Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 9, Number 4, Oct-Dec 2005 Previous Issue / Next Issue Genes ETV6 (ETS variant 6 (TEL oncogene)) (12p13.1) - updated. Stevan Knezevich. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 520-528. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ETV6ID38.html FLT3 (FMS-like tyrosine kinase 3) (13q12.2) - updated. Susanne Schnittger. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 529-536. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/FLT3ID144.html NDRG2 (NDRG family member 2) (14q11.2). Libo Yao, Lifeng Wang, Jiang Zhang, Na Liu. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 537-543. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/NDRG2ID41513ch14q11.html POU6F2 (POU domain, class 6, transcription factor 2) (7p14.1). Daniela Perotti, Luisa Doneda, Paolo Radice. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 544-549. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/POU6F2ID42963ch7p14.html WFDC1 (WAP four- core domain 1) (16q24.1) - updated. Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 550-555. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/WFDC1ID424.html BUB1B (BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)) (15q15). Sandra Hanks, Nazneen Rahman. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 556-560. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 I URL : http://AtlasGeneticsOncology.org/Genes/BUB1BID854ch15q15.html E2F3 (E2F transcription factor 3) (6p22.3). Roderick AF MacLeod, Stefan Nagel. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 561-574. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/E2F3ID40384ch6p22.html MSH2 (human mutS homolog 2) (2p22-p21). Enric Domingo, Sim Schwartz Jr. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 575-580. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MSH2ID340ch2p22.html PAX2 (Paired box gene 2) (10q24). Ewan Robson, Jess Whall, Michael Eccles. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 581-586. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PAX2ID41642ch10q24.html PDGFRB (platelet-derived growth factor receptor, beta polypeptide) (5q31-q32). José Luis Vizmanos. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 587-597. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PDGFRBID21ch5q32.html TBX2 (T-box 2) (17q23). Ayse Elif Erson, Elizabeth M. Petty. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 598-607. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TBX2ID42485ch17q23.html TMPRSS3 (transmembrane protease, serine 3) (21q22.3). Malte Buchholz, Thomas M Gress. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 608-613. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TMPRSS3ID42593ch21q22.html CIP29 (cytokine induced 29 kDa) (12q13). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 6140-616. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CIP29ID42967ch12q13.html LASP1 (LIM and SH3 protein) -(17q12-21) - updated. Sabine Strehl. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 617-622. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/Lasp1ID203.html MSI2 (musashi homolog 2 (drosophila)) (17q23.2). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 623-626. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MSI2ID42893ch17q23.html

Atlas Genet Cytogenet Oncol Haematol 2005; 4 II MTHFR (5,10-Methylenetetrahydrofolate reductase) (1p36.22). Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 627-634. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MTHFRID41448ch1p36.html PAX5 (paired box gene 5) (9p13) - updated. Sabine Strehl. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 635-640. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PAX5ID62.html PAX9 (Paired box gene 9) (14q12). Ewan Robson, Jess Whall, Michael Eccles. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 641-645. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PAX9ID41644ch14q12.html SET (SET translocation (myeloid leukemia-associated)) (9q34). Sabine Strehl. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 646-650. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SETID42272ch9q34.html TAL2 (T-cell acute lymphoblastic leukemia 2) (9q31). Katrina Vanura. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 651-655. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TAL2ID28ch9q31.html Leukaemias t(X;21)(p22;q22). Yanming Zhang, Janet D Rowley. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 656-658. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/tx21p22q22ID1377.html 12p rearrangements in CLL. Kavita S Reddy. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 659-660. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/rear12pCLLID2023.html t(3;14)(p14;q32). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 661-662. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0314p14q32ID1398.html t(9;14)(q34;q32). Kim De Keersmaecker, Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 663-664. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0914q34q32ID1399.html

Atlas Genet Cytogenet Oncol Haematol 2005; 4 III Solid Tumours Breast tumors: an overview - updated. Maria Luisa Carcangiu, Patrizia Casalini, Sylvie Ménard. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 665-677. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/breastID5018.html Pituitary Adenomas. Palma Finelli, Lidia Larizza. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 678-683. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/PituitAdenomID5051.html Cancer Prone Diseases Noonan syndrome. Marco Tartaglia, Bruce D Gelb. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 684-695. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/NoonanID10085.html Deep Insights Genomic Imprinting: Parental differentiation of the genome. J Keith Killian. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 696-714. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/GenomImprintID20032.html Case Reports Educational Items Neonatal Screening. Louis Dallaire, Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (4): 715-722. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Educ/NeonatID30056ES.html

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Atlas Genet Cytogenet Oncol Haematol 2005; 4 IV Atlas of Genetics and Cytogenetics in Oncology and Haematology

ETV6 (ETS variant gene 6 (TEL oncogene))

Identity Other TEL (translocation ets leukemia) names Hugo ETV6 Location 12p13.1

ETV6 (12p13.1) in normal cells: clone dJ852F10 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are wellcome: contact M Rocchi

DNA/RNA Description A member of the ets (E-26 transforming specific) family of transcription factors; the gene spans a region of 240 kb and consists of 8 exons. Transcription transcription is from telomere to centromere; there are three species of transcripts : 2400kb, 4300kb and 6200 kb; the gene encodes for a 1356 kb cDNA Protein

Description There are two alternative start codons that correspondingly result in two isoforms. Codon 1 gives rise to a 57kDa protein while codon 43 gives rise to a 53 kDa protein. It has been demonstrated that these two isoforms are phosphorylated. ETV6 shares homology at the 5' and 3' ends with other ets family members, namely the helix-loop-helix (HLH) and ETS domains, respectively. HLH domain is encoded by exons 3 and 4 and has also been referred to as the pointed or sterile alpha motif (SAM) domain. It is responsible for hetero- and homodimerization with other ETV6 and possibly other ets family members. The ETS domain is encoded by exons 6 through 8 and is responsible for

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -520- sequence specific DNA-binding. It is positively charged, allowing it to bind to purine rich segments of DNA. A central domain also exists that is involved in the recruitment of a repression complex including NCOR2 and SIN3. Expression Expression arrays and Northern analysis have shown ubiquitous expression with greater expression in bone marrow, spleen and thymus. Localisation Immunofluorescence has shown a nuclear localization Function Acts as a transcriptional regulator; important in vitelline angiogenesis and in bone marrow hematopoiesis. Mutations Note ETV6 is implicated in leukemia, myelodysplastic syndromes and sarcoma Implicated in

Entity t(1;12)(p36;p13) --> MDS2/ETV6 Disease One CML with t(9;22) and one refractory anemia with excess of blasts in transformation.

Entity t(1;12)(q21;p13) --> ARNT/ETV6 Disease AML-M2

Entity t(1;12)(q25;p13) --> ABL2/ETV6 Disease AML-M3, -M4, T-cell ALL

Entity t(3;12)(q26;p13) --> EVI1/ETV6 Disease CML

Entity t(4;12) (p16;p13) --> FGFR3/ETV6 Disease Peripheral T-cell lymphoma

Entity t(4;12)(q11;p13) --> CHIC2 (BTL)/ETV6 Disease AML (FAB type M0)

Entity t(5;12)(q31;p13) --> FACL6/ETV6 Disease Acute myelogenous leukemia with eosinophilia

Entity t(5;12)(q33;p13) --> PDGFRb/ETV6 Disease CMML

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -521- Entity t(6;12)(q23;p13) --> STL/ETV6 Disease B-cell ALL

Entity t(7;12)(q36;p13) --> HLXB9/ETV6 Disease AML (FAB type M1)

Entity dic(9;12)(p13;p13) --> PAX5/ETV6 Disease ALL

Entity t(9;12) (p24;p13) --> JAK2/ETV6 Disease Leukemias

Entity t(9;12)(q22;p13) --> SYK/ETV6 Disease MDS

Entity t(9;12)(q34;p13) --> ABL1/ETV6 Disease Acute myeloblastic leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL)

Entity t(10;12)(q24;p13) --> ?/ETV6 Disease CMML

Entity t(12;13)(p13;q12) --> ETV6/ CDX2 Disease CML in transformation, myelodysplastic syndrome (MDS), acute non lymphocytic leukemai (ANLL), B and T- ALL

Entity t(12;13)(p13;q14) --> ETV6/ TTL Disease ALL

Entity t(12;15)(p13;q25) --> ETV6 / NTRK3 Disease Congenital Fibrosarcoma, Congenital Mesoblastic Nephroma (cellular and mixed variants), Secretory Ductal Carcinoma of Breast, AML.

Entity t(12;17)(p13;p12-p13) --> ETV6 / PER1 Disease AML

Entity t(12;21)(p13;q22) --> ETV6 / AML1 Disease Childhood B-cell (ALL)

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -522- Entity t(12;22)(p13;q11) --> ETV6 / MN1 Disease Refractory Anemia with Excess Blasts

Breakpoints

External links Nomenclature Hugo ETV6 GDB ETV6 Entrez_Gene ETV6 2120 ets variant gene 6 (TEL oncogene) Cards Atlas ETV6ID38 GeneCards ETV6 Ensembl ETV6 CancerGene ETV6 Genatlas ETV6 GeneLynx ETV6 eGenome ETV6 euGene 2120 Genomic and cartography ETV6 - 12p13.1 chr12:11694055-11939590 + 12p13.2 (hg17- GoldenPath May_2004) Ensembl ETV6 - 12p13.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -523- OMIM Disease map [OMIM] HomoloGene ETV6 Gene and transcription

Genbank U45432 [ SRS ] U45432 [ ]

Genbank U61375 [ SRS ] U61375 [ ENTREZ ]

Genbank U63312 [ SRS ] U63312 [ ENTREZ ]

Genbank U63313 [ SRS ] U63313 [ ENTREZ ]

Genbank U81830 [ SRS ] U81830 [ ENTREZ ]

RefSeq NM_001987 [ SRS ] NM_001987 [ ENTREZ ]

RefSeq NT_086793 [ SRS ] NT_086793 [ ENTREZ ] AceView ETV6 AceView - NCBI TRASER ETV6 Traser - Stanford

Unigene Hs.504765 [ SRS ] Hs.504765 [ NCBI ] HS504765 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P41212 [ SRS] P41212 [ EXPASY ] P41212 [ 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 [ SRS ] IPR002341 HSF_ETS [ EBI ]

Interpro IPR010993 SAM_homology [ SRS ] IPR010993 SAM_homology [ EBI ]

Interpro IPR003118 SAM_PNT [ SRS ] IPR003118 SAM_PNT [ EBI ]

IPR009058 Wing_hlx_DNA_bnd [ SRS ] IPR009058 Interpro Wing_hlx_DNA_bnd [ EBI ] CluSTr P41212

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 P41212

PDB 1JI7 [ SRS ] 1JI7 [ PdbSum ], 1JI7 [ IMB ]

PDB 1LKY [ SRS ] 1LKY [ PdbSum ], 1LKY [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 600618 [ map ] GENECLINICS 600618

SNP ETV6 [dbSNP-NCBI]

SNP NM_001987 [SNP-NCI]

SNP ETV6 [GeneSNPs - Utah] ETV6 [SNP - CSHL] ETV6] [HGBASE - SRS]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -524- General knowledge Family ETV6 [UCSC Family Browser] Browser SOURCE NM_001987 SMD Hs.504765 SAGE Hs.504765 Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity PubGene ETV6 Other databases Probes Probe ETV6 (TEL) (12p13.1) in normal cells (Bari) Probe ETV6 Related clones (RZPD - Berlin) PubMed PubMed 37 Pubmed reference(s) in LocusLink Bibliography t(5; 12)(q31; p12). A clinical entity with features of both myeloid leukemia and chronic myelomonocytic leukemia. Wessels JW, Fibbe WE, van der Keur D, Landegent JE, van der Plas DC, den Ottolander GJ, Roozendaal KJ, Beverstock GC. Cancer Genet Cytogenet 1993; 65: 7-11. Medline 8431918

Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P, Morgan E, Raimondi SC, Rowley JD, Gilliland DG. Proc Nat Acad Sci 1995; 92: 4917-4921. Medline 7761424

Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P. Blood 1997; 90(7): 2535-2540. Medline 9326218

Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -525- Cancer Res 1997; 57(4): 564-569. Medline 9044825

A t(6;12)(q23;p13) results in the fusion of ETV6 to a novel gene, STL, in a B-cell ALL cell line. Suto Y, Sato Y, Smith SD, Rowley JD, Bohlander SK. Genes Cancer 1997; 18(4): 254-268. Medline 9087565

Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Chase A, Reiter A, Burci L, Cazzaniga G, Biondi A, Pickard J, Roberts IA, Goldman JM, Cross NC. Blood 1999; 93(3): 1025-1031. Medline 9920852

Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13). Cools J, Bilhou-Nabera C, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P. Blood 1999; 94(5): 1820-1824. Medline 10477709

Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K. Genes Chromosomes Cancer 1999; 26: 192-202. Medline 10502316

The MN1-TEL fusion protein, encoded by the translocation (12;22)(p13;q11) in myeloid leukemia, is a transcription factor with transforming activity. Buijs A, van Rompaey L, Molijn AC, Davis JN, Vertegaal AC, Potter MD, Adams C, van Baal S, Zwarthoff EC, Roussel MF, Grosveld GC. Mol Cell Biol 2000; 20(24): 9281-9293. Medline 11094079

A new ETV6/TEL partner gene, ARG (ABL-related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. Iijima Y, Ito T, Oikawa T, Eguchi M, Eguchi-Ishimae M, Kamada N, Kishi K, Asano S, Sakaki Y, Sato Y. Blood 2000; 95(6): 2126-2131. Medline 10706884

The t(1;12)(q21;p13) translocation of human acute myeloblastic leukemia results in a TEL-ARNT fusion.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -526- Salomon-Nguyen F, Della-Valle V, Mauchauffe M, Busson-Le Coniat M, Ghysdael J, Berger R, Bernard OA. Proc Natl Acad Sci USA 2000; 97(12): 6757-6762. Medline 10829078

Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Beverloo HB, Panagopoulos I, Isaksson M, van Wering E, van Drunen E, de Klein A, Johansson B, Slater R. Cancer Res 2001; 61(14): 5374-5377. Medline 11454678

The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case. Cazzaniga G, Daniotti M, Tosi S, Giudici G, Aloisi A, Pogliani E, Kearney L, Biondi A. Cancer Res 2001; 61(12): 4666-4670. Medline 11406533

Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. Yagasaki F, Wakao D, Yokoyama Y, Uchida Y, Murohashi I, Kayano H, Taniwaki M, Matsuda A, Bessho M. Cancer Res 2001; 61(23): 8371-8374. Medline 11731410

Chronic myelocytic leukemia with eosinophilia, t(9;12)(q34;p13), and ETV6-ABL gene rearrangement: case report and review of the literature. Keung YK, Beaty M, Steward W, Jackle B, Pettnati M. Cancer Genet Cytogenet 2002; 138 (2): 139-142. Medline 12505259

A novel gene, MDS2, is fused to ETV6/TEL in a t(1;12)(p36.1;p13) in a patient with myelodysplastic syndrome. Odero MD, Vizmanos JL, Roman JP, Lahortiga I, Panizo C, Calasanz MJ, Zeleznik- Le NJ, Rowley JD, Novo FJ. Genes Chromosomes Cancer 2002; 35(1): 11-19. Medline 12203785

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

A novel cryptic translocation t(12;17)(p13;p12-p13) in a secondary acute

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -527- myeloid leukemia results in a fusion of the ETV6 gene and the antisense strand of the PER1 gene. Penas EM, Cools J, Algenstaedt P, Hinz K, Seeger D, Schafhausen P, Schilling G, Marynen P, Hossfeld DK, Dierlamm J. Genes Chromosomes Cancer 2003; 37(1): 79-83. Medline 12661008

Identification of a novel fusion gene, TTL, fused to ETV6 in acute lymphoblastic leukemia with t(12;13)(p13;q14), and its implication in leukemogenesis. Qiao Y, Ogawa S, Hangaishi A, Yuji K, Izutsu K, Kunisato A, Imai Y, Wang L, Hosoya N, Nannya Y, Sato Y, Maki K, Mitani K, Hirai H. Leukemia 2003; 17(6): 1112-1120. Medline 12764377

Pediatric malignancies provide unique cancer therapy targets. Uren A, Toretsky JA. Curr Opin Pediatr 2005; 17(1): 14-19. Medline 15659957

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- Serge Pierrick Romana 1999 Updated 06- Stevan Knezevich 2005 Citation This paper should be referenced as such : Romana S . ETV6 (ETS variant gene 6 (TEL oncogene)). Atlas Genet Cytogenet Oncol Haematol. December 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ETV6ID38.html Knezevich S . ETV6 (ETS variant gene 6 (TEL oncogene)). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ETV6ID38.html

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Atlas Genet Cytogenet Oncol Haematol 2005; 4 -528-

Atlas of Genetics and Cytogenetics in Oncology and Haematology

FLT3 (FMS-like tyrosine kinase 3)

Identity Other CD135 names FLK2 (Fetal liver kinase 2) STK1 (Stem cell kinase 1) Hugo FLT3 Location 13q12.2 DNA/RNA Description the FLT3 gene contains 24 exons and spans 96,982 bases (start:27,475,753 bp to end 27,572,735 from 13pter) oriented at the minus strand. Transcription 3.7 kb; 2979 bp open reading frame Protein

Description Size: 993 amino acids; 112804 Da; FLT3 is a class III receptor tyrosine kinase (RTK) structurally related to the receptors for platelet derived growth factor (PDGF), colony stimulating factor 1 (CSF1), and KIT ligand (KL).; these RTK contain five immunoglobulin-like domains in the extracellular region and an intracelular tyrosine kinase domain splitted in two by a specific hydrophilic insertion (kinase insert); immunoprecipitation of the human FLT3 protein results in the appearance of a minor band of Mr 130 000 and a major band of Mr 155 000/160 000; the high-molecular-weight band corresponds to the mature, N-glycosylated form, and the low- molecular-weight band to the immature, high mannose-containing form; N-linked glycosylations account for 50 000 daltons. Expression FLT3 expression was described on bone marrow CD34-positive cells, corresponding to multipotential, myeloid and B-lymphoid progenitor cells, and on monocytic cells; FLT3 expression is restricted to cells of the fetal liver expressing high levels of CD34; in addition, the FLT3 protein is expressed on blast cells from most ANLL and B-ALL. Localisation Subcellular location: Type I membrane protein. 3D structure: PDB id 1RJB (3D). Function FLT3 receptor function can be defined by the activity of its ligand (FL); FL is an early acting factor and supports the survival, proliferation and

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -529- differentiation of primitive hemopoietic progenitor cells. Ligand binding to FLT3 promotes receptor dimerization and subsequent signalling through posphorylation of multiple cytoplasmatic proteins, including SHC, SHP-2, SHIP, Cbl, Cbl-b, Gab1 and Gab2, as well as the activation of several downstream signalling pathways, such as the Ras/Raf/MAPK and PI3 kinase cascades. Function: Receptor for the FL cytokine. Has a tyrosine-protein kinase activity. Catalytic activity: ATP + a protein tyrosine = ADP + protein tyrosine phosphate. Similarity: Belongs to the Tyr protein kinase family. CSF-1/PDGF receptor subfamily. Contains 1 immunoglobulin-like C2-type domain. Homology Other tyrosine kinases: KIT, PDGFRA, PDGFRB, VEGFR Mutations Somatic Mutations in the FLT3 gene are the most frequent genetic aberration that have been described in acute myeloid leukemia. With 20-25% length mutations in the juxtamembrane domain are the most frequent, followed by 7-8% mutations in the second tyrosine kinase kinase domain, mostly point mutations in codon 835 or deletions of codon 836. Also point mutations in the juxta membrane domain have been described and the number of new mutations all over the total gene is still growing. Implicated in Entity FLT3-length mutation (FLT3-LM) Disease Internal tandem duplications and/or insertions and, rarely, deletions in the FLT3-gene are implicated in 20-25% of all acute myeloid leukemias (AML). It was also described to be involved in 5-10 % myelodysplastic syndromes (MDS) refractory anaemia with excess of blasts (RAEB 1 and RAEB 2) and rare cases with acute lymphoblastic leukemia (ALL) The duplicated sequence belongs to exon 11 but sometimes involves intron 11 and exon 12. The most frequently used nomenclature is FLT3-ITD (internal tandem duplication). Because of the very heterogenous molecular structure the term FLT3-LM (length mutation) seems to be more adequate. Prognosis An unfavourable impact on prognosis especially a high relapse rate of the FLT3-LM has been shown by many study groups. Patients with loss of the wildtype allele have an even worse prognosis than the mutated with retention of the wildtype allele. Perspective : It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients. Cytogenetics FLT3-LM are highly correlated with a) normal karyotype, b) t(15;17)(q25;q21) c) CYTOGENETICS Perspective: It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients. Oncogenesis This mutation leads to constitutive ligand independent

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -530- autophosphorylation of the receptor. The FLT3-LM vary in size and position in a nearly patient specific manner. Overall the aberrant structure of the juxtamembrane domain disrupts a negative regulatory domain, which leads to the constitutive receptor activation. Several Groups have reported qualitative differences in the intracellular signals provided by wild type and mutated receptors.Mutated receptor weakly works through MAP kinase and Akt but instead through strong and constitutively activated STAT5.

Entity FLT3 Tyrosine Kinase Domain Mutation (FLT3-TKD) Disease In the second tyrosine kinase domain point mutations and small deletions mostly of codons 835 and 836, respectively, can be found in 7-8% of all AML. Prognosis No independent impact on prognosis shown yet. Cytogenetics In contrast to the FLT3-LM they do not seem to be specifically correlated to a certain AML type. Oncogenesis These mutations also lead to constitutive autoactivation of the receptor. It has been suggested that TKD mutation may both trigger the activation loop and stabilize it in the active state.

External links Nomenclature Hugo FLT3 GDB FLT3 Entrez_Gene FLT3 2322 fms-related tyrosine kinase 3 Cards Atlas FLT3ID144 GeneCards FLT3 Ensembl FLT3 CancerGene FLT3 Genatlas FLT3 GeneLynx FLT3 eGenome FLT3 euGene 2322 Genomic and cartography FLT3 - 13q12.2 chr13:27475753-27572703 - 13q12.2 (hg17- GoldenPath May_2004) Ensembl FLT3 - 13q12.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene FLT3

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -531- Gene and transcription

Genbank AL445262 [ SRS ] AL445262 [ ENTREZ ]

Genbank AL591024 [ SRS ] AL591024 [ ENTREZ ]

Genbank L36162 [ SRS ] L36162 [ ENTREZ ]

Genbank U02687 [ SRS ] U02687 [ ENTREZ ]

Genbank Z26652 [ SRS ] Z26652 [ ENTREZ ]

RefSeq NM_004119 [ SRS ] NM_004119 [ ENTREZ ]

RefSeq NT_086801 [ SRS ] NT_086801 [ ENTREZ ] AceView FLT3 AceView - NCBI TRASER FLT3 Traser - Stanford

Unigene Hs.507590 [ SRS ] Hs.507590 [ NCBI ] HS507590 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P36888 [ SRS] P36888 [ EXPASY ] P36888 [ INTERPRO ]

Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 Prosite PROTEIN_KINASE_TYR [ Expasy ]

PS00240 RECEPTOR_TYR_KIN_III [ SRS ] PS00240 Prosite RECEPTOR_TYR_KIN_III [ Expasy ]

Interpro IPR003599 Ig [ SRS ] IPR003599 Ig [ EBI ]

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

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ]

Interpro IPR001824 RecepttyrkinsIII [ SRS ] IPR001824 RecepttyrkinsIII [ EBI ]

Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]

Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ] CluSTr P36888

Pfam PF00047 ig [ SRS ] PF00047 ig [ Sanger ] pfam00047 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00409 IG [EMBL]

Smart SM00219 TyrKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom P36888 FLT3_HUMAN [ Domain structure ] P36888 FLT3_HUMAN [ sequences sharing at least 1 domain ] Blocks P36888

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

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -532- Polymorphism : SNP, mutations, diseases OMIM 136351 [ map ] GENECLINICS 136351

SNP FLT3 [dbSNP-NCBI]

SNP NM_004119 [SNP-NCI]

SNP FLT3 [GeneSNPs - Utah] FLT3 [SNP - CSHL] FLT3] [HGBASE - SRS] General knowledge Family FLT3 [UCSC Family Browser] Browser SOURCE NM_004119 SMD Hs.507590 SAGE Hs.507590

2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG Enzyme ] 2.7.1.112 [ WIT ] Amigo function|ATP binding Amigo component|integral to plasma membrane Amigo process|positive regulation of cell proliferation Amigo process|protein phosphorylation Amigo function|receptor activity Amigo function|transferase activity process|transmembrane receptor protein tyrosine kinase signaling Amigo pathway Amigo function|vascular endothelial growth factor receptor activity BIOCARTA Erythrocyte Differentiation Pathway PubGene FLT3 Other databases Other Somatic mutation (COSMIC-CGP-Sanger) database Probes Probe FLT3 Related clones (RZPD - Berlin) PubMed PubMed 42 Pubmed reference(s) in LocusLink Bibliography A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell- enriched populations. Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR Cell 1991 Jun 28;65(7):1143-52 Medline 91292518

Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -533- PDGFR/CSF1R family. Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D Oncogene 1991 Sep;6(9):1641-50 Medline 92019834

Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Birg F, Courcoul M, Rosnet O, Bardin F, Pebusque MJ, Marchetto S, Tabilio A, Mannoni P, Birnbaum D Blood 1992 Nov 15;80(10):2584-93 Medline 93043306

Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Lyman SD, James L, Vanden Bos T, de Vries P, Brasel K, Gliniak B, Hollingsworth LT, Picha KS, McKenna HJ, Splett RR, et al Cell 1993 Dec 17;75(6):1157-67 Medline 94084791

Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Rosnet O, Schiff C, Pebusque MJ, Marchetto S, Tonnelle C, Toiron Y, Birg F, Birnbaum D Blood 1993 Aug 15;82(4):1110-9 Medline 93357464

Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J, et al Nature 1994 Apr 14;368(6472):643-8 Medline 94195428

Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells. Zeigler FC, Bennett BD, Jordan CT, Spencer SD, Baumhueter S, Carroll KJ, Hooley J, Bauer K, Matthews W Blood 1994 Oct 15;84(8):2422-30 Medline 95002959

Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR Immunity 1995 Jul;3(1):147-61 Medline 95346505

Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -534- normal and malignant hematopoietic cells. Rosnet O, Buhring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, Arnoulet C, Chabannon C, Kanz L, Hannum C, Birnbaum D Leukemia 1996 Feb;10(2):238-48 Medline 96200134

Flt3 ligand induces tumor regression and antitumor immune responses in vivo. Lynch DH, Andreasen A, Maraskovsky E, Whitmore J, Miller RE, Schuh JC Nat Med 1997 Jun;3(6):625-31 Medline 97319585

Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase. Rappold I, Ziegler BL, Kohler I, Marchetto S, Rosnet O, Birnbaum D, Simmons PJ, Zannettino AC, Hill B, Neu S, Knapp W, Alitalo R, Alitalo K, Ullrich A, Kanz L, Buhring HJ Blood 1997 Jul 1;90(1):111-25 Medline 97351069 c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Lyman SD, Jacobsen SE Blood 1998 Feb 15;91(4):1101-34 Medline 98122762

Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R Blood 1999 May 1;93(9):3074-80 Medline 99233671

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Olivier Rosnet 1999 Updated 06- Susanne Schnittger 2005 Citation This paper should be referenced as such : Rosnet O . FLT3 (FMS-like tyrosine kinase 3). Atlas Genet Cytogenet Oncol

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -535- Haematol. May 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FLT3ID144.html Schnittger S . FLT3 (FMS-like tyrosine kinase 3). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FLT3ID144.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -536- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NDRG2 (NDRG family member 2)

Identity Other SYLD names KIAA1248 DKFZp781G1938 HGNC:14460 Hugo NDRG2 Location 14q11.2 DNA/RNA Description The gene encompasses 9013 bp of DNA; 16 or 17 exons (the first and second are non-coding). Transcription Eight splicing mRNAs are found. 2142 bp mRNA; CDS: 174-1289bp ;1113 bp open reading frame 2100 bp mRNA; CDS: 174-1247bp ;1071 bp open reading frame 2033 bp mRNA; CDS: 107-1180bp ;1071 bp open reading frame 2075 bp mRNA; CDS: 107-1222bp ;1113 bp open reading frame 2010 bp mRNA; CDS: 84-1157bp ;1071 bp open reading frame 2052 bp mRNA; CDS: 84-1199bp ;1113 bp open reading frame 2119 bp mRNA; CDS: 151-1266bp ;1113 bp open reading frame 2077 bp mRNA; CDS: 151-1224bp ;1071 bp open reading frame. Protein

Description 357 amino acids ; another isoform has 371 amino acids ; 40 or 43 kDa ; Thr348 is a Akt phosphorylation site, Ser332 is a PKC teta- phosphorylation site. NDRG2 has the alpha/beta hydrolase fold motif. Expression Widely expressed, especially in brain, heart, skeletal muscle and kidney. Localisation cytosol Function A candidate . Ndrg2 expressed much higher in normal tissues than the tumors (brain, liver, pancreas tissues etc) . Overexpression of ndrg2 can inhibit the proliferation of glioblastoma U373 and U138 cells. NDRG2 upregulation is associated with disease pathogenesis in the human brain. Ndrg2 is expressed during the differentiation of DCs, and the expression is differentially regulated by maturation-inducing stimuli such as LPS and CD40. The expression of ndrg2 in rat frontal cortex was decreased by chronic antidepressant

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -537- treatment. Homology At the amino acid level, human NDRG2 shows 57% identical to NDRG1 and NDRG3, 65% identical to NDRG4-B, 63% identical to NDRG4-Bvar and 61% identical to NDRG4-H respectively. Also human NDRG2 shows 92% identical to mouse NDRG2. Implicated in Entity Alzheimer's disease Disease Alzheimer's disease is the most common cause of dementia. Dementia is a collective name for progressive degenerative brain syndromes, which affect memory, thinking, behavior and emotion. Symptoms may include: 1) lose of memory ; 2) difficulty in finding the right words or understanding what people are saying; 3) difficulty in performing previously routine tasks; 4) personality and mood changes. Prognosis The probable outcome is poor. The disorder is usually not acute, but progresses steadily. Total disability is common. Death normally occurs within 15 years, usually from an infection or a failure of other body systems. The duration of illness, from onset of symptoms to death, averages 8 to 10 years Hybrid/Mutated NDRG2 is upregulated at both the RNA and protein levels in AD Gene brains. Expression of NDRG2 in affected brains was revealed in : (1) cortical pyramidal neurons, (2) senile plaques and (3) cellular processes of dystrophic neurons. NDRG2 upregulation is associated with disease pathogenesis in the human brain

Entity Liver cancers Disease Liver cancers are primary liver tumors (hepatoma/hepatocellular carcinoma, bile duct cancer/cholangio-carcinoma) or metastatic liver tumor. Oncogenesis Compared with adjacent normal tissues, the expression levels of NDRG2 mRNA in liver cancer tissues reduced significantly, but the mutation in the whole coding region of NDRG2 was not found.

Entity Glioblastoma Disease Glioblastoma multiforme (GBM) is the most aggressive form of the primary brain tumors known collectively as gliomas. These tumors arise from the supporting, glial cells of the brain during childhood and in adults. These growths do not spread throughout the body like other forms of cancer, but cause symptoms by invading the brain.NDRG2 gene was first found in this tissue by using subtraction cloning. Oncogenesis Ndrg2 is present at low levels in human GBM tissues and glioblastoma cell lines comparing with normal tissue and cells. Transient transfection exogenous NDRG2 gene will inhibits glioblastoma U373 and U138 cells proliferation.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -538-

Entity Gastric cancer Disease Gastric cancer is the result of cell changes in the lining of the stomach. The most common types of stomach cancer start in the glandular cells of the stomach lining and are known as adenocarcinomas. These are rare cancers that usually start from the cells of the muscle layer of the stomach. The most common type of sarcoma to affect the stomach is a leiomyosarcoma. Another type of sarcoma is a gastrointestinal stromal tumour (GIST). Oncogenesis Ndrg2 is present at low level in some stomach cancer tissue and cell lines.

External links Nomenclature Hugo NDRG2 GDB NDRG2 Entrez_Gene NDRG2 57447 NDRG family member 2 Cards Atlas NDRG2ID41513ch14q11 GeneCards NDRG2 Ensembl NDRG2 CancerGene NDRG2 Genatlas NDRG2 GeneLynx NDRG2 eGenome NDRG2 euGene 57447 Genomic and cartography NDRG2 - 14q11.2 chr14:20554763-20563775 - 14q11.2 (hg17- GoldenPath May_2004) Ensembl NDRG2 - 14q11.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NDRG2 Gene and transcription

Genbank AY028430 [ SRS ] AY028430 [ ENTREZ ]

Genbank AB033074 [ SRS ] AB033074 [ ENTREZ ]

Genbank AF087872 [ SRS ] AF087872 [ ENTREZ ]

Genbank AF159092 [ SRS ] AF159092 [ ENTREZ ]

Genbank AF304051 [ SRS ] AF304051 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -539- RefSeq NM_016250 [ SRS ] NM_016250 [ ENTREZ ]

RefSeq NM_201535 [ SRS ] NM_201535 [ ENTREZ ]

RefSeq NM_201536 [ SRS ] NM_201536 [ ENTREZ ]

RefSeq NM_201537 [ SRS ] NM_201537 [ ENTREZ ]

RefSeq NM_201538 [ SRS ] NM_201538 [ ENTREZ ]

RefSeq NM_201539 [ SRS ] NM_201539 [ ENTREZ ]

RefSeq NM_201540 [ SRS ] NM_201540 [ ENTREZ ]

RefSeq NM_201541 [ SRS ] NM_201541 [ ENTREZ ]

RefSeq NT_086806 [ SRS ] NT_086806 [ ENTREZ ] AceView NDRG2 AceView - NCBI TRASER NDRG2 Traser - Stanford

Unigene Hs.525205 [ SRS ] Hs.525205 [ NCBI ] HS525205 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9UN36 [ SRS] Q9UN36 [ EXPASY ] Q9UN36 [ INTERPRO ]

Interpro IPR004142 Ndr [ SRS ] IPR004142 Ndr [ EBI ] CluSTr Q9UN36

Pfam PF03096 Ndr [ SRS ] PF03096 Ndr [ Sanger ] pfam03096 [ NCBI-CDD ] Blocks Q9UN36 Polymorphism : SNP, mutations, diseases OMIM 605272 [ map ] GENECLINICS 605272

SNP NDRG2 [dbSNP-NCBI]

SNP NM_016250 [SNP-NCI]

SNP NM_201535 [SNP-NCI]

SNP NM_201536 [SNP-NCI]

SNP NM_201537 [SNP-NCI]

SNP NM_201538 [SNP-NCI]

SNP NM_201539 [SNP-NCI]

SNP NM_201540 [SNP-NCI]

SNP NM_201541 [SNP-NCI]

SNP NDRG2 [GeneSNPs - Utah] NDRG2 [SNP - CSHL] NDRG2] [HGBASE - SRS] General knowledge Family NDRG2 [UCSC Family Browser] Browser SOURCE NM_016250 SOURCE NM_201535 SOURCE NM_201536 SOURCE NM_201537

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -540- SOURCE NM_201538 SOURCE NM_201539 SOURCE NM_201540 SOURCE NM_201541 SMD Hs.525205 SAGE Hs.525205 Amigo process|cell differentiation Amigo process|cell differentiation Amigo component|cytosol Amigo function|molecular_function unknown PubGene NDRG2 Other databases Probes Probe NDRG2 Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in LocusLink Bibliography Embryonic lethality in mice homozygous for a targeted disruption of the N-myc gene. Charron J, Malynn BA, Goff SP, Alt FW. Genes Dev 1992; 6(12A): 2248-57. Medline 1459450

Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop. Stanton BR, Perkins AS, Parada LF. Genes Dev 1992; 6(12A): 2235-2247. Medline 1459449

Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis GRP78/BiP and novel genes. Kokame K, Kato H, Miyata T. J Biol Chem 1996; 271(47): 29659-65. Medline 8939898

A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms. van Belzen N, Dinjens WN, Trapman J, Bosman FT. Lab Invest 1997; 77(1): 85-92. Medline 9251681

Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -541- DNA damage. Kurdistani SK, Arizti P, Lee SW. Cancer Res 1998; 58(19): 4439-4444. Medline 9766676

Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc. Okuda T,Kondoh H. Biochem Biophys Res Commun 1999; 266(1): 208-15. Medline 10581191

N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant. Shimono A, Okuda T, Kondoh H. Mech Dev 1999; 83(1-2): 39-52. Medline 10381566

Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Zhou RH, Kokame K, Miyata T. Genomics 2001; 73(1): 86-97. Medline 11352569

Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family. Qu X, Zhai Y, He F. Mol Cell Biochem 2002; 229(1-2): 35-44. Medline 11936845

N-myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Deng Y, Yao L, Liu X. Int J Cancer 2003; 106(6): 984. Medline 12845671

NDRG2 expression and mutation in human liver and pancreatic cancers. Hu XL, Liu XP, Yao LB. World J Gastroenterol 2004; 10(23): 3518-3521. Medline 15526377

NDRG2: a novel Alzheimer's disease associated protein. Mitchelmore C, Buchmann-Moller S, Jensen NA. Neurobiol Dis 2004; 16(1): 48-58. Medline 15207261

REVIEW articles automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -542- Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Libo Yao, Lifeng Wang, Jiang Zhang, Na Liu 2005 Citation This paper should be referenced as such : Yao L, Wang L, Zhang J, Na Liu N . NDRG2 (NDRG family member 2). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NDRG2ID41513ch14q11.html

© Atlas of Genetics and Cytogenetics in Oncology and indexed on : Tue Aug 30 18:26:26 MEST Haematology 2005

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -543- Atlas of Genetics and Cytogenetics in Oncology and Haematology

POU6F2 (POU domain, class 6, transcription factor 2)

Identity Other RPF-1 (Retina-derived POU-domain factor-1) names Hugo POU6F2 Location 7p14.1 Cen-CDC2L5-RALA-POU6F2-VPS41-AMPH-Tel DNA/RNA Note POU6F2, previously named RPF-1 was isolated from a retina cDNA library

modified from http://genome.ucsc.edu/. Exons 1D to 10 of the gene are indicated by the vertical bars.

Description Thirteen exons, including 4 alternative exons 1, encompassing 458 Kb of genomic DNA (exons 1D to 10). Transcription Representative mRNA: U91935 2159 bases. Alternative splicings: four alternative exons 1; variable skipping of exon 6; variable skipping of both exons 8 and 9; +/- 36 aminoacids at the 5' end of exon 10. Protein

modified from: http://www.ebi.ac.uk/

Description POU6F2 is a member of a gene family whose products are characterized by the presence of a bipartite DNA-binding domain,

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -544- consisting of a POU-specific domain and a POU heterodomain, separated by a variable polylinker. Both subdomains contain helix-turn- helix motifs that directly associate with the two components of bipartite DNA-binding sites. In addition, the POU6F2 protein contains a poly- glutamine (poly-Q) domain. Glutamine repeats are evolutionary conserved domains that may act as polar zippers by joining proteins bound to separate DNA segments and thus regulating their activity. POU domain family members are transcriptional regulators, many of which show highly restricted patterns of expression and are known to control cell type-specific differentiation pathways. POU6F2 encodes a deduced 648-amino acid protein. potentially generates 24 distinct mRNA isoforms coding for proteins with different DNA-binding activity. The most abundant POU6F2 isoforms in human retina have an insertion of an evolutionarily conserved 36-amino acid peptide into the DNA recognition helix of the POU-specific domain. In vitro, the POU domain of POU6F2 lacking the insert binds to a consensus binding site for the product of another gene of the POU family, OCT1, whereas the alternatively spliced POU domain does not. Expression Immunohistochemical and ribonuclease protection assays showed that in adult mouse Pou6f2 is expressed within the central nervous system, where its expression is restricted to the medial habenula, to a dispersed population of neurons in the dorsal hypothalamus, and to subsets of ganglion and amacrine cells in the retina. In mouse embryo, Pou6f2 expression was detected during the earliest stages of retinal differentiation where it appears to be involved in the initial steps of amacrine and ganglion cell commitment. RT-PCR analysis of the mouse Pou6f2 gene revealed expression in kidney, adrenal gland, heart, stomach, muscle, and eye, but not in lung or skin, of mouse fetuses at embryonic day (E) 18, and in kidney, heart, muscle, spleen, and ovary, but not in lung, of adult mice. Localisation nuclear (presumptive). Function POU-domain family transcription factor (presumptive). Homology Other POU-domain family genes Mutations Note The POU6F2 gene is located within an interval on 7p14 where loss of heterozygosity (LOH) was detected in a fraction of Wilms tumors (WTs), a kidney malignancy of childhood characterized by highly heterogeneous genetic alterations. By sequencing the POU6F2 gene in 12 WTs showing LOH on chromosome 7p14, 2 germline mutations of possible pathogenic significance were identified. The finding of the expression of the POU6F2 mouse homolog in both fetal and adult kidney, together with the demonstration of mutations in WT patients, suggest that the gene is a tumor suppressor and is involved in hereditary predisposition to WT. Germinal In a patient with WT and LOH at chromosome 7p14, a germline 552G-T transversion in exon 5 of the POU6F2 gene, resulting in a gln184-to-his (Q184H) substitution in a glutamine repeat domain, was identified. The

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -545- patient showed loss of the constitutionally wildtype allele in tumor DNA. Neither the mother nor the father carried this mutation. Marker studies indicated that the deletion in tumor DNA was of maternal origin, suggesting that the identified base change most likely occurred as a de novo germline point mutation on the paternal chromosome. In a patient with WT showing LOH at chromosome 7p14, a germline C- to-G transversion in the untranslated portion of the alternatively spliced exon 1C of the POU6F2 gene was identified. The mutation was inherited from the unaffected mother. Implicated in Entity Wilms tumor, or nephroblastoma Prognosis good with treatment according to National Wilms Tumor Study Group (NWTSG) or International Society of Paediatric Oncology (SIOP) or Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)

External links Nomenclature Hugo POU6F2 GDB POU6F2 Entrez_Gene POU6F2 11281 POU domain, class 6, transcription factor 2 Cards GeneCards POU6F2 Ensembl POU6F2 Genatlas POU6F2 GeneLynx POU6F2 eGenome POU6F2 euGene 11281 Genomic and cartography POU6F2 - 7p14.1 chr7:38819648-39277630 + 7p14.1 (hg17- GoldenPath May_2004) Ensembl POU6F2 - 7p14.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene POU6F2 Gene and transcription

Genbank AC005483g [ SRS ] AC005483g [ ENTREZ ]

Genbank AC073345g [ SRS ] AC073345g [ ENTREZ ]

Genbank AC092174g [ SRS ] AC092174g [ ENTREZ ]

Genbank U91934g [ SRS ] U91934g [ ENTREZ ]

Genbank U91935m [ SRS ] U91935m [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -546- RefSeq NM_007252 [ SRS ] NM_007252 [ ENTREZ ]

RefSeq NT_086706 [ SRS ] NT_086706 [ ENTREZ ] AceView POU6F2 AceView - NCBI TRASER POU6F2 Traser - Stanford

Unigene Hs.137106 [ SRS ] Hs.137106 [ NCBI ] HS137106 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P78424 [ SRS] P78424 [ EXPASY ] P78424 [ INTERPRO ]

Prosite PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Expasy ]

Prosite PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Expasy ]

Prosite PS00035 POU_1 [ SRS ] PS00035 POU_1 [ Expasy ]

Prosite PS00465 POU_2 [ SRS ] PS00465 POU_2 [ Expasy ]

Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ] Interpro IPR010982 Lambda_like_DNA [ SRS ] IPR010982 Lambda_like_DNA [ EBI ]

Interpro IPR000327 POU [ SRS ] IPR000327 POU [ EBI ]

Interpro IPR007103 POU_homeo [ SRS ] IPR007103 POU_homeo [ EBI ] CluSTr P78424

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

PF00157 Pou SM00389 [ SRS ] PF00157 Pou SM00389 [ Sanger Pfam ] pfam00157 [ NCBI-CDD ]

Prodom PD000010 Homeobox[INRA-Toulouse] Prodom P78424 PO6F2_HUMAN [ Domain structure ] P78424 PO6F2_HUMAN [ sequences sharing at least 1 domain ]

Prodom PD000010[INRA-Toulouse] Prodom P78424 PO6F2_HUMAN [ Domain structure ] P78424 PO6F2_HUMAN [ sequences sharing at least 1 domain ] Blocks P78424 Polymorphism : SNP, mutations, diseases OMIM 609062 [ map ] GENECLINICS 609062

SNP POU6F2 [dbSNP-NCBI]

SNP NM_007252 [SNP-NCI]

SNP POU6F2 [GeneSNPs - Utah] POU6F2 [SNP - CSHL] POU6F2] [HGBASE - SRS] General knowledge Family POU6F2 [UCSC Family Browser] Browser SOURCE NM_007252

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -547- SMD Hs.137106 SAGE Hs.137106 Amigo process|central nervous system development Amigo process|ganglion mother cell fate determination Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity Amigo process|transcription from RNA polymerase II promoter Amigo process|visual perception PubGene POU6F2 Other databases Probes Probe POU6F2 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Retina-derived POU-domain factor-1: a complex POU-domain gene implicated in the development of retinal ganglion and amacrine cells. Zhou H, Yoshioka T, Nathans J. J Neurosci 1996 Apr 1; 16(7): 2261-2274. Medline 8601806

The virtuoso of versatility: POU proteins that flex to fit. Phillips K, Luisi B. J Mol Biol 2000 Oct 6; 302(5): 1023-1039. Review. Medline 11183772

Refinement within single yeast artificial chromosome clones of a minimal region commonly deleted on the short arm of chromosome 7 in Wilms tumours. Perotti D, Testi MA, Mondini P, Pilotti S, Green ED, Pession A, Sozzi G, Pierotti MA, Fossati-Bellani F, Radice P. Genes Chromosomes Cancer 2001 May; 31(1): 42-47. Medline 11284034

Germline mutations of the POU6F2 gene in Wilms tumors with loss of heterozygosity on chromosome 7p14. Perotti D, De Vecchi G, Testi MA, Lualdi E, Modena P, Mondini P, Ravagnani F, Collini P, Di Renzo F, Spreafico F, Terenziani M, Sozzi G, Fossati-Bellani F, Radice P. Hum Mutat 2004 Nov; 24(5): 400-407. Medline 15459955

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -548- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 06- Daniela Perotti, Luisa Doneda, Paolo Radice 2005 Citation This paper should be referenced as such : Perotti D, Doneda L, Radice P . POU6F2 (POU domain, class 6, transcription factor 2). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/POU6F2ID42963ch7p14.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -549- Atlas of Genetics and Cytogenetics in Oncology and Haematology

WFDC1 (WAP four-disulfide core domain 1)

Identity Other ps20 names Hugo WFDC1 Location 16q24.1 DNA/RNA Description The gene encompasses 35 kb of DNA; 7 exons. Transcription 1366 nucleotides mRNA; 660 bp open reading frame. Protein

Representation of the position of the conserved cysteines for the category of "four-disulfide core" domain and the location of the signature pattern for such a domain in the human WFDC1 amino acid sequence.

Description 220 amino acids; 24 kDa protein. Like rat ps20, human ps20 protein contains a WAP signature domain. Expression Widely expressed, absent in thymus. Function The rat homologue of ps20 was originally identified as a secreted growth inhibitor. These growth regulatory effects and the cell phenotypic properties in vitro, suggest that ps20 may function as a mediator of stromal-epithelial interactions and contribute to the maintenance of tissue homeostasis. The ps20 protein is assumed to function as a protease inhibitor. In vitro studies indicate that exogeneous addition of ps20 protein stimulates endothelial cell migration, and promotes angiogenesis and tumour growth in a xenograft model of prostate

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -550- cancer. Homology The human WFDC1 protein shares approximately 86% and 88% identity with the rat and mouse proteins, respectively. WFDC1 is related to a family of human proteins that also have homology with WAP. The WFDC1 gene organization presents similarities with that of the KAL gene, which extends on 210 kb of DNA, includes 14 exons and is the largest gene in the WAP signature domain family. Mutations Note Although WFDC1 was mapped to human chromosome 16q24, an area of frequent loss of heterozygosity (LOH) in prostate and hepatocellular carcinomas, no tumour-associated mutations were identified in the coding region of WFDC1 in these cancer types. Mutations in WFDC1 gene resulting in Gly9Asp, Pro211Ser and Lys217Arg substitutions have been found at low frequency in the stroma of breast carcinomas. One mutation resulting in a Pro167Ser substitution has been identified in the epithelium of breast carcinoma. Implicated in Disease Prostate cancer Oncogenesis WFDC1 is significantly down-regulated in prostate cancer making it a candidate tumour suppressor gene. However, WFDC1 seems predominantly expressed in the stroma of normal prostate. In tumors, decreased stromal WFDC1 expression has been associated with increased epithelial WFDC1 expression. This correlate with shorter recurrence-free survival times and may indicate progression to a more aggressive epithelial phenotype and an epithelial mesenchymal transition process.

External links Nomenclature Hugo WFDC1 GDB WFDC1 Entrez_Gene WFDC1 58189 WAP four-disulfide core domain 1 Cards Atlas WFDC1ID424 GeneCards WFDC1 Ensembl WFDC1 CancerGene WFDC1 Genatlas WFDC1 GeneLynx WFDC1 eGenome WFDC1 euGene 58189 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -551- WFDC1 - 16q24.1 chr16:82885902-82920950 + 16q24.1 (hg17- GoldenPath May_2004) Ensembl WFDC1 - 16q24.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene WFDC1 Gene and transcription

Genbank AF169631 [ SRS ] AF169631 [ ENTREZ ]

Genbank AF302109 [ SRS ] AF302109 [ ENTREZ ]

Genbank AK075061 [ SRS ] AK075061 [ ENTREZ ]

Genbank AL713785 [ SRS ] AL713785 [ ENTREZ ]

Genbank BC029159 [ SRS ] BC029159 [ ENTREZ ]

RefSeq NM_021197 [ SRS ] NM_021197 [ ENTREZ ]

RefSeq NT_086855 [ SRS ] NT_086855 [ ENTREZ ] AceView WFDC1 AceView - NCBI TRASER WFDC1 Traser - Stanford

Unigene Hs.36688 [ SRS ] Hs.36688 [ NCBI ] HS36688 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9HC57 [ SRS] Q9HC57 [ EXPASY ] Q9HC57 [ INTERPRO ]

PS00317 4_DISULFIDE_CORE [ SRS ] PS00317 Prosite 4_DISULFIDE_CORE [ Expasy ]

Interpro IPR008197 WAP [ SRS ] IPR008197 WAP [ EBI ] CluSTr Q9HC57

Pfam PF00095 WAP [ SRS ] PF00095 WAP [ Sanger ] pfam00095 [ NCBI-CDD ]

Smart SM00217 WAP [EMBL] Blocks Q9HC57 Polymorphism : SNP, mutations, diseases OMIM 605322 [ map ] GENECLINICS 605322

SNP WFDC1 [dbSNP-NCBI]

SNP NM_021197 [SNP-NCI]

SNP WFDC1 [GeneSNPs - Utah] WFDC1 [SNP - CSHL] WFDC1] [HGBASE - SRS] General knowledge Family WFDC1 [UCSC Family Browser] Browser SOURCE NM_021197 SMD Hs.36688 SAGE Hs.36688 Amigo component|extracellular space

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -552- Amigo process|negative regulation of cell growth Amigo function|serine-type endopeptidase inhibitor activity PubGene WFDC1 Other databases Probes Probe WFDC1 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Responses of NBT-II bladder carcinoma cells to conditioned medium from normal fetal urogenital sinus. Rowley DR, Tindall DJ. Cancer Res 1987; 47: 2955-2960. Medline 3567912

Characterization of a fetal urogenital sinus mesenchymal cell line U4F: secretion of a negative growth factor regulatory activity. Rowley DR. In Vitro Cell Dev Biol 1992; 28A: 29-38. Medline 1730568

Purification of a novel protein (ps20) from urogenital sinus mesenchymal cells with growth inhibitory properties in vitro. Rowley DR, Dang TD, Larsen M, Gerdes MJ, McBride L, Lu B. J Biol Chem 1995; 270: 22058-22065. Medline 7665628

Molecular cloning and expression of ps20 growth inhibitor: a novel WAP-type 'four-disulfide core' domain protein expressed in smooth muscle. Larsen M, Ressler SJ, Lu B, Gerdes MJ, McBride L, Dang TD, Rowley DR. J Biol Chem 1998; 273: 4574-4584. Medline 9468514

The WFDC1 gene encoding ps20 localizes to 16q24, a region of LOH in multiple cancers. Larsen M, Ressler SJ, Gerdes MJ, Lu B, Byron M, Lawrence JB, Rowley DR. Mamm Genome 2000; 11: 767-773. Medline 10967136

Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C. Nat Genet 2002; 32: 355-357. Medline 12379854

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -553-

Analysis of alterations of WFDC1, a new putative tumour suppressor gene, in hepatocellular carcinoma. Saffroy R, Riou P, Soler G, Azoulay D, Emile JF, Debuire B, Lemoine A. Eur J Hum Genet 2002; 10: 239-244. Medline 12032731

Promotion of angiogenesis by ps20 in the differential reactive stroma prostate cancer xenograft model. McAlhany SJ, Ressler SJ, Larsen M, Tuxhorn JA, Yang F, Dang TD, Rowley DR. Cancer Res 2003; 63: 5859-5865. Medline 145228910

Integration of high-resolution array comparative genomic hybridization analysis of chromosome 16q with expression array data refines common regions of loss at 16q23-qter and identifies underlying candidate tumor suppressor genes in prostate cancer. Watson JE, Doggett NA, Albertson DG, Andaya A, Chinnaiyan A, van Dekken H, Ginzinger D, Haqq C, James K, Kamkar S, Kowbel D, Pinkel D, Schmitt L, Simko JP, Volik S, Weinberg VK, Paris PL, Collins C. Oncogene 2004; 23: 3487-3494. Medline 15007382

Decreased stromal expression and increased epithelial expression of WFDC1/ps20 in prostate cancer is associated with reduced recurrence-free survival. McAlhany SJ, Ayala GE, Frolov A, Ressler SJ, Wheeler TM, Watson JE, Collins C, Rowley DR. Prostate 2004; 61: 182-191. Medline 15305341

Molecular analysis of WFDC1/ps20 gene in prostate cancer. Watson JE, Kamkar S, James K, Kowbel D, Andaya A, Paris PL, Simko J, Carroll P, McAlhany S, Rowley D, Collins C. Prostate 2004;61:192-9. Medline 15305342

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

BiblioGene - INIST

Contributor(s) Written 03- Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire 2003

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -554- Updated 06- Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire 2005 Citation This paper should be referenced as such : Saffroy R, Lemoine A, Debuire B . WFDC1 (WAP four-disulfide core domain 1). Atlas Genet Cytogenet Oncol Haematol. March 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WFDC1ID424.html Saffroy R, Lemoine A, Debuire B . WFDC1 (WAP four-disulfide core domain 1). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WFDC1ID424.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -555- Atlas of Genetics and Cytogenetics in Oncology and Haematology

BUB1B (BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast))

Identity Other BUBR1 names Bub1A MAD3L Hugo BUB1B Location 15q15 DNA/RNA

Figure 1 : Schematic representation of BUB1B demonstrating the relative exon sizes (introns are not drawn to scale)

Description The gene spans 60 kb and is composed of 23 exons Protein

Figure 2 : Schematic representation of BUBR1 showing position of mutations, with truncating mutations depicted above the protein and missense mutations below.

Note Protein name: BUBR1 Description 1050 amino acids, 120 kDa Expression Ubiquituously expressed.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -556- Localisation Cytoplasmic in interphase cells. Bound to BUB3 or CENPE, it can be localized to nuclear kinetochores. Function A central component of the mitotic spindle checkpoint that directly inhibits the anaphase-promoting complex/cyclosome until sister chromatids are correctly attached to the spindle, thus ensuring proper chromosome segregation during cell division. Also binds the motor protein CENPE, an interaction required for regulation of kinetochore- microtubule interactions and checkpoint signalling. Homology BUBR1 is the mammalian homolog of yeast Mad3, a significant difference being that BUBR1 possesses a kinase domain which is absent in Mad3. Mutations Note See figure 2 above Germinal Biallelic germline mutations found in five Mosaic Variegated Aneuploidy (MVA) cases. Each family carries one missense mutation and one mutation that results in premature protein truncation or an absent transcript. Somatic Deletion of T at codon 1023 predicted to remove part of the kinase domain. Implicated in Entity Mosaic variegated aneuploidy (MVA) Note is a rare recessive condition characterised by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay and a broad spectrum of additional congenital abnormalities and medical conditions may also occur Prognosis There is early mortality in a significant proportion of cases due to failure to thrive and/or complications of congenital abnormalities, epilepsy, infections or malignancy. Cytogenetics The proportion of aneuploid cells varies but is usually >25% and is substantially greater than in normal individuals. Oncogenesis The risk of malignancy in MVA is high, with rhabdomyosarcoma, Wilms tumour and leukaemia reported in several cases. Two of the five cases with BUB1B mutations developed an embryonal rhabdomyosarcoma.

External links Nomenclature Hugo BUB1B GDB BUB1B BUB1B 701 BUB1 budding uninhibited by benzimidazoles 1 Entrez_Gene homolog beta (yeast)

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -557- Cards GeneCards BUB1B Ensembl BUB1B CancerGene BUB1B Genatlas BUB1B GeneLynx BUB1B eGenome BUB1B euGene 701 Genomic and cartography BUB1B - 15q15 chr15:38240580-38300613 + 15q15.1 (hg17- GoldenPath May_2004) Ensembl BUB1B - 15q15.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BUB1B Gene and transcription

Genbank AF310214 [ SRS ] AF310214 [ ENTREZ ]

Genbank AF035933 [ SRS ] AF035933 [ ENTREZ ]

Genbank AF046079 [ SRS ] AF046079 [ ENTREZ ]

Genbank AF046918 [ SRS ] AF046918 [ ENTREZ ]

Genbank AF053306 [ SRS ] AF053306 [ ENTREZ ]

RefSeq NM_001211 [ SRS ] NM_001211 [ ENTREZ ]

RefSeq NT_086821 [ SRS ] NT_086821 [ ENTREZ ] AceView BUB1B AceView - NCBI TRASER BUB1B Traser - Stanford

Unigene Hs.36708 [ SRS ] Hs.36708 [ NCBI ] HS36708 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O60566 [ SRS] O60566 [ EXPASY ] O60566 [ INTERPRO ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 Prosite PROTEIN_KINASE_ST [ Expasy ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ] CluSTr O60566

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -558- Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom O60566 BU1B_HUMAN [ Domain structure ] O60566 BU1B_HUMAN [ sequences sharing at least 1 domain ] Blocks O60566 Polymorphism : SNP, mutations, diseases OMIM 602860 [ map ] GENECLINICS 602860

SNP BUB1B [dbSNP-NCBI]

SNP NM_001211 [SNP-NCI]

SNP BUB1B [GeneSNPs - Utah] BUB1B [SNP - CSHL] BUB1B] [HGBASE - SRS] General knowledge Family BUB1B [UCSC Family Browser] Browser SOURCE NM_001211 SMD Hs.36708 SAGE Hs.36708 Enzyme 2.7.1.37 [ Enzyme-SRS ] 2.7.1.37 [ Brenda-SRS ] 2.7.1.37 [ KEGG ] 2.7.1.37 [ WIT ] Amigo function|ATP binding Amigo component|anaphase-promoting complex Amigo process|cell cycle Amigo component|kinetochore Amigo process|mitosis Amigo process|mitotic checkpoint Amigo component|nucleus Amigo process|protein amino acid phosphorylation Amigo function|protein serine/threonine kinase activity Amigo function|transferase activity PubGene BUB1B Other databases Probes Probe BUB1B Related clones (RZPD - Berlin) PubMed PubMed 19 Pubmed reference(s) in LocusLink Bibliography Mutations of mitotic checkpoint genes in human cancers. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JKV, Markowitz SD, Kinzler KW, Vogelstein B. Nature 1998; 392: 300-303. Medline 9521327

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Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma. Limwongse C, Schwartz S, BocianM, Robin NH. Am J Med Genet 1999; 82: 20-24. Medline 9916837

Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease. Plaja A, Vendrell T, Smeets D, Sarret E, Gili T, Catala V, Mediano C, Scheres JM. Am J Med Genet 2001; 98: 216-223. Medline 11169558

The spindle checkpoint, aneuploidy, and cancer Bharadwaj R, Yu H Oncogene 2004; 23: 2016-2027 Medline 15021889

Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, Kidd A, Mehes K, Nash R, Robin N, Shannon N, Tolmie J, Swansbury J, Irrthum A, Douglas J, Rahman N Nat Genet 2004; 36: 1159-1161 Medline 15475955

The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments Lampson MA, Kapoor TM. Nat Cell Biol 2005; 7: 93-98 Medline 15592459

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Sandra Hanks, Nazneen Rahman 2005 Citation This paper should be referenced as such : Hanks S, Rahman N . BUB1B (BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/BUB1BID854ch15q15.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -560- Atlas of Genetics and Cytogenetics in Oncology and Haematology

E2F3 (E2F transcription factor 3)

Identity Other E2F-3 names KIAA0075 Y10479 Hugo E2F3 Location 6p22.3 tel-OACT1-E2F3-CDKAL1-cen DNA/RNA

Schematic diagram of the E2F3 gene comprising 7 exons (in blue). Exons 1a or 1b are used alternatively to produce variants E2F3A or E2F3B, respectively. The sizes in base pairs (bp) of exons (above) and introns (below) are shown.

Description The gene has 7 exons (two alternative exons 1) and 6 introns comprising 91545 bp. Transcription Transcription takes place in a centromeric -> telomeric orientation. The length of the processed mRNA is about 4744 bp. EMBL lists two alternativly spliced forms other than those concerning exons 1a/b. Pseudogene 2q33-q35, 17q11-q12 Protein

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -561-

Schematic diagram of E2F3 protein structure. E2F3A is shown in the upper part, E2F3B below. The proteins differ in their N-terminal regions comprising 132 and 6 amino acid residues, respectively. N: nuclear localization sequence, LZ: leucine zipper (blue), RBD: pRB binding domain (light blue). DNA binding domain (yellow), dimerization domain (red), transactivation domain (green). The positions of amino acid residues are indicated.

Description E2F3A comprises 465 amino acid residues (49 kDa), E2F3B comprises 334 amino acid residues. Expression ubiquitous Localisation nuclear Function E2F3 is a sequence-specific transcription factor implicated in cell cycle regulation (S-phase). It is a transcriptional activator for E2F-responsive genes. E2F proteins heterodimerize with DP proteins and are subject to inhibition by binding to the pocket domain of (pRB). Phosphorylation of pRB sets E2F proteins free to regulate their target genes. Homology E2F transcription factor family consists of E2F-proteins (E2F1-6) and DP-proteins (DP1, DP2). Mutations Note Gene mutations have not been described hitherto. Germinal Not known Somatic Not known Implicated in Entity amp(6)(p22) Note Medium-to-high-level genomic amplification sometimes resulting in HSR formation and believed to target E2F3 which lies within the common amplified region (see image below). Genomic amplification may not be required for over-expression. Disease Notably, bladder and prostate cancers. Prognosis Associated with invasiveness in bladder cancer, and with poor survival in prostate cancer. Circa 33% of primary transitional cell carcinomas of the bladder overexpress nuclear E2F3 protein. Cytogenetics Presumptive target of genomic amplification at 6p22 in bladder cancer where it effects E2F3 overexpression (as exemplified by the bladder cancer cell lines 5637 and HT-1367). However, E2F3 may not be the only target gene inside the common amplified region.

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Genomic amplification of E2F3: FISH image shows HT-1376 bladder cancer cell line (DSMZ acc 397) hybridized with a BAC clone (RPMI-99F1) covering the E2F3 at 6p22.3. (See breakpoint diagram below for map.) Note high level genomic amplification comprising multiple tandemly repeated copies of E2F3 via formation of an homogeneously staining region (HSR) in a marker chromosome - a hallmark of oncogene activity. Similar findings have been reported in both primary bladder and prostate cancers. Analysis of E2F3 protein has confirmed overexpression in cell lines evidencing genomic amplification, including HT-1376 as well as 5637 (DSMZ acc 35) and TCC-SUP (DSMZ acc 377).

Hybrid/Mutated Not yet reported Gene

Entity t(6;9)(p22;p13) Note Observed in a DLBCL cell line: yet to be described clinically. Disease Diffuse large B-cell lymphoma (DLBCL). Prognosis Unknown Cytogenetics Breakpoint lies upstream of E2F3 and juxtaposes upstream (regulatory)

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -563- region of PAX5. See below

Hybrid/Mutated Not yet reported Gene Oncogenesis E2F3 behaves like a classical oncogene and is subject to upregulation via genomic amplification in bladder and prostate cancers. Upregulated E2F3 stimulates cycle progression and proliferation. E2F3 transcription is induced by MYC and these together conspire to promote G1/S-phase transition. This activity is negatively regulated by binding of the E2F transactivation domain to RB1 or p107. In prostate cancer, oncogenesis directed by E2F3 may be mediated by the polycomb group protein Enhancer of Zeste Homolog gene 2 (EZH2). E2F3 may also activate survivin transcription. In Hodgkin lymphoma which, though lacking recurrent chromosomal rearrangements at 6p22, shows a pattern of gene dysregulation reminiscent of prostate cancer, E2F3 regulates HLXB9 expression which in turn drives IL-6 expression thought to play a central role in this enigmatic tumor. E2F3 may also act as a tumor suppressor though the supporting evidence is tentative. Thus, while E2F3 loss results in centrosome defects associated with aneuploidy and promotes metastasis of medullary thyroid carcinoma, E2F3 -/- mice show no excess tumor incidence. Furthermore, loss of E2F3 has been associated with suppression of pituitary tumors.

Breakpoints

Figure depicts location of sole E2F3 breakpoint described hitherto, lying approximately 50-150 Kbp upstream of the transcription unit as detected in a complex t(6;9)(p22;p13) in a DLBCL cell line. The upstream region of E2F3 is thus juxtaposed with the upstream regulatory region of PAX5. Figure shows genes flanking E2F3 together with RPCI-11 library clones. External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -564- Hugo E2F3 GDB E2F3 Entrez_Gene E2F3 1871 E2F transcription factor 3 Cards GeneCards E2F3 Ensembl E2F3 CancerGene E2F3 Genatlas E2F3 GeneLynx E2F3 eGenome E2F3 euGene 1871 Genomic and cartography E2F3 - 6p22.3 chr6:20510377-20601921 + 6p22.3 (hg17- GoldenPath May_2004) Ensembl E2F3 - 6p22.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene E2F3 Gene and transcription

Genbank AF547386 [ SRS ] AF547386 [ ENTREZ ]

Genbank BC016847 [ SRS ] BC016847 [ ENTREZ ]

Genbank CR749285 [ SRS ] CR749285 [ ENTREZ ]

Genbank D38550 [ SRS ] D38550 [ ENTREZ ]

Genbank Y10479 [ SRS ] Y10479 [ ENTREZ ]

RefSeq NM_001949 [ SRS ] NM_001949 [ ENTREZ ]

RefSeq NT_086686 [ SRS ] NT_086686 [ ENTREZ ] AceView E2F3 AceView - NCBI TRASER E2F3 Traser - Stanford

Unigene Hs.269408 [ SRS ] Hs.269408 [ NCBI ] HS269408 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O00716 [ SRS] O00716 [ EXPASY ] O00716 [ INTERPRO ]

Interpro IPR003316 E2F_TDP [ SRS ] IPR003316 E2F_TDP [ EBI ]

IPR009058 Wing_hlx_DNA_bnd [ SRS ] IPR009058 Interpro Wing_hlