaku M, Yamashita T, Hiai I, Fukumoto M. Int J Cancer 1997; 74: 576-581. Medline 9421351

FISH characterization of head and neck squamous cell carcinomas reveals that amplification of band 11q13 is associated with deletion of distal 11q. Jin Y, Höglund M, Jin C, Martins C, Wennerberg J, Åkervall J, Mandahl N, Mitelman F, Mertens F. Genes Chromosomes Cancer 1998; 22: 312-320. Medline 9669669

Cytogenetic and FISH characterization of chromosome 1 rearrangements in head and neck carcinomas delineate a target region for deletions within 1p11-1p13. Jin Y, Jin C, Wennerberg J, Mertens F, Höglund M. Cancer Res 1998; 58: 5859-5865. Medline 9865746

Loss of heterozygosity at 5q21-22 (adenomatous polyposis coli gene region) in oral squamous cell carcinoma is common and correlated with advanced disease. Mao EJ, Schwartz SM, Daling JR, Beckmann AM. J Oral Pathol Med 1998; 27: 297-302. Medline 9725566

Allelic loss of chromosome 13q14.3 in human oral cancer: correlation with lymph node metastasis. Ogawara K, Miyakawa A, Shiba M, Uzawa K, Watanabe T, Wang XL, Sato T, Kubosawa H, Kondo Y, Tanzawa H. Int J Cancer 1998; 79: 312-317. Medline 9699520

Functional evidence for involvement of multiple putative tumor suppressor genes on the short arm of chromosome 3 in human oral squamous cell carcinogenesis. Uzawa N, Yoshida MA, Hosoe S, Oshimura M, Amagasa T, Ikeuchi T. Cancer Genet Cytogenet 1998; 107: 125-131.

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Expression of cyclin D1 is correlated with poor prognosis in patients with areca quid chewing- related oral squamous cell carcinomas in Taiwan. Kuo MY, Lin CY, Hahn LJ, Cheng SJ, Chiang CP. J Oral Pathol Med 1999; 28: 165-169. Medline 10235369

Fluorescent in situ hybridization (FISH) characterisation of pericentromeric breakpoints on chromosome 5 in head and neck Squamous cell carcinomas. Martins C, Jin Y, Jin C, Wennerberg J, Höglund M, Mertens F. Euro J of cancer 1999; 35: 498-501. Medline 10448306

Location of candidate tumour suppressor gene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas. Partridge M, Emilion G, Pateromichelakis S, Phillips E, Langdon J. Int J Cancer 1999; 83: 318-325. Medline 10495423

Cyclin D1 overexpression correlates with poor prognosis in patients with tongue squamous cell carcinoma. Mineta H, Miura K, Takebayashi S, Ueda Y, Misawa K, Harada H, Wennerberg J, Dictor M. Oral Oncol 2000; 36: 194-198. Medline 10745172

Alterations of Rb, p16(INK4A) and cyclin D1 in the tumorigenesis of oral squamous cell carcinomas. Nakahara Y, Shintani S, Mihara M, Kiyota A, Ueyama Y, Matsumura T. Cancer Lett 2000; 160: 3-8. Medline 11098077

The FHIT gene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon. Pateromichelakis S, Lee G, Langdon JD, Partridge M. Oral Oncol 2000; 36: 180-188. Medline 10745170

Genetic aberrations in oral or head and neck squamous cell carcinoma 2: chromosomal aberrations. Scully C, Field JK, Tanzawa H. Oral Oncol 2000; 36: 311-327. (Review) Medline 10899669

Abnormalities of the FHIT gene in human oral carcinogenesis. Tanimoto K, Hayashi S, Tsuchiya E, Tokuchi Y, Kobayashi Y, Yoshiga K, Okui T, Kobayashi M, Ichikawa T. Br J Cancer 2000; 82: 838-843. Medline 10732756

Cyclin D1 amplification correlates with early recurrence of squamous cell carcinoma of the tongue. Fujii M, Ishiguro R, Yamashita T, Tashiro M. Cancer Lett 2001; 172: 187-192.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -73- Medline 11566495

Quantitation of epidermal growth factor receptor gene amplification by competitive polymerase chain reaction in pre-malignant and malignant oral epithelial lesions. Nagatsuka H, Ishiwari Y, Tsujigiwa H, Nakano K, Nagai N. Oral Oncol 2001; 37: 599-604. Medline 11564582

The role of novel oncogenes squamous cell carcinoma-related oncogene and phosphatidylinositol 3-kinase p110alpha in squamous cell carcinoma of the oral tongue. Estilo CL, O-Charoenrat P, Ngai I, Patel SG, Reddy PG, Dao S, Shaha AR, Kraus DH, Boyle JO, Wong RJ, Pfister DG, Huryn JM, Zlotolow IM, Shah JP, Singh B. Clin Cancer Res 2003; 9: 2300-2306. Medline 12796399

Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas. Ono K, Uzawa K, Nakatsuru M, Shiiba M, Mochida Y, Tada A, Bukawa H, Miyakawa A, Yokoe H, Tanzawa H. Int J Oncol 2003; 23: 297-302. Medline 12851677

Epigenetic changes of tumor suppressor genes, P15, P16, VHL and P53 in oral cancer. Yeh KT, Chang JG, Lin TH, Wang YF, Tien N, Chang JY, Chen JC, Shih MC. Oncol Rep 2003; 10: 659-663. Medline 12684640

Targeting of epidermal growth factor receptor by cyclopentenone prostaglandin 15-Deoxy- Delta12, 14-prostaglandin J2 in human oral squamous carcinoma cells. Siavash H, Nikitakis NG, Sauk JJ. Cancer Lett 2004; 211: 97-103. Medline 15194221

Abrogation of IL-6-mediated JAK signalling by the cyclopentenone prostaglandin 15d-PGJ(2) in oral squamous carcinoma cells. Siavash H, Nikitakis NG, Sauk JJ. Br J Cancer 2004; 91: 1074-1080. Medline 15316561

Expression of adenomatous polyposis coli (APC) in tumorigenesis of human oral squamous cell carcinoma. Tsuchiya R, Yamamoto G, Nagoshi Y, Aida T, Irie T, Tachikawa T. Oral Oncol 2004; 40: 932-940. Medline 15380172

Mutations of the APC, beta-catenin, and axin 1 genes and cytoplasmic accumulation of beta- catenin in oral squamous cell carcinoma. Iwai S, Katagiri W, Kong C, Amekawa S, Nakazawa M, Yura Y. J Cancer Res Clin Oncol 2005; 131: 773-782. Medline 16163548

Mitelman Database of Chromosome Aberrations in Cancer. Mitelman F, Johansson B, Mertens F (eds.), 2005. http://cgap.nci.nih.gov/Chromosomes/Mitelman

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Cytogenetic abnormalities in 106 oral squamous cell carcinomas. Jin C, Jin Y, Wennerberg J, Annertz K, Enoksson J, Mertens F. Cancer Genet Cytogenet 2006; 164: 44-53. Medline 16364762

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 09-2006 Yuesheng Jin , Charlotte Jin Citation This paper should be referenced as such : Jin Y, Jin C . Oral squamous cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Tumors/OralSquamCellID5368.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -75- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Laryngeal squamous cell carcinoma Classification Note The larynx extends from the tip of the epiglottis to the inferior border of the cricoid cartilage. The vast majorities of malignant neoplasms of the larynx arise from the surface epithelium and are therefore classified as keratinizing or nonkeratinizing squamous cell carcinomas (SCC). Other rare malignant forms include verrucous carcinoma, adenocarcinoma, fibrosarcoma, and chondrosarcoma. Laryngeal carcinoma infiltrates locally in the mucosa and beneath the mucosa and can metastasize via the lymphatic system and the bloodstream. According to their anatomical localization, laryngeal carcinomas could be subdivided into: 1) supraglottic carcinomas, confined to the supraglottic space and spreading interiorly into the preepiglottic space. 2) glottic carcinomas, rarely spreading into the supraglottic area but rather into the subglottic space. 3) subglottic carcinomas, often showing an infiltrative growth pattern unrestricted by tissue barriers. Clinics and Pathology Epidemiology Laryngeal carcinoma accounts for a small fraction of all human malignancies (less than 2%), but the incidence varies among geographically. Laryngeal SCC occurs most often in the sixth and seventh decades. Men are more frequently affected than women. The etiology is not well known, but exposure of the mucosa to a wide variety of ingested and inhaled exogenous carcinogenic agents, such as tobacco smoke, alcohol, and HPV infections greatly increases the risk of developing these tumors. Avoiding cigarettes and alcohol could prevent about 90% of laryngeal SCC. Pathology Histopathologically, laryngeal SCC can further be classified into: well differentiated (more than 75% keratinization), moderately differentiated (25-75% keratinization), and poorly differentiated (<25% keratinization). Carcinoma of the supra- and subglottic larynx are more likely to be non-keratinizing and poorly differentiated, and, in general, they are often large at the time of diagnosis, and have a more aggressive behavior and tend to metastasize early (20-40% of the cases). In contrast, lesions of the true vocal cords are typically small when detected, and more often moderately to well differentiated, rarely metastasize, and tend to be associated with a better prognosis. Cytogenetics Note Chromosome abnormalities 115 laryngeal carcinomas with clonal chromosome abnormalities have been reported. In general, the karyotypes are relatively complex with a nonrandom pattern of deleted and amplified chromosome segments. This is in line with the notion that laryngeal carcinoma, like most other malignancies, develops through the accumulation of multiple genetic changes. The chromosomes most frequently involved in structural rearrangements are chromosomes 1, 2, 3, 4, 5, 7, 8, 11, 12, and 15, with breakpoints clustering to the pericentromeric regions, i.e., the centromeric bands p10 and q10 and the juxtacentromeric bands p11 and q11, accounting for 43% of the total breakpoints. The most common imbalances brought about by numerical and unbalanced structural rearrangements are loss of chromosomal region 3p21-pter, part of or the entire chromosome arms 4p, 6q, 8p, 10p, 13p, 14p, 15p, and 17p, and gain of chromosomal

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -76- regions 3q21-ter, 7q31-pter, and 8q. A total of 17 recurrent structural aberrations, mostly in the form of whole-arm translocations, isochromosomes (i), and deletions (del), have been identified. The most common among them were i(8q), i(3q), i(5p), del(3)(p11), and homogeneously staining regions (hsr), a cytogenetically detectable sign of gene amplification, in band 11q13. A subgroup of laryngeal SCC have had multiple, unrelated abnormal clones, with simple, often balanced structural rearrangements or numerical changes. These clones have always had near-diploid chromosome numbers. The finding of such cytogenetic polyclonality could be interpreted as evidence of "field cancerization"but it cannot be ruled out that the cytogenetically unrelated clones are united by a submicroscopic, pathogenetic mutation; the cytogenetic differences would then only reflect differences in clonal evolution. The third alternative is that some of the near-diploid clones actually represent preneoplastic lesions or genetically damaged, nonneoplastic epithelial or stromal cells in the tumor surrounding. Fluorescence in situ hybridization (FISH) FISH analysis has recently been undertaken to verify and in detail characterize the most common recurrent chromosomal changes in head and neck SCC (HNSCC), including laryngeal SCC. FISH has demonstrated that cytogenetically detectable hsr in these tumors almost always corresponds to amplification of DNA sequences originating from 11q13, and the amplicons mapped vary in size from 3.5 to 4.5 Mb with a core of 1.5 - 1.7 Mb, and often many oncogenes in this region are coamplified, including CCND1, FGF3, FGF4, EMS1, and SHANK2. Another finding is that the amplification of 11q13 is often concomitant with deletion of distal 11q. The latter finding indicates that not only the amplification of one or more dominantly acting oncogenes in 11q13, but also loss of a tumor suppressor gene in the distal part of 11q, are critical for the development of laryngeal SCC. Detailed FISH characterization of pericentromeric rearrangements, in particular for chromosomes 1 and 8, with the use of YAC clones spanning the pericentromeric region of chromosomes, suggest that the essential outcome of these rearrangements at DNA level is the resulting genomic imbalances, i.e., loss or gain of neoplasia- associated genes. Furthermore, more precise mapping of breakpoints on chromosomal arms 1p and 8p has delineated critical regions for deletions within 1p11- p13 and the subtelomeric region of 8p.

Genetic imbalances revealed by CGH, allelotyping, and LOH studies A large scale effort has been devoted to the identification of tumor suppressor gene loci and amplified oncogenes in laryngeal carcinomas. Earlier loss of heterozygosity (LOH) studies focused on specific chromosomal arms pointed out the frequent loss of alleles from 3p, 8p, 9p, 13q and 17p in head and neck SCC (HNSCC) in general as well as in laryngeal SCC. A number of recent studies based on allelotyping or comparative genomic hybridization (CGH) indicate that HNSCC, including laryngeal SCC, display massive and widespread genomic imbalances and that certain chromosome segments are lost more often than others. Combined data in these studies indicate that the most frequent imbalances is loss of genetic material from 3p, 8 p, 9p, 13q, and 17p, found in more than 50% of the cases and less frequently, deletions in 3q, 4p, 4q, 6p, 6q, 8p, 8q, 11q, 14q, 17q, 19q, and 20p observed in 30-50% of the cases. Overrepresentation of genetic material occurs often in chromosomal arms 3q, 7p, 8q, 9q, and in chromosomal band 11q13.

Cytogenetics Functional studies of genes involved by chromosomal imbalances Morphological Cytogenetics Tumor suppressor genes (TSG) Molecular Chromosomal arms 3p: Partial and entire loss of 3p is one of the most common changes in laryngeal SCC detected by various techniques. A number of TSG are localized in this chromosomal arm. Among them, only FHIT was investigated in laryngeal SCC and its precursor lesions. In a recent study, decreased expression of this gene, through deletion or promoter methylation was detected in about 42% of SCC and 23% of dysplasia lesions.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -77- Chromosome arm 8p: Loss of 8p has been mapped in detail with the use of microsatellite markers. However, no candidate TSG in this arm has so far been investigated in these neoplasms. Chromosome arm 9p: CDKN2A (also known as p16), localized at 9p21, has been extensively investigated in laryngeal SCC. Using various detection techniques, such as immunohistochemistry and RT-PCR, it was shown that loss of CDKN2A expression, through either homozygous deletion or promoter hypermethylation, were present in 52-82 % of HNSCC, including laryngeal SCC. Furthermore, a number of studies have shown that the decreased expression of this gene was associated with poor survival in patients with laryngeal SCC. Chromosomal arm 13q: Allelic loss of the RB1 gene, mapped to 13q14, is frequent in laryngeal SCC. Expression analysis of RB1 has yielded inconsistent results, and the role of RB1 inactivation in laryngeal SCC has not been clearly established. Chromosome arm 17p: TP53 mutation and the alteration of its protein have been extensively studied in laryngeal SCC. These studies suggest that TP53 mutations occur early in the neoplastic transformation of these tumors. Furthermore, a significant correlation between expression of mutated TP53 and clinical outcome has been shown in patients with laryngeal SCC; overexpression of mutated TP53 predicts poor disease-free and overall survival rates. Oncogenes Chromosomal band 11q13: The pathogenetic importance of 11q13 rearrangements is supported by extensive molecular studies showing that genomic amplification of several loci within this band, including oncogenes CCND1, FGF3, FGF4, and EMS1, is found in up to 30% of primary HNSCC including laryngeal SCC. Among the genes in the amplicon, CCND1 appears to be the prime target as its overexpression has been demonstrated by various molecular techniques in about 15-60% percent of primary HNSCC. Interestingly, a recent study has shown that Cyclin D1 overexpression alone can induce extension of the replicate life span of normal keratinocytes, and the combination of cyclin D1 overexpression and TP53 inactivation led to their immortalization. Several attempts have been made to correlate cytogenetic or molecular genetic data with clinical outcome in laryngeal carcinoma patients, and it has been shown that 11q13 rearrangements and amplification/overexpression of CCND1 are associated with a poor prognosis. Chromosome arm 7p: Overrepresentation of partial or entire chromosome 7 has been a common finding in HNSCC and laryngeal SCC. Epidermal growth factor receptor EGFR and the insulin like growth factors IGFB1 and IGFB2 are three potentially interesting genes located in the 7p13-22 region. The EGFR gene has been extensively investigated in HNSCC and laryngeal SCC and their precursor lesions. The results of these studies suggest that amplification and/or overexpression of EGFR gene occurs in the relatively early stage of the development of HNSCC and a high level of EGFR gene accumulation probably plays an important role in the progression to invasive cancer. Furthermore, overexpression of this gene has been significantly associated with short disease-free and overall survival in HNSCC and laryngeal SCC patients. Chromosome 8q: Partial or entire gain of 8q through the formation of isochromosome i(8q) and unbalanced structural rearrangements is one of the most common structural changes in laryngeal SCC. Several genes of interest, such as MYC and PTK2, are localized at 8q23-24. In a number of recent studies using FISH, tissue microarray and immunohistochemistry, a high frequency (30-68%) of MYC gain/amplification and overexpression has been observed in laryngeal SCC. Bibliography Field cancerization in oral stratified squamous epithelium. Clinical implications of multicentric origin. Slaughter DP, Southwick HW, Smejkal W. Cancer 1953; 6: 963-968. Medline 13094644

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REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 09-2006 Charlotte Jin, Yuesheng Jin Citation This paper should be referenced as such : Jin C, Jin Y . Laryngeal squamous cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Tumors/LarynSquamCellID5367.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -83- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Kidney: Nephroblastoma (Wilms tumor) Identity Note Wilms'tumor, although generally rare, is the most common abdominal malignancy in children. Wilms' tumor cells are believed to derive from pluripotent embyronic renal precursor cells. Thus, Wilms' tumors are linked to the early development of the kidney. While most are isolated sporadic tumors, approximately 10% of cases are associated with genetic syndromes and extrarenal manifestations. Other names Nephroblastoma Classification According to the staging system employed by the National Wilms' Tumor Study Committee, there are 5 stages of Wilms' tumors. Stage I: Tumor is limited to the kidney and is completely resected and the renal capsule is intact. The tumor is not ruptured or biopsied prior to removal. Renal sinus vessels shouldn't be involved and there shouldn't be any evidence of the tumor at or beyond the margins of resection. 43% of Wilms' tumor patients fall into this category. Stage II: Tumor is completely resected and there is no evidence of tumor at or beyond the margins of resection. In this stage tumor extends beyond the kidney either by regional extension or the blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor. 23% of Wilms' tumor patients fall into this category. Stage III: After surgery, residual nonhematogenous tumor is present in the abdomianl area. In stage III any of the following criteria may be present: 1.Lymph nodes within the abdomenal or pelvic lymph nodes contain the tumor. The tumor has penetrated through the peritoneal surface. 2.Peritoneal surface has tumor implants. 3.Gross or microscopic tumor remains postoperatively. 4.The tumor is not completely resectable due to local infiltration into vital structures. 5.Either before or during the surgery, tumor spillage occurs. 6.The tumor was biopsied (using tru-cut biopsy, open biopsy, or fine needle aspiration) before removal. 7.The tumor is removed in more than one piece. 23% of Wilms' tumor patients fall into this category. Stage IV: At this stage, lung, liver, bone, brain, etc or lymph node metastases outside the abdominopelvic region are detected. 10% of Wilms' tumor patients fall into this category. Stage V: Bilateral involvement is detected. Each side should be staged according to the criteria to determine the extent of the disease. 5% of Wilms' tumor patients fall into this category. Clinics and Pathology Phenotype / Wilms' tumor is believed to result from malignant transformation of abnormally cell stem persistent renal stem cells that may retain embryonic differentiation potential. Classic origin Wilms' tumors are triphasic and composed of epithelial, blastemal, and stromal elements. Most tumors have favorable histology but up to 7% of have unfavorable histology with anaplastic changes. Diffuse anaplastic changes generally predict a poor outcome. Wilms tumors with anaplastic changes are called unfavorable histology and require more aggressive treatment. Etiology Wilms tumours are either sporadic or familial (1-2%); it may be associated with

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -84- hemihypertrophia or genitourinary malformations (10%) and part of a recognized syndrome (2%). The syndromes predisposing to Wilms tumours are: WAGR (Wilms tumour, aniridia, genitourinary abnormalities and mental retardation), Denys-Drash syndrome (DDS): mesangial sclerosis, male pseudohermaphrodism and Wilms tumours, Beckwith-Weideman (BWS): exomphalos, macroglossia, gigantism and Simpson Golabi Behemel syndrome (SGBS): overgrowth, mental impairment, craniofacial anomalies. Wilms tumors can also be seen in association with Trisomy 18. Epidemiology Wilms' tumor affects 1 in 10,000 children in North America. Therefore it is the most common pediatric abdominal malignancy and the fourth most common childhood malignancy. 50% of cases occurs before the age of 3 years and 90% before 6 years. Clinics There doesn't seem to be a sex preference concerning the incidence. Sporadic forms are usually unilateral and constitute the majority of cases whereas bilateral or multifocal cases account for 10% of the cases possibly due to a germline mutation. Pathology Wilms tumours show a mimicry of nephrogenesis as the tumour comprises undifferentiated blastemal cells, differentiated epithelial cells and stromal cells; ectopic components, particularly skeletal muscle, are observed in 5-10% of tumours; the presence of identical deletions of WT1 in all components of some sporadic Wilms tumours suggests that the stromal components are neoplastic, raising the possibility that undifferentiated blastema cells are precursors of the stromal and heterologous elements.

Blastematous tissue with some differentiated glomerular structures associated with mesenchymal tissue and tubules. Courtesy Pierre Bedossa

Treatment Multimodality therapy including nephrectomy is used for the management of all stages of Wilms' tumor. Chemotherapy has proven beneficial in all stages of the disease and radiation therapy is used to improve the outcome of later stage tumors, including stage II malignancies with diffuse anaplastic changes. Prognosis Wilms' tumor can be classified into favorable and anaplastic histology groups for prognostic purposes. Favorable histology group does not have anaplastic cells in the tumor. Histology is similar to the normal kidney development. On the other hand, anaplastic histology group indicates either focal or diffused structures. Diffuse anaplasia confers poor prognosis, has chemotherapy resistance and may still be present after preoperative chemotherapy, however; children with stage I anaplastic tumors (Stage I-IV Anaplasia) have an excellent prognosis. Stage V bilateral patients have a 4-year survival rate of 94% for those with the most advanced lesion of stage I

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -85- or stage II, and 76% for those with the most advanced lesion of stage III. Genetics Note This entity is heterogenous at the genetic level. Cytogenetics Cytogenetics The observed heterogeneity reflects the complexity of the genetic changes. Trisomies Morphological 8, 12, and 18; 11p deletions occur in 20% of cases, trisomy 12 in 25%, del(16q) in 20%; the der(16)t(1;16), also described in a wide range of tumours, is considered a marker of tumour progression. Recurrent chromosomal abnormalities detected in Wilms' tumor patients are loss of heterozygosity at 1p, 7p and 16q. A study of 67 Wilms' tumor patients detected that 48 (72%) tumors showed an abnormal karyotype. In this study, chromosomal gains were more common compared to chromosomal losses. Hyperdiploidy was seen in 30 cases and hypodiploidy in 4 cases. The most common aneuploidies detected were gains of chromosomes 6, 7, 8, 12, 13, and 18. Rare translocations involving chromosome the 11p13 WT1 gene have been reported associated with desmoplastic small round cell tumors (DSRCT) most often involving the abdominal serosal of young males. These tumors usually have a poor prognosis.

del(11)(p13) G-banding - Courtesy G. Reza Hafez, Eric B.Johnson, and Sara Morrison-Delap Cytogenetics at the Waisman Center

Genes involved and Proteins Note Approximately 10% of Wilms' tumors are bilateral and a small fraction of these are associated with gross congenital syndromes, most often overgrowth syndromes or syndromes associated with hemihypertrophy such as Beckwith-Weidemann syndrome. In most cases of bilateral Wilms' tumors are believed to arise from de novo germ line mutations rather than familial transmission. Genetic defects underlying most cases of Wilms' tumors are not known. However, mutations or deletions in the WT1 gene on 11p13 underlie a subset of Wilms' tumors. Two other familial pre-disposition loci are known. FWT1 (Familial Wilms' tumor 1, aka WT4) maps to 17q12-q21 and FWT2 maps to 19q13.4. Other genes believed to be involved in Wilms' tumor development are, CTNNB1 (Beta- catenin), IGF2/H19 (and other imprinted genes on 11p15), GPC3 (Glypican 3; Simpson-Golabi-Behmel gene). Another interesting observation is about Mulibrey nanism (for muscle-liver-brain-eye nanism, MUL). MUL is an autosomal recessive disorder that involves several tissues of mesodermal origin, implying a defect in a highly pleiotropic gene. About 4% of MUL patients develop Wilms' tumour. Gene Name WT1 Location 11p13 Note Mutations in the WT1 gene have been identified in patients with Wilms tumor, WAGR syndrome, and Denys-Drash syndrome (DDS), Frasier syndrome, and isolated diffuse mesangial sclerosis (IDMS). There are rare inherited mutations. Coding region mutations of WT1 has been reported as nonsense and missense changes. Constitutional deletion of one copy of the WT1 gene (11p13) is responsible for predisposition to Wilms tumours and for genitourinary malformations in WAGR patients. Constitutional heterozygous intragenic mutations have been described in

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -86- DDS; WT1 is somatically involved in 10% of the sporadic cases. Dna / Rna The gene spans 50 kbs and has 10 exons. Four transcipt variants have also been detected. Transcript variant A, 2969 bp, lacks exon 5 and the additional sequence coding for KTS at the end of exon 9. Transcriptional Variant B, 3020 bp, has all 10 exons except the sequence coding KTS at the end of exon 9. Transcriptional Variant C, 2978 bp, lacks exon 5 but has the additional sequence coding KTS at the end of exon 9. Transcriptional Variant D, 3029 bp, has all 10 exons and the additional sequence coding KTS at the end of exon 9. This transcript is the longest known compared to all others. Protein 55kDa zing finger transcription factor expressed during renal and gonadal development. It can act as an activator of transcription or a transcriptional repressor depending on the cellular context in which it is expressed. It is most commonly considered to function as a tumor suppressor. Exons 1-6 encode a proline/glutamine rich transcriptional regulation region; exons 7- 10 encode the four zinc fingers; two alternative splicing regions allow synthesis of four isoforms showing different binding specificity; WT1 regulates transcription of several genes, including IGF2 and PDGFA; the WT1-KTS isoforms associate and synergize with SF-1 (steroidogenic factor 1) to promote AMH (anti mullerian hormone or MIS, mullerian inhibiting substance). Isoforms of WT1 are: Isoform A: Translation starts from a CUG codon and also from a downstream, in-frame AUG to generate the same reading frame that is 20 amino acids shorter than the longest isoform D. Isoform B: Translation starts from a CUG codon and also from a downstream, in-frame AUG to generate the same reading frame that is 3 amino acids shorter than the longest isoform D. Isoform C: Translation starts from a CUG codon and also from a downstream, in-frame AUG to generate the same reading frame that is 17 amino acids shorter than the longest isoform D. Isoform D: Translation starts from a CUG codon and also from a downstream, in-frame AUG to generate the longest isoform, 517 amino acids. Germinal Missense mutations of exons 8 and 9 in DDS; in the proximal part of the gene leading mutation to truncated proteins in WAGR, genitourinary malformations and Wilms Tumours; in the donor splice site of intron 9 in Frasier syndrome (pseudohermaphroditism, glomerulopathy, not associated Wilms Tumours). In germline heterozygous mutations of WT1, renal and genitourinary defects are observed in patients. Arginine to tryptophan transition in exon 3 of WT1 is also associated with DDS as well as exon 2 mutations and N-terminal truncations. Somatic Stop and frameshift mutations in about 10% of Wilms Tumours. Aberrant splice forms mutation have also been detected.

Note Other chromosomal regions involved are: 11p15 : BWS, an overgrowth syndrome, is caused by alterations of 11p15, a region subject to genomic imprinting: loss of of imprinting of IGF2 is the most common defect found; WT1 is rarely implicated solely in sporadic Wilms tumours, but maternal alleles often displays a loss of heterozygosity (LOH) at 11p15, which suggests the existence of a second locus WT2. 7p, 17q, 19q : a third locus WT3, at least, is likely , on the grounds of the existence of familial cases of Wilms tumour without 11p13 nor 11p15 involvement; one locus has been identified in 17q in one large Wilms tumours family, and another one in 19q13 in five families; another predisposing gene to Wilms tumours maps to 7p, where constitutional translocations and somatic deletions have been described; in tumours, loss of heterozygosity for 16q has been reported for two different loci: 16q13 and 16q21. Xq26 : the gene of SGBS, an overgrowth syndrome, has been cloned at Xq26.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -87- Mutations of P53 occur in 5% of Wilms tumours and are associated with tumour progression.

Bibliography Epidemiological features of Wilms' tumor: results of the National Wilms' Tumor Study. Breslow NE, Beckwith JB. J Natl Cancer Inst. 1982; 68: 429-436. Medline 6278194

Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. D'Angio GJ, Breslow N, Beckwith JB, Evans A, Baum H, deLorimier A, Fernbach D, Hrabovsky E, Jones B, Kelalis P, et al. Cancer. 1989; 64: 349-360. Medline 2544249

Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee. J Clin Oncol 1991; 9: 877-887. Medline 1849987

Management and outcome of inoperable Wilms tumor. A report of National Wilms Tumor Study-3. Ritchey ML, Pringle KC, Breslow NE, Takashima J, Moksness J, Zuppan CW, Beckwith JB, Thomas PR, Kelalis PP. Ann Surg. 1994; 220: 683-690. Medline 7979618

The management of synchronous bilateral Wilms tumor. Ritchey ML, Coppes MJ. Hematol Oncol Clin North Am. 1995; 9: 1303-1315. Review. Medline 8591967

Characterization of regions of chromosomes 12 and 16 involved in nephroblastoma tumorigenesis. Austruy E, Candon S, Henry I, Gyapay G, Tournade MF, Mannens M, Callen D, Junien C, Jeanpierre C Genes Chromosomes Cancer 1995; 14: 285-294. Medline 96187127

Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21. Rahman N, Arbour L, Tonin P, Renshaw J, Pelletier J, Baruchel S, Pritchard-Jones K, Stratton MR, Narod SA. Nat Genet. 1996; 13: 461-463. Medline 8696342

A clinical overview of WT1 gene mutations. Little M and Wells C. Hum Mutat 1997; 9: 209-225. Medline 97245884

Wilms tumor: summary of 54 cytogenetic analyses. Soukup S, Gotwals B, Blough R, Lampkin B. Cancer Genet Cytogenet 1997; 97: 169-171.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -88- Medline 97429254

Identical genetic changes in different histologic components of Wilms tumor. Zhung Z, Merino MJ, Vortmeyer AO, Bryant B, Lash AE, Wang C, Deavers MT, Shelton WF, Kapur S, Chandra RS. J Natl Cancer Inst 1997; 89: 1148-1152. Medline 97404167

Software And Database for the analysis of mutations in the human WT1. Jeanpierre C, Beroud C, Niaudet P, Junien C. Nucleic Acid Res 1998; 26: 271-274. Medline 98062444

Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group. Green DM, Breslow NE, Beckwith JB, Finklestein JZ, Grundy PE, Thomas PR, Kim T, Shochat SJ, Haase GM, Ritchey ML, Kelalis PP, D'Angio GJ. J Clin Oncol 1998; 16: 237-245. Medline 9440748

Linkage of familial Wilms tumor predisposition to chromosome 19 and two-locus model for the etiology of familial tumors. McDonald JM, Douglass EC, Fisher R, Geiser CF, Krill CE, Strong LC, Veishup D, Huff V. Cancer Res 1998; 58: 1387-1390. Medline 98196526

Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group. Green DM, Breslow NE, Beckwith JB, Ritchey ML, Shamberger RC, Haase GM, D'Angio GJ, Perlman E, Donaldson M, Grundy PE, Weetman R, Coppes MJ, Malogolowkin M, Shearer P, Coccia P, Kletzel M, Thomas PR, Macklis R, Tomlinson G, Huff V, Newbury R, Weeks D. J Clin Oncol. 2001;19: 3719-3724. Medline 11533093

Cytogenetic and histologic findings in Wilms' tumor. Gow KW, Murphy JJ. J Pediatr Surg. 2002; 37: 823-827. Medline 12037743

Wilms' tumour: connecting tumorigenesis and organ development in the kidney. Rivera MN, Haber DA. Nat Rev Cancer. 2005; 5: 699-712. Review. (Erratum in: Nat Rev Cancer. 2005; 5: 835) Medline 16110318

Wilms' tumor: past, present and (possibly) future. Spreafico F, Bellani FF. Expert Rev Anticancer Ther. 2006; 6: 249-258. Review. Medline 16445377

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -89- Written 11-1998 Monica Miozzo Updated 09-2006 Ayse Elif Erson, Elizabeth M. Petty Citation This paper should be referenced as such : Miozzo M . Kidney: Nephroblastoma (Wilms tumor). Atlas Genet Cytogenet Oncol Haematol. November 1998 . URL : http://AtlasGeneticsOncology.org/Tumors/WilmsID5034.html Erson A E, Petty E M . Kidney: Nephroblastoma (Wilms tumor). Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Tumors/WilmsID5034.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -90- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Soft tissue chondroma with t(3;12)(q27;q15) Clinics and Pathology Disease Soft tissue chondroma with t(3;12)(q27;q15). Note Only one case has been described to date. Embryonic The embryonic origin is unknown, but the tumor cells presumably derive from the origin mesoderm. Etiology Unknown. Epidemiology The only case of soft tissue chondroma with t(3;12)(q27;q15) described to date was a tumor resected from a 62-year-old man. Clinics The tumor presented as a solitary mass (8 x 6 x 8 cm) in the elbow region (fossa cubiti). Pathology The tumor displayed a multilobulated growth pattern and was composed of mature adult hyaline cartilage with peripheral areas of myxofibromatous/lipomatous tissue and metaplastic bone tissue. Treatment The tumor was removed with marginal excision. Cytogenetics Cytogenetics The t(3;12)(q27;q15) has so far been described in one case of soft tissue chondroma. Morphological The same translocation has been identified as a recurrent chromosomal aberration in ordinary lipoma and pulmonary chondroid hamartoma. Cytogenetics Metaphase FISH mapping using cosmid probes specific for exons 1-2 (142H1) and Molecular exons 4-5 (27E12) of HMGA2 revealed that the breakpoint in chromosome band 12q15 was located within the large intron 3 of HMGA2. Genes involved and Proteins Gene Name HMGA2 (high mobility group AT-hook 2). Location 12q15. Dna / Rna The gene consists of 5 exons that span approximately 160 kb of genomic DNA in the centromere-to-telomere orientation. The first three exons are separated from the last two exons by a particularly large intron (about 112 kb). The corresponding transcript is approximately 4,1 kb (referred to as "wildtype" or "isoform a" transcript of HMGA2). The translation initiation codon ATG is located in exon 1 and the stop codon in exon 5. Several alternative splice products of HMGA2 have been reported (referred to as "isoforms b, c, d, e and f" transcripts of HMGA2, respectively). Protein The open reading frame encodes a 108 amino acid protein with an estimated molecular weight of approximately 12 kDa. The first 3 exons each encode a DNA-binding domain. Exons 4 and 5 encode a spacer domain and an acidic domain, respectively. It has been suggested that the 3'-UTR acts as a negative regulator of the expression of HMGA2. The HMGA2 protein is a member of the HMGA (high mobility group A) family of proteins and is believed to affect transcription as architectural elements by bending the DNA and by interacting with a large number of proteins, mainly transcription factors. Reported specific targets of the HMGA2 protein are the pRB protein, as well as the promoter regions of the DNA-repair gene ERCC1 and the cyclin A gene.

Gene Name LPP (LIM domain containing preferred translocation partner in lipoma).

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -91- Location 3q27-28. Dna / Rna The gene consists of 11 exons and spans approximately 667 kb of genomic DNA in the centromere-to-telomere orientation. The corresponding transcript is approximately 7,3 kb. The translation initiation codon is located in exon 3 and the stop codon in exon 11. Protein The open reading frame encodes a 612 amino acid protein. The protein is composed of a proline rich N-terminal and 3 LIM domains in its C- terminal. Exons 3-7 encode the proline-rich domain. Exon 8 encodes the LIM1 domain and exon 9 encodes the LIM2 domain. Exon 10 and parts of exon 11 encode the LIM3 domain. The LPP protein is a member of the zyxin family (also referred to as "group 3") of LIM domain proteins. The LIM-domain encodes a double zink finger motif involved in protein-protein interactions. Functionally the LPP protein interacts with cytoplasmic proteins involved in focal adhesion and cell-to-cell contact, but it does also shuttle between the cytoplasm and the nucleus and has therefore been attributed a role in signal transduction processes. It has recently been shown that the LIM domains of LPP function as a transcriptional coactivator of the transcription factor PEA3/ ETV4.

Result of the chromosomal anomaly Hybrid Gene Note Only one case has been described to date. Description The structure of the hybrid gene has not been investigated at the genomic level in soft tissue chondroma with t(3;12)(q27;q15). Transcript The detected HMGA2-LPP fusion transcript was composed of the first 3 exons of HMGA2 and exons 9-11 of LPP. Identical fusion transcripts have previously been detected in ordinary lipoma and pulmonary chondroid hamartoma. The findings of identical fusion transcripts in different tumor types have strengthened the notion that it is not the formation of the HMGA2-LPP fusion per se that directs tumor cell differentiation. Detection Several detailed protocols for the detection of the HMGA2-LPP fusion transcript have been published. Fusion

Protein Note The HMGA2-LPP fusion protein has not been functionally studied in soft tissue chondroma with t(3;12)(q27;q15). Description The HMGA2-LPP fusion protein is composed of the DNA-binding domains of HMGA2 and the LIM2 and LIM3 domains of LPP. Expression In transfection assays of 3T3-L1 cells it has been shown that the HMGA2-LPP fusion Localisation protein is located in the nucleus. Oncogenesis It has been suggested that the abnormal tumor cell proliferation is caused by a disruption in the balance of co-expression between the wildtype HMGA2 transcript and its splice variants.

Bibliography Three major cytogenetic subgroups can be identified among chromosomally abnormal solitary lipomas. Mandahl N, Heim S, Arheden K, Rydholm A, Willén H, Mitelman F. Hum Genet 1988; 79:203-208. Medline 3402992

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -92- cDNA cloning of the HMGI-C phosphoprotein, a nuclear protein associated with neoplastic and undifferentiated phenotypes. Manfioletti G, Giancotti V, Bandiera A, Buratti E, Sautière P, Cary P, Crane-Robinson C, Coles B, Goodwin GH. Nucleic Acids Res 1991; 19:6793-6797. Medline 1762909

Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumors. Schoenmakers EFPM, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJM. Nat Genet 1995; 10:436-444. Medline 7670494

LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family. Petit MMR, Mols R, Schoenmakers EFPM, Mandahl N, Van de Ven W. Genomics 1996; 36:118-129. Medline 8812423

LIM domains: multiple roles as adapters and functional modifiers in protein interactions. Dawid IB, Breen JJ, Toyama R. Trends Genet 1998; 14:156-162. Medline 9594664

Chromosomal translocations in benign tumors: the HMGI proteins Hess JL. Am J Clin Pathol 1998; 109:251-261 (review). Medline 9495195

The t(3;12)(q27;q14-q15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype. Rogalla P, Kazmierczak B, Meyer-Bolte K, Tran KH, Bullerdiek J. Genes Chromosomes Cancer 1998; 22:100-104. Medline 9598796

A high frequency of tumors with rearrangements of genes of the HMGI(Y) family in a series of 191 pulmonary chondroid hamartomas. Kazmierczak B, Meyer-Bolte K, Tran KH, Wöckel W, Breightman I, Rosigkeit J, Bartnitzke S, Bullerdiek J. Genes Chromosomes Cancer 1999; 26:125-133. Medline 10469450

LPP, an actin cytoskeleton protein related to zyxin, harbors a nuclear export signal and transcriptional activation capacity. Petit MMR, Fradelizi J, Golsteyn RM, Ayoubi TAY, Menichi B, Louvard D, Van de Ven WJM, Friedrich E. Mol Biol Cell 2000; 11:117-129. Medline 10637295

The expression of HMGA genes is regulated by their 3'UTR. Borrmann L, Wilkening S, Bullerdiek J. Oncogene 2001; 20:4537-4541. Medline 11494149

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Sequencing of intron 3 of HMGA2 uncovers the existence of a novel exon. Hauke S, Flohr AM, Rogalla P, Bullerdiek J. Genes Chromosomes Cancer 2002; 34:17-23. Medline 11921278

High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity. Borrmann L, Schwanbeck R, Heyduk T, Seebeck B, Rogalla P, Bullerdiek J, Wisniewski JR. Nucleic Acids Res 2003; 31:6841-6851. Medline 14627817

Fusion, disruption and expression of HMGA2 in bone and soft tissue chondromas. Dahlén A, Mertens F, Rydholm A, Brosjö O, Wejde J, Mandahl N, Panagopoulos I. Mod Pathol 2003; 16:1132-1140. Medline 14614053

Transcriptional activation of the Cyclin A gene by the architectural transcription factor HMGA2. Tessari MA, Gostissa M, Altamura S, Sgarra R, Rustighi A, Salvagno C, Caretti G, Imbriano C, Mantovani R, Del Sal G, Giancotti V, Manfioletti G. Mol Cell Biol 2003; 23:9104-9116. Medline 14645522

Extensive expression studies revealed a complex alternative splicing pattern of the HMGA2 gene. Hauke S, Leopold S, Schlueter C, Flohr AM, Murua Escobar H, Rogalla P, Bullerdiek J. Biochim Biophys Acta 2005; 1729:24-31. Medline 15882911

E2F1 activation is responible for pituitary adenomas induced by HMGA2 gene overexpresion. Fedele M, Pierantoni GM, Visone R, Fusco A. Cell Div 2006; 1:17 (review). Medline 16914062

The LIM domain protein LPP is a coactivator for the ETS domain transcription factor PEA3. Guo B, Sallis RE, Greenall A, Petit MMR, Jansen E, Young L, Van de Ven WJM, Sharrocks AD. Mol Cell Biol 2006; 26:4529-4538. Medline 16738319

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 10-2006 Anna Collin Citation This paper should be referenced as such : Collin A . Soft tissue chondroma with t(3;12)(q27;q15). Atlas Genet Cytogenet Oncol Haematol. October 2006 . URL : http://AtlasGeneticsOncology.org/Tumors/Chondromat0312ID5428.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -94- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Schwannomatosis

Identity Note A third major form of neurofibromatosis Inheritance Up to 90% of schwannomatosis are isolated cases. An annual incidence of newly identified cases was estimated to be approximately 1 in 1,700,000. Inheritance in familial cases is autosomal dominant with incomplete penetrance. Clinics Note Clinical spectrum of schwannomatosis has similarity to neurofibromatosis type 2 (NF2) and overlap to some extent with that of NF2. Both disorders share the predisposition to multiple schwannomas. Phenotype Critetia for definite diagnosis: two or more pathologically sampled schwannomas and clinics and lack of evidence of vestibular nerve tumor on magnetic resonance imaging performed after age 18 years. Criteria for presumptive diagnosis: two or more pathologically ascertained schwannomas without symptoms of eighth nerve dysfunction at age above 30 years or two or more pathologically sampled schwannomas in an anatomically limited distribution without symptoms of eighth nerve dysfunction at any age Neoplastic risk Benign schwannomas of peripheral nerve. Treatment Surgical resection upon indication for pain and neurological symptoms. Electromyographical or electrohpysiological monitoring can be used to minimize the risk of iatrogenic injery to the nerve or spinal cord during surgery. Prognosis Schwannomatosis-associated tumors are basically of benign nature. Surgical outcome depends on anatomical localization and size of the tumor. No reduction in life-span expectation. Cytogenetics Inborn No special feature. conditions Genes involved and Proteins Note The genetic cause for schwannomatosis has not yet be identified. Linkage analysis has exclude the NF2 gene region and located the responsible locus to a 5 mega- basepair interval proximal to the NF2 gene on chromosome 22

Mutations Note Though alterations of the NF2 gene have been found in schwannomatosis-associated tumors, none of them has ever been found in any non-tumor tissues such as peripheral leukocytes of the patients. Somatic Somatic mutations and allele loss of the NF2 gene have been found in schwannomatosis-associated schwannomas.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -95- Bibliography Schwannomatosis: a clinical and pathologic study. MacCollin M, Woodfin W, Kronn D, Short MP. Neurology 1996; 46: 1072-1079 (Review) Medline 8780094

Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Jacoby LB, Jones D, Davis K, Kronn D, Short MP, Gusella J, MacCollin M. Am J Hum Genet 1997; 61: 1293-1302. Medline 9399891

Multiple schwannomas: schwannomatosis or neurofibromatosis type 2? Seppala MT, Sainio MA, Haltia MJ, Kinnunen JJ, Setala KH, Jaaskelainen JE. J Neurosurg 1998; 89: 36-41. Medline 9647170

Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Antinheimo J, Sankila R, Carpen O, Pukkala E, Sainio M, Jaaskelainen J. Neurology 2000; 54: 71-76. Medline 10636128

Familial schwannomatosis: exclusion of the NF2 locus as the germline event. MacCollin M, Willett C, Heinrich B, Jacoby LB, Acierno JS Jr, Perry A, Louis DN. Neurology 2003; 60: 1968-1974. Medline 12821741

Diagnostic criteria for schwannomatosis. MacCollin M, Chiocca EA, Evans DG, Friedman JM, Horvitz R, Jaramillo D, Lev M, Mautner VF, Niimura M, Plotkin SR, Sang CN, Stemmer-Rachamimov A, Roach ES. Neurology 2005; 64: 1838-1845 (Review) Medline 15955931

Increasing the specificity of diagnostic criteria for schwannomatosis. Baser ME, Friedman JM, Evans DG. Neurology 2006; 66: 730-732. Medline 16534111

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 08-2006 Lan Kluwe Citation This paper should be referenced as such : Kluwe L . Schwannomatosis. Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/SchwannomatID10122.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -96- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Hereditary Desmoid Disease.

Identity Other names Familial Infiltrative Fibromatosis. Inheritance Autosomal dominant disorder; frequency is less than 1/105 newborns; unknown new mutation rate; variable disease expression; penetrance is unknown. Hereditary desmoid disease occurs primarily in association with familial adenomatous polyposis. Clinics Phenotype Normally, presence of multiple desmoid tumours especially in the mesentery. Desmoid and clinics tumours can develop elsewhere and are often initiated after trauma. Micro-adenomas in the lower gastrointestinal tract, often not reported. Upper GI polyps are often observed. Neoplastic risk Strictly speaking desmoid tumours are not neoplastic but they are locally invasive and highly destructive. Often associated with extreme pain and respond poorly to treatment. Usually they occur in association with familial adenomatous polyposis. Desmoid tumours usually occur in the abdominal cavity and have been associated with traumatic events that include surgery and childbirth. They have been reported at other anatomical sites. Treatment There is no defined treatment that is affective in all cases. Nevertheless, the use of non-steroidal anti-inflammatory drugs (NSAIDs) in combination with tamoxifen has been suggested but there is no firm evidence to indicate its benefit. Evolution Disease development involves the loss of APC and appears to be associated with 3¹ APC germline mutations. Little is known about downstream events in the evolution of the disease. Prognosis Patients with hereditary desmoid disease fall into three categories; those that develop disease, which spontaneously regresses (very rarely reported); patients with stabile disease that does not progress: and patients with severe progressive and fatal disease. Genes involved and Proteins

Gene Name APC (Adenomatous Polyposis Coli) Location 5q21-q22 Protein Description Tumour suppressor gene with multiple functions; Normal APC gene product interacts with adherens junction proteins a-catenin and b-catenin. Expression APC expression is present in all cells but at varying levels. Localisation Mainly in the cytoplasm but there is a nuclear localization signal and it is observed in the nucleus. Function Primary function appears to be the regulation of b-catenin in association with GSK-b via the ubiquitin degradation pathway. It has also been shown to help orientate the

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -97- mitotic spindle during cell replication. Homology Partial homology with , where it is about 76% homologous in the first half of the protein. Mutations Germinal Many mutations have been described in the APC gene, most of which result in premature termination codons. With respect to familial desmoid disease two sites have been described that occur in the sparsely mutated 3'- region of the gene. Germline mutations at codon 1924 and 1860 have been reported in rare families with desmoid disease. Somatic There appears to be a mutation cluster region in the APC gene that is centered around codon 1309. These mutations have only been described in colorectal tumours and there is little information with respect to desmoid disease.

Bibliography Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y. Hum Mol Genet 1992; 1: 229-233. Medline 1338904

Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Am J Hum Genet 1996; 59: 1193-1201. Medline 8940264

Familial infiltrative fibromatosis (desmoid tumours) (MIM 135290) caused by a recurrent 3¹ APC gene mutation. Scott RJ, Froggatt NJ, Trembath RC, Evans GR, Hodgson SV, Maher ER. Human Molecular Genetics 1996; 5: 1921-1924. Medline 8968744

Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Science.1997; 275: 1784-1787. Medline 9065401

Desmoid tumour: a pleomorphic lesion. Kulaylat MN, Karakousis CP, Keaney CM, McCorvey D, Bem J, Ambrus Sr JL. Eur J Surg Oncol 1999; 25: 487-497. Medline 10527597

Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Yamashita YM, Jones DL, Fuller MT. Science 2003; 301: 1547-1550. Medline 12970569

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 08-2006 Rodney J Scott.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -98- Citation This paper should be referenced as such : Scott JR . Hereditary Desmoid Disease.. Atlas Genet Cytogenet Oncol Haematol. August 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/HereditDesmoidID10119.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -99- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Mechanisms of hepatocarcinogenesis Raphaël Saffroy (1), Antoinette Lemoine (1), Brigitte Debuire (1) 1) Service de Biochimie et Biologie moléculaire; U602 Inserm/Université Paris XI; Hôpital Paul Brousse, 14 avenue Paul Vaillant Couturier - 94804 Villejuif Cedex, Assistance Publique-Hôpitaux de Paris ; France.

September 2006

Hepatocellular carcinoma (HCC) is among the fifth most common cancers worlwide. The geographic areas at higher risk are located in China and eastern Asia, middle Africa and some countries of western Africa. Lower incidences are encountered in Japan, Europe and America, but this incidence is still rising in part because of the high level of hepatitis C virus infection. The preponderance in males is universal and HCC is the commonest in subjects over the age of 40, although it can be observed in younger. The prognosis is generally poor, especially in Africans and Chinese where survival time may be as short as 11 weeks from the onset of symptoms. The causes of more than 85% of HCC cases are known (hepatitis B and C, aflatoxin B1, ethanol, metabolic diseases). HCC is an epithelial tumor developing from hepatocytes. In the majority of cases, cirrhosis is the major underlying risk factor, but HCC may occur also on chronic hepatitis or normal liver. Mechanisms of hepatocarcinogenesis are not completely understood but, like most solid tumors, the development and progression of HCC are believed to be caused by the accumulation of genetic changes resulting in altered expression of cancer-related genes, such as oncogenes or tumor suppressor genes, as well as genes involved in different regulatory pathways. The genetic changes involved can be divided in at least 4 different pathways, each pathway contributing to a limited number of tumors. These are : 1. the p53 pathway involved in response to DNA damage,

2. the retinoblastoma pathway involved in control of the cell cycle,

3. the transforming growth factor-beta (TGF-beta) pathway involved in growth inhibition, and

4. the Wnt pathway involved in cell-cell adhesion and signal transduction.

Sequential changes in the liver leading to HCC HCC is probably one of the tumors the etiologic factors of which are the best known. However, in spite of numerous studies and thousands of tumors analyzed, fractionnal data relative to the genetic mechanisms of hepatocarcinogenesis are known and genetic predisposition has been rarely described. HCC generally develops in the setting of chronic hepatitis or cirrhosis in which there is continuous inflammation and regeneration of hepatocytes (Figure 1).

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Figure 1 : Sequential changes in the liver leading to HCC

Hepatocarcinogenesis may begin in preneoplastic lesions such as macroregenerative nodules, low- grade and high grade dysplastic nodules (Takayama et al, 1990; Orsatti et al, 1993). Accelerated proliferation of hepatocytes and development of monoclonal hepatocyte populations occur in all preneoplastic conditions. Accumulation of genetic alterations in these preneoplastic lesions is believed to lead to the development of HCC. Genomic alterations occur randomly, and they accumulate in dysplastic hepatocytes and HCC. Although genetic changes may occur independently of etiologic conditions, some molecular mechanisms have been more frequently related to a specific etiology. For example, molecular pathways of HBV- and HCV-induced hepatocarcinogenesis involving Rb1, p53, and Wnt families are different from those associated with alcoholism (Wang et al, 2002; Suriawinata et al, 2004, Morgan et al, 2004).

Alterations during the preneoplastic phase The important heterogeneity of genomic lesions found in HCC suggests that HCC may be produced by selection of both genomic and epigenetic alterations that compromise more than one regulatory pathway. During the preneoplastic stage leading to HCC, alterations concern mainly quantitative modification of gene expression induced by epigenetic mechanisms. Growth factor genes such as transforming growth factora (TGF-a) or insulin growth factor-2 (IGF-2) are mainly involved. Dysregulation of these genes results from combinated actions of cytokines produced by chronic inflammatory cells that infiltrate the liver and the regenerative response of the liver, viral transactivation, or action of carcinogens. Genome-wide hypomethylation and aberrant methylation of genes and chromosomal segments are also observed. Expression of DNA methyltransferases which catalyze the methylation and demethylation of CpG groups is increased in livers affected with cirrhosis and chronic hepatitis (Lin et al, 2001). Cis- and transactivation of genes resulting from the actions of integrated viral promoters or viral transactivating molecules are other possible causes of epigenetic changes. For example, during HBV chronic infection, the HBx antigen binds and alters functionally tumor suppressor P53. Morever, integration of viral genome sequences may induce genomic instability and structural changes such as mutations, breaks or chromosomal rearrangements. These early genetic or epigenetic alterations are not sufficient to induce malignant phenotypes in hepatocytes. It is the accumulation of these events in critical combinations that allow the malignant transformation, several genes being simultaneously altered in each tumor.

Alterations in HCC Microsatellite instability (MSI) has been frequently reported by different teams, including in liver cirrhosis, mainly when cirrhosis is associated with HBV infection (Salvucci et al, 1996; Salvucci et al, 1999; Karachristos et al, 1999; Kondo et al, 1999; Kawai et al,

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -101- 2000; Dore et al, 2001). However, the frequency of MSI in HCC exhibits large variations (10-43%) and high-MSI phenotype has rarely been described (MacDonald et al, 1998; Chiappini et al, 2004). It is still unclear whether some HCC have DNA mismatch repair genes alterations. Allelic deletions, mainly in chromosomes 1p, 4q, 5q, 6q, 7p, 8p, 9p, 10q, 11p, 13q, 16p, 16q et al, 2002and 17p, or gains in chromosomes 1p, 6p, 8q and 17q are frequently observed (Thorgeirsson).This genomic instability contributes to activation or inactivation of oncogenes or tumor suppressor genes. In some cases, epigenetic changes directly precede structural alterations in the same genes as it has been described for CDKN2A gene in 16q chromosome or c-myc oncogene in 8q. Some carcinogens may induce specific alterations. Indeed, aflatoxin B1 is responsable of a G/T transversion at codon 249 in the p53 gene. Complete erosion of telomeres, which may exist in highly replicated preneoplastic and neoplastic hepatocytes, may also contribute to genomic instability and could play a cooperative role with altered p53 in the progression of hepatocellular carcinoma (Farazi et al, 2006). Morever oxydative damage occuring in a chronically inflamed liver can lead to mutations in genomic, but also in mitochondrial DNA (Seitz et al, 2006). Production of new genetic alterations in clones of malignant hepatocytes leads to clonal divergence. Finally, HCC appears as a diverse mixture of genomic aberrations in which more than one signal pathway is affected. Some genes have been clearly identified to play a role in hepatocarcinogenesis. But other genes are suspected, sometimes because of high frequencies of allelic deletions in some chromosomal segments (table 1).

Table 1 . Main candidate tumor suppressor genes located in chromosomal segments with high level of loss of heterozygozity in HCC.

LOH Candidate genes

1p p73, RIZ (retinoblastoma-interacting zinc- finger protein)

2p hMSH2

3p hMLH1

5q APC

6q M6P/IGFIIR (mannose 6-phosphate/insulin- like growth factor II receptor)

9p CDKN2A (ou p16INK4A, MTS1/p16)

10q PTEN/MMAC1

13q RB (retinoblastoma), BRCA2

16p axine 1,

16q CDH13

17p p53

Late events in hepatocarcinogenesis (metastasis) Lack of control of recurrence and metastatic foci is the most prevalent cause of death in patients with HCC. HCC metastasis is probably initiated in the primary tumor and is a multigene-involved, multistep, and changing process. The molecular signature of primary hepatocellular carcinoma (HCC) has been found very similar to that of their corresponding metastases, while it differs significantly in primary HCCs with or without metastasis. These findings imply that many of the metastasis-promoting genes are embedded in the primary tumors and that the ability to metastasize may be an inherent quality of the tumor from the beginning (Budhu et al, 2005). Allelic losses have been proposed as being related to the survival and prognosis of cancer patients. Loss of heterozygosity (LOH) on chromosomes 13q, 16q, and 17p has been particularly associated with the progression of HCC. LOH on 16q has been

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -102- identified as one of the most significant negatively predictive factors for metastasis-free survival of HCC patients (Salvucci et al, 1999; Okabe et al, 2000; Nishida et al, 2002, Gross-Goupil et al, 2003). Nevertheless, the genes altered have not still been identified. Metastatic process need intercellular exchange betwen tumoral cells and environmental cells such as endothelial cells or fibroblasts. Different molecules may be involved in these interactions. Some adhesion molecules are suspected to play a role in the metastatic process in HCC such as laminin-5 (Giannelli et al, 2003), variants of CD44 glycoprotein (Endo et al, 2000), or osteopontin (Pan et al, 2003, Ye et al, 2003). Proteins involved in the degradation of the extracellular matrix may also play an important role such as urokinase plasminogen ativator / plasminogen activator inhibitor-1 (uPA/PAI-1) (Zheng et al, 2000) or matrix metalloproteinases (Giannelli et al, 2002). Angiogenesis is critical to HCC since it is such a hypervascular tumor. Various angiogenic factors have been identified in HCC. In particular VEGF and its receptors have been demonstrated to be upregulated in HCC both at the tissue and serum levels.

Main genes involved in HCC Gene p53 P53 protein is a DNA-binding, cell regulating, transcription factor that has multiple critical roles in the pathway governing cell-cycle and in the balance between cell division and apoptosis.The p53 gene is the most commonly mutated tumor suppressor gene in various human cancers. The frequency and type of p53 mutations differ according to the geographic origin and suspected etiology of HCC. The specific codon 249 mutation has been linked to aflatoxin exposure in 36% of tumors from Africa and 32% of tumors from China, respectively (Ozturk et al, 1999). In contrast, the codon 249 mutation is seen in less than 4% of HCCs from Japan, Europe, and north America, where HBV and HCV, but not aflatoxins, are the main etiologic factors. Other codons of the p53 gene can be altered in HCC and overall this gene is mutated in 15% of tumors in Europe and 42% in China. The wild-type P53 protein can accumulate in HCC tumor cells by complexing with cellular or viral proteins (Bourdon et al, 1995). Experimentally, the HBx protein, encoded by the HBV genome, interacts with wild-type P53 and inhibit its function. Morever, P53 antibodies have been detected in the serum of HCC patients (Shiota et al, 1997; Saffroy et al, 1999; Charuruks et al, 2001). P53 alterations have been globally associated with poor prognosis. b-catenin and the Wnt pathway b-catenin is a submembranous protein associated with E-cadherin and participates in cell-cell adhesion. It is involved in the Wnt carcinogenesis pathway. The Wnt signal inducing cellular proliferation implicates formation of a complex with axin, GSK-3b kinase and APC proteins and finally degradation of b-catenin. Dysregulation of the Wnt pathway inhibits these complexes and induces b- catenin stabilization. Translocation of b-catenin to the nucleus causes transcriptional activation of target genes, including the c-myc and cyclin D1 genes. Most of b-catenin point mutations alter 1 of the 4 serine or threonine residues which are targets for phosphorylation by GSK3-b and are crucial for down-regulation of the protein. b-catenin mutations have been found in 19 to 41% of human HCCs of different etiologies (de la coste et al, 1998; legoix et al, 1999). Clinical significance of intense nuclear localization of b-catenin in HCC is controversial (Terris et al 1999; Hsu et al, 2000; Endo et al, 2000; Wong et al, 2001; Fujito et al, 2004). It has been shown that b-catenin mutations are more prevalent in HCCs related to HCV than HBV (Laurent-Puig et al, 2001). They have not been detected in non tumorous tissue, dysplastic lesions, and cirrhotic nodules. HCCs harboring b-catenin mutations have a limited number of chromosomal aberrations detected by microsatellite marker analysis (Legoix et al, 1999, Hsu et al, 2000, Laurent Puig et al, 2001) suggesting an independant mechanism of hepatocarcinogenesis. In mouse models of hepatocarcinogenesis, the incidence of b-catenin mutations is highly variable between tumors induced by different carcinogens (Devereux et al, 1999) or developed on different p53 backgrounds (Renard et al, 2000). Mutant b-catenin is not associated with metastases in HCC patients. This suggests that b-catenin mutation is an early event in hepatocarcinogenesis (Mao et al, 2001). No mutations of APC gene have been observed in HCC, but other actors of the Wnt pathway may be altered. Indeed, axin 1 gene is mutated in about 5-10% of HCCs (Satoh et al, 2000; Taniguchi et al, 2002). Although frequent alteration of E-cadherin expression has been observed, no mutation of the gene has been found. Loss of E-cadherin function may be related to LOH associated with de novo methylation (Kanai et al, 1997). Taken together, the b-catenin pathway appears to be altered in more than one third of the HCCs.

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Retinoblastoma and cell-cycle regulators The Retinoblastoma (Rb) gene is involved in regulation of the G1 phase of the cell-cycle. It is the first tumor suppressor gene identified and one of the most frequently mutated in human tumors. Although Rb expression is frequently decreased in HCCs, mutations are observed in only 15% of the tumors (Ozturk et al, 1999). So inactivation of Rb may be further related to alterations of other interacting proteins such as p16-INK4. Both germline and somatic mutations of p16-INK4 have been found in HCC patients. But hypermethylation of the gene promoter (reported in about 50% of the tumors) associated with loss of heterozygoty seems here the main mechanism for gene inactivation. Other genes are less frequently altered. Cyclin D, A or E were shown to be amplified in 10-20% of HCCs. A surexpression of cdc2 has also been described associated with poor prognosis (Qin et al, 2002). Overexpression of p28/gankyrin, a gene involved in the degradation of Rb by the proteasome system, could also contribute to the metastasis potential in the process of hepatocarcinogenesis (Fu et al, 2002; Dawson et al, 2006).

TGF-beta pathway Loss of the response to TGF-b, which induces both growth inhibition and apoptosis in hepatocytes, may also play a role in hepatocarcinogenesis. The mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), involved in the activation of TGF-b and degradation of IGF2, is a candidate gene. But if loss of heterozygosity is frequently observed at 6q25, presence of mutations in the M6P/IGF2R locus, is controversial. SMAD2 and SMAD4 are intracellular mediators of TGF-b. Nevertheless, these genes appear to be mutated in less than 10% of HCCs (Yakicier et al, 1999). In contrast, no mutation of TGF-b receptor II was found in HCC. Overall, the TGF-b pathway appears to be altered in about 25% of HCCs. ras and myc oncogenes By contrast to other types of cancer, oncogenes do not seem to play an important role in hepatocarcinogenesis. However, surexpression and amplification of c-myc (located in 8q) have been observed in some cases. Mutation of the 3 main ras genes have been observed in less than 10% of HCCs. Some K-ras mutations have been related to vinyl chloride exposure.

In conclusion, the number of altered genes in HCC is high, but the frequency of each individual gene mutations is generally low. The main pathways affected may represent individually a distinct step of hepatocarcinogenesis but they probably are related to each other. To date, our knowledge of the order of events for the initiation and progression of HCC is still incomplete. Prospectively, development of global methods of analysis such as proteomics or microarray methods will probably increase discovery of new genes or pathways involved in hepatocarcinogenesis.

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Atlas Genet Cytogenet Oncol Haematol 2007; 1 -104- 7. Devereux TR, Anna CH, Foley JF, White CM, Sills RC, Barrett JC. Mutation of beta-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis. Oncogene 1999; 18: 4726- 4733. 8. Dore MP, Realdi G, Mura D, Onida A, Massarelli G, Dettori G, Graham DY, Sepulveda AR. Genomic instability in chronic viral hepatitis and hepatocellular carcinoma. Hum Pathol 2001; 32: 698- 703. 9. Endo K, Ueda T, Ueyama J, Ohta T, Terada T. Immunoreactive E-cadherin, alpha-catenin, beta- catenin, and gamma-catenin proteins in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patients' survival. Hum Pathol 2000; 31: 558-565. 10. Farazi PA, Glickman J, Horner J, Depinho RA. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res 2006; 66: 4766-4773. 11. Fu XY, Wang HY, Tan L, Liu SQ, Cao HF, Wu MC. Overexpression of p28/gankyrin in human hepatocellular carcinoma and its clinical significance. World J Gastroenterol 2002; 8: 638-643. 12. Fujito T, Sasaki Y, Iwao K, Miyoshi Y, Tamada T, Ohigashi H, Ishikawa O, Imaoka S. Prognostic significance of beta-catenin nuclear expression in hepatocellular carcinoma. Hepatogastroenterology 2004; 51: 921-924. 13. Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L, Schiraldi O, Antonaci S. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J cancer 2002; 97: 425-431. 14. Giannelli G, Fransvea E, Bergamini C, Marinosci F, Antonaci S. Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma. Clin Cancer Res 2003; 9: 3684-3691. 15. Gross-Goupil M, Riou P, Emile JF, Saffroy R, Azoulay D, Lacherade I, Receveur A, Piatier- Tonneau D, Castaing D, Debuire B, Lemoine A. Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation. Int J Cancer 2003; 104: 745-751. 16. Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol 2000; 157: 763-770. 17. Kanai Y, Ushijima S, Hui AM, Ochiai A, Tsuda H, Sakamoto M, Hirohashi S. The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas. Int J cancer 1997; 71: 355-359. 18. Karachristos A, Liloglou T, Field JK, Deligiorgi E, Kouskouni E, Spandidos DA. Microsatellite instability and p53 mutations in hepatocellular carcinoma. Mol Cell Biol Res Commun 1999; 2: 155- 161. 19. Kawai H, Suda T, Aoyagi Y, Isokawa O, Mita Y, Waguri N, Kuroiwa T, Igarashi M, Tsukada K, Mori S, Shimizu T, Suzuki Y, Abe Y, Takahashi T, Nomoto M, Asakura H. Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology 2000; 31: 1246-1250. 20. Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S. Microsatellite instability associated with hepatocarcinogenesis. J Hepatol 1999 ; 31 : 529-536. 21. Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, Monges G, Thomas G, Bioulac- Sage P, Zucman-Rossi J. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 2001; 120: 1763-1773. 22. Legoix P, Bluteau O, Bayer J, Perret C, Balabaud C, Belghiti J, Franco D, Thomas G, Laurent-Puig P, Zucman-Rossi J. Beta-catenin mutations in hepatocellular carcinoma correlate with a low rate of loss of heterozygosity. Oncogene 1999; 18: 4044-4046. 23. Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC, Liaw YF. Genome-wide hypomethylation in hepatocellular carcinogenesis. Cancer Res 2001; 61: 4238-4243. 24. Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatocellular carcinoma, absence of portal vein spread, and good prognosis. J Pathol 2001; 193: 95-101. 25. Macdonald GA, Greenson JK, Saito K, Cherian SP, Appelman HD, Boland CR. Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis. Hepatology 1998; 28: 91-97. 26. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology 2004; 127: S87-96. 27. Nishida N, Fukuda Y, Komeda T, Ito T, Nishimura T, Minata M, Kuno M, Katsuma H, Ikai I, Yamaoka Y, Nakao K. Prognostic impact of multiple allelic losses on metastatic recurrence in hepatocellular carcinoma after curative resection. Oncology 2002; 62: 141-148.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -105- 28. Okabe H, Ikai I, Matsuo K, Satoh S, Momoi H, Kamikawa T, Katsura N, Nishitai R, Takeyama O, Fukumoto M, Yamaoka Y. Comprehensive allelotype study of hepatocellular carcinoma: potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and -negative tumors. Hepatology 2000; 31: 1073-1079. 29. Orsatti G, Theise ND, Thung SN, Paronetto F. DNA image cytometric analysis of macroregeneratives nodules (adenomatous hyperplasia) of the liver: evidence in support of their preneoplastic nature. Hepatology 1993; 17: 621-627. 30. Ozturk M. Genetic aspects of hepatocellular carcinogenesis. Semin Lievr Dis 1999; 19: 235-242. 31. Pan HW, Ou YH, Peng SY, Liu SH, Lai PL, Lee PH, Sheu JC, Chen CL, Hsu HC. Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer 2003; 98: 119-127. 32. Qin LX, Tang ZY. The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol 2002; 8: 385-392. 33. Renard CA, Fourel G, Bralet MP, Degott C, De La Coste A, Perret C, Tiollais P, Buendia MA. Hepatocellular carcinoma in WHV/N-myc2 transgenic mice: oncogenic mutations of beta-catenin and synergistic effect of p53 null alleles. Oncogene 2000; 19: 2678-2686. 34. Saffroy R, Lelong JC, Azoulay D, Salvucci M, Reynes M, Bismuth H, Debuire B, Lemoine A. Clinical significance of circulating anti-p53 antibodies in European patients with hepatocellular carcinoma. Br J cancer 1999; 79: 604-610. 35. Salvucci M, Lemoine A, Azoulay D, Sebagh M, Bismuth H, Reyns M, May E, Debuire B. Frequent microsatellite instability in post hepatitis B viral cirrhosis. Oncogene 1996; 13: 2681-2685. 36. Salvucci M, Lemoine A, Saffroy R, Azoulay D, Lepere B, Gaillard S, Bismuth H, Reynes M, Debuire B. Microsatellite instability in European hepatocellular carcinoma. Oncogene 1999; 18: 181- 187. 37. Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000; 24: 245-250. 38. Seitz HK, Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 2006; 387: 349-360. 39. Shiota G, Kishimoto Y, Suyama A, Okubo M, Katayama S, Harada K, Ishida M, Hori K, Suou T, Kawasaki H. Prognostic significance of serum anti-p53 antibody in patients with hepatocellular carcinoma. J Hepatol 1997; 27: 661-668. 40. Suriawinata A, Xu R. An Update on the molecular genetics of hepatocellular carcinoma. Semin Liver Dis 2004; 24: 77-88. 41. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Okazaki N, Takayasu K, Kosuge T, Motoo Y, Yamazaki S, Hasegawa H. Malignant transformation of adematous hyperplasia to hepatocellular carcinoma. Lancet 1990; 336: 1150-1153. 42. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002; 21: 4863-4871. 43. Terris B, Pineau P, Bregeaud L, Valla D, Belghiti J, Tiollais P, Degott C, Dejean A. Close correlation between beta-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 1999; 18: 6583-6588. 44. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nature Genet 2002; 31: 339-346. 45. Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ, Brechot C, Harris CC. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 2002; 181-182: 43-47. 46. Wong CM, Fan ST, Ng IO. Beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001; 92: 136-145. 47. Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 1999; 18: 4879-4883. 48. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003; 9: 416-423. 49. Zheng Q, Tang ZY, Xue Q, Shi DR, Song HY, Tang HB. Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator, its receptor and inhibitor. J Cancer Res Clin Oncol 2000; 126: 641-646.

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Contributor(s) Written 09-2006 Raphael Saffroy, Antoinette Lemoine, Citation This paper should be referenced as such : Saffroy R, Lemoine A, Debuire B . . Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Deep/HepatocarcinogenesisID20055.html

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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)

Isolated trisomy 2 is non-random and may be found in myelodysplastic syndrome and in acute myeloblastic leukaemia. Case 1

Catherine Roche-Lestienne, Agnès Charpentier, Sandrine Geffroy, Joris Andrieux, Jean-Loup Demory, Jean-Luc Laï

Clinics Age and sex : 58 yrs old male patient Previous history : preleukaemia; no previous malignant disease; -no inborn condition of note; Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 1.9 x 109/l; Hb : 9.1 g/dl; platelets : 282 x 109/l; Bone marrow : 1.4 % blasts% Survival Date of diagnosis: 1979 Treatment : red cell transfusion monthly Complete remission was obtained Treatment related death : - Relapse : - Status : A Survival : 26 yrs + Karyotype Sample : Bone marrow; culture time : 24H and 48 H; banding : GTG Results : 46,XY, [6]/ 47, XY, +2 [14] Other molecular cytogenetics technics : FISH using the BAC probe RP11-375H16 (2q23.1)

G-banding karyotype revealed isolated trisomy 2 of case 1 Comments Trisomy 2 as single chromosomal abnormality appears to be associated with MDS on the contrary to

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -108- AML where it is frequently encountered in association to other unbalanced chromosomal abnormalities [ref.1]. This observation therefore suggests that trisomy 2 could be an early genetic abnormality in MDS. Indeed, from the 9 MDS/AML described cases with isolated trisomy 2 (including our 2 cases), 7 cases revealed isolated trisomy 2 at MDS presentation. MDS in transformation was diagnosed among the 4 oldest patients, though age does not carry prognostic significance according to the IPSS [ref.2]. 5 of the 9 published cases evolved to acute leukaemia. Internal links Atlas Card +2 or trisomy 2 Case Report Isolated trisomy 2, Case 2 Bibliography International scoring system for evaluating prognosis in myelodysplastic syndromes. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. Blood 1997; 89: 2079-2088. Medline 9058730 Cross-validation of prognostic scores in myelodysplastic syndromes on 386 patients from a single institution confirms importance of cytogenetics. Pfeilstöcker M, Reisner R, Nosslinger T, Gruner H, Nowotny H, Tuchler H, Schlogl E, Pittermann E, Heinz R. Br J Haematol 1999; 106: 455-463. Medline 10460606 Contributor(s) Written Catherine Roche-Lestienne, Agnès Charpentier, Sandrine Geffroy, Joris 09-2006 Andrieux, Jean-Loup Demory, Jean-Luc Laï Citation This paper should be referenced as such : Roche-Lestienne C, Charpentier A, Geffroy S, Andrieux J, Demory JL, Laï JL . Isolated trisomy 2 is non-random and may be found in myelodysplastic syndrome and in acute myeloblastic leukaemia. Case 1. Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Reports/02RocheID100015.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -109- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)

Isolated trisomy 2 is non-random and may be found in myelodysplastic syndrome and in acute myeloblastic leukaemia. Case 2

Catherine Roche-Lestienne, Agnès Charpentier, Sandrine Geffroy, Joris Andrieux, Jean-Loup Demory, Jean-Luc Laï

Clinics Age and sex : 69 yrs old female patient Previous history : no preleukemia; no previous malignant disease; -no inborn condition of note; Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 1.7 x 109/l; Hb : 7.4 g/dl; platelets : 45 x 109/l; Bone marrow : 85% blasts% Survival Date of diagnosis: 12-2000 Treatment : Daunorobucin and cytosine-arabinoside Complete remission was obtained Treatment related death : Died after several septicemic episodes during bone marrow suppression treatment Relapse : - Status : Dead 05-2001 Survival : 12 months Karyotype Sample : Bone marrow; culture time : 24H and 48 H; banding : GTG Results : 46,XX, [4]/ 47, XX,+2 [18] Other molecular cytogenetics technics : FISH using the BAC probe RP11-375H16 (2q23.1)

G-banding karyotype revealed isolated trisomy 2 of case 2 Comments Trisomy 2 as single chromosomal abnormality appears to be associated with MDS on the contrary to AML where it is frequently encountered in association to other unbalanced chromosomal abnormalities [ref.1]. This observation therefore suggests that trisomy 2 could be an early genetic abnormality in MDS. Indeed, from the 9 MDS/AML described cases with isolated trisomy 2 (including our 2 cases), 7 cases revealed isolated trisomy 2 at MDS presentation. MDS in transformation was diagnosed among the 4 oldest patients, though age does not carry prognostic significance according to the IPSS [ref.2]. 5 of the 9 published cases evolved to acute leukaemia.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -110- Internal links Atlas Card +2 or trisomy 2 Case Report Isolated trisomy 2, Case 1 Bibliography International scoring system for evaluating prognosis in myelodysplastic syndromes. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. Blood 1997; 89: 2079-2088. Medline 9058730 Cross-validation of prognostic scores in myelodysplastic syndromes on 386 patients from a single institution confirms importance of cytogenetics. Pfeilstöcker M, Reisner R, Nosslinger T, Gruner H, Nowotny H, Tuchler H, Schlogl E, Pittermann E, Heinz R. Br J Haematol 1999; 106: 455-463. Medline 10460606 Contributor(s) Written Catherine Roche-Lestienne, Agnès Charpentier, Sandrine Geffroy, Joris 09-2006 Andrieux, Jean-Loup Demory, Jean-Luc Laï Citation This paper should be referenced as such : Roche-Lestienne C, Charpentier A, Geffroy S, Andrieux J, Demory JL, Laï JL . Isolated trisomy 2 is non-random and may be found in myelodysplastic syndrome and in acute myeloblastic leukaemia. Case 2. Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Reports/02RocheID100016.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -111- Atlas of Genetics and Cytogenetics in Oncology and Haematology

DNA: molecular structure

* I Primary structure of the molecule: covalent backbone and bases aside I-1 Phosphoric acid I-2 Sugar I-3 Nitrogenous bases II Secondary and tertiary structures of the molecule -Three- dimentional conformation of DNA II.1 Dinucleotides II.2 DNA molecule II.2.1 Hydrogen bounds: bases pairing French

II.2.2 Major groove and minor groove

II.3 Non-B DNA pdf version II.3.1 Z-DNA II.3.2 Cruciform DNA and hairpin DNA II.3.3 H-DNA or triplex DNA II.3.4 G4-DNA III Quaternary structure of the molecule - Chromatin IV Various IV.1 DNA and mitochondria IV.2 DNA denaturation *

Deoxyribonucleic acid (DNA) IS the genetic information of most living organisms (a contrario, some viruses, called retroviruses, use ribonucleic acid as genetic information). - DNA can be copied over generations of cells: DNA replication. - DNA can be translated into proteins: DNA transcription into RNA, further translated into proteins. - DNA can be repaired when needed: DNA repair. Ribonucleic acids (RNAs) are described in another chapter.

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -112- - DNA is a polymere, made of units called nucleotides (or mononucleotides). - Nucleotides also have other functions: (energy carriers: ATP, GTP; cellular respiration: NAD, FAD; signal transduction: cyclic AMP; coenzymes: CoA, UDP; vitamins: nicotinamide mononucleotide, Vit B2). Using the protein nomenclature, we could speak in terms of primary, secondary, tertiary and quaternary structures of the molecule:

I Primary structure of the molecule: covalent backbone and bases aside A nucleoside is made of a sugar + a nitrogenous base. A nucleotide is made of a phosphate + a sugar + a nitrogenous base. In DNA, the nucleotide is a deoxyribonucleotide (in RNA, the nucleotide is a ribonucleotide).

I-1 Phosphoric acid Gives a phosphate group.

I-2 Sugar: Deoxyribose, which is a cyclic pentose (5-carbon sugar). Note: the sugar in RNA is a ribose. Carbons in the sugar are noted from 1' to 5'. A nitrogen atom from the nitrogenous base links to C1' (glycosidic link), and the phosphate links to C5' (ester link) to make the nucleotide. The nucleotide is therefore: phosphate - C5' sugar C1' - base.

I-3 Nitrogenous bases: Aromatic heterocycles; there are purines and pyrimidines. - Purines: adenine (A) and guanine (G). - Pyrimidines: cytosine (C) and thymine (T) (Note: thymine is replaced by uracyle (U) in RNA). Note: other nitrogenous bases exist, in particular methylated bases derived from the above mentioned; of the bases has a functional role (see chapter ad hoc).

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Glossary: - Nucleoside names: deoxyribonucleosides in DNA: deoxyadenosine, deoxyguanosine, deoxycytidine, deoxythymidine in DNA (ribonucleosides in RNA: adenosine, guanosine, cytidine, uridine). - Nucleotide names: deoxyribonucleotides in DNA: deoxyadenylic acid, deoxyguanylic acid, deoxycytidylic acid, deoxythymidylic acid (ribonucleotides in RNA: adenylic acid, guanylic acid, cytidylic acid, uridylic acid).

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -114- II Secondary and tertiary structures of the molecule - Three-dimentional conformation of DNA II.1 Dinucleotides Dinucleotides form from a phosphodiester link between 2 mononucleotides. The phosphate of a mononucleotide (in C5' of its sugar) being linked to the C3' of the sugar of the previous mononucleotide. Then, we start with a phosphate, a 5' sugar (+base) and the 3' of this sugar, linked to a second phosphate - 5' sugar, which 3' is free for next step. The link -and the orientation of the molecule- is therefore 5' -> 3'. Polynucleotides are made of the successive addition of monomeres in a general 5' -> 3' configuration. The backbone of the molecule is made of a succession of phosphate-sugar (nucleotide n) - phosphate-sugar (nucleotide n+1), and so on, covalently linked, the bases being aside.

II.2 DNA molecule DNA is made of two ("duplex DNA") dextrogyre (like a screw; right-handed) helical chains or strands ("the double helix"), coiled around an axis to form a double helix of 20A° of diameter. The two strands are antiparallel (id est: their 5'->3' orientations are in opposite direction). The general appearance of the polymere shows a periodicity of 3.4 A°, corresponding to the distance between 2 bases, and another one of 34 A°, corresponding to one helix turn (and also to 10 bases pairs).

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II.2.1 Hydrogen bounds: bases pairing The (hydrophobic) bases are stacked on the inside, there planes are perpendicular to the axis of the double helix. The outside (phosphate and sugar) is hydrophilic. Hydrogen bounds between the bases of one strand and that of the other strand hold the two strands together (dashed lines in the drawing). A purine on one strand shall link to a pyrimidine on the other strand. As a corollary, the number of purines residues equals the number of pyrimidine residues.

A binds T (with 2 hydrogen bounds). G binds C (with 3 hydrogen bounds: more stable link: 5.5 kcal vs 3.5 kcal).

Note: the content in A in the DNA is therefore equal to the content in T, and the content in G equals the content in C. This strict correspondance (A<->T and G<->C) makes the 2 strands complementary. One is the template of the other one, and reciprocally: this property will allow exact replication (semi-conservative

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -116- replication: one strand -the template- is conserved, another is newly synthesized, same with the second strand, conserved, allowing another one to be newly synthesized; see chapter ad hoc).

Notes: Hydrogen bounds in base pairing are sometimes different from the model of Watson and Crick above described, using the N7 atom of the purine instead of the N1 (Hoogsteen model).

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II.2.2 Major groove and minor groove The double helix is a quite rigid and viscous molecule of an immense length and a small diameter. It presents a major groove and a minor groove. The major groove is deep and wide, the minor groove is narrow and shallow.

DNA-protein interactions are major/essential processes in the cell life (transcription activation or repression, DNA replication and repair). Proteins bind at the floor of the DNA grooves, using specific binding: hydrogen bounds, and non specific binding: van der Waals interactions, generalized electrostatic interactions. Proteins recognize H-bond donnors, H-bond acceptors, metyl groups (hydrophobic), the later being exclusively in the major groove; there are 4 possible patterns of recognition with the major groove, and only 2 with the minor groove (see iconography).

Some proteins bind DNA in its major groove, some other in the minor groove, and some need to bind to both.

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Notes: - The 2 strands are called "plus" and "minus" strands, or "direct" and "reverse" strands. At a given location where one strand (any of the two) bears coding sequences, it is unlikely (but not impossible) that the other strand also bears coding sequences. - DNA is ionized in vivo and behave like a polyanion. The double helix as described above is the "B" form of the DNA; it is the form the most commonly found in vivo, but other forms exist in vivo (see below) or in vitro. The "A" form resemble B-DNA but it is less hydrated than B-DNA, "A" form is not found in vivo.

II.3 Non-B DNA

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -119- DNA is a molecule which moves, fidgets, does gymnastics, dances. The structures below cited are being proved to have funtional roles; on the other hand, they may favour DNA breaks and further deletions, amplification, recombination, and mutations.

Glossary: Palindromes: these are words or sentences that read the same backwards and forwards (e.g. "DNA LAND"). DNA uses to play with palindromes: see below).

II.3.1 Z-DNA - Z form is a levogyre (left handed) double helix with a zig-zag conformation of the backbone (less smooth than B-DNA). Only one groove is observed, resembling the minor groove, the base pairs (which form the major groove -close to the axis- in B-DNA) being set off to the side, at the outer surface, far from the axis. Phosphates are closer together than in B-DNA. Z-DNA cannot form nucleosomes. - A high G-C content favours Z conformation. Cytosine methylation, and molecules which can be present in vivo such as spermine and spermidine can stabilize Z conformation. - DNA sequences can flip from a B form to a Z form and vice versa: Z-DNA is a transient form in vivo.

- Z-DNA formation occurs during transcription of genes, at transription start sites near promoters of actively transcribed genes. During transcription, the movement of RNA polymerase induces negative supercoiling upstream and positive supercoiling downstream the site of transcription The negative supercoiling upstream favours Z-DNA formation; a Z-DNA function would be to absorb negative supercoiling. At the end of transcription, topoisomerase relaxes DNA back to B conformation. - Certain proteins bind to Z-DNA, in particular double-stranded RNA adenosine deaminase (ADAR1), a Z-DNA binding nuclear-RNA-editing enzyme; this enzyme converts adenine to inosine in the pre- mRNA. Following, ribosomes will interpret inosine as guanine, and the protein coded with this epigenetic modification will be different (see chpater on Epigenetics). Notes: - Z-DNA antibodies are found in lupus erythematosus and other autoimmune diseases. - Double stranded RNA (dsRNA) can adopt a Z conformation.

II.3.2 cruciform DNA and hairpin DNA - Holliday junctions (formed during recombination) are cruciform structures. Inverted (or mirror) repeats (palindromes) of polypurine/polypyrimidine DNA stretches can also form cruciform or hairpin structures through intra-strand pairing. - Palindromic AT-rich repeats are found at the breakpoints of the t(11;22)(q23;q11), the only known recurrent constitutional reciprocal translocation. - Nucleases bind and cleave holliday junctions after recombination. Other well known proteins such as HMG proteins and MLL (for further reading, see: MLL) can also bind cruciform DNA.

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II.3.3 H-DNA or triplex DNA - Inverted repeats (palindromes) of polypurine/polypyrimidine DNA stretches can form triplex structures (triple helix). A triple-stranded plus a single stranded DNA are formed. - H-DNA may have a role in functional regulation of gene expression as well as on RNAs (e.g. repression of transcription).

II.3.4 G4-DNA - G4 DNA or quadruplex DNA: folding of double stranded GC-rich sequence onto itself forming Hoogsteen base pairing between 4 guanines ("G4"), a highly stable structure. Often found near promotors of genes and at the telomeres. - Role in meiosis and recombination; may be regulatory elements. - RecQ family helicases are able to unwind G4 DNA (e.g. BLM, the gene mutated in Bloom syndrome (for further reading, see: Bloom syndrome)).

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Atlas Genet Cytogenet Oncol Haematol 2007; 1 -122- III Quaternary structure of the molecule - Chromatin DNA is associated with proteins: histones and non histone proteins, to form the chromatin. DNA as a whole is acidic (negatively charged) and binds to basic (positively charged) proteins called histones: see chapter Chromatin There is 3 x 10 9 nucleotide pairs in the human haploid genome representing about 30 000 genes dispersed over 23 chromosomes for a haploid set.

IV Various

IV.1 DNA and mitochondria See also Mitochondrial inheritance - DNA is found in the nucleus of the cell, but a small amount is also present in the mitochondria. - Mitochondrias would originate from archeobacterias which became endosymbiotic to eukaryotic cells. - Their genetic code is different from the so-called "universal" code (UGA, AUA, AGA, AGG: respectively STOP, Ile, Arg, Arg in the universal code, and Trp, Met, STOP, STOP in the mitochondria of mammals, and other meanings in mitochondria of other spieces). - The number of DNA copies in one given mitochondria is variable. - Mitochondrial DNA is circular, with a heavy and a light chains, has no introns, not any non-coding sequence. - Genes from the mitochondria code for proteins involved in electron transport, ribosomic RNAs (rRNAs), and transfer RNAs (tRNAs). - Each DNA strand is transcribed, then cut into the mRNAs, but also into rRNAs and tRNAs. Note: the mitochondria also use proteins imported from the cytoplasm of the cell (and coded by the nucleus); so far, proteins from the mitochondria are not exported into the cytoplasm except in case of apoptosis.

IV.2 DNA denaturation: The double helix undergoes unwinding in vitro with heat, extremes ph, and other conditions (urea, ...). A melting point can be calculated; it is characteristic of the A/T versus G/C proportion of the specimen studied, due to the fact that there is only 2 hydrogen bounds in A/T, and 3 in G/C, a more stable binding. Upon denaturation, the physical properties of the DNA change; e.g. hyperchromic effect: light absorption at 260 nm is higher with denatured DNA than with double standed DNA. Light absorption also varies according to the A/T vs G/C proportion: it is higher in A/T rich specimens than in G/C rich ones. DNA denaturation is to be known, because: 1- it allows to measure A/T vs G/C content; 2- it is the basis of hybridization techniques (in situ hybridization, blots, see Methods in Genetics).

Contributor(s) Written 09-2006 Jean-Loup Huret Citation This paper should be referenced as such : Huret JL . DNA: molecular structure. Atlas Genet Cytogenet Oncol Haematol. September 2006 . URL : http://AtlasGeneticsOncology.org/Educ/DNAEngID30001ES.html

Atlas Genet Cytogenet Oncol Haematol 2007; 1 -123-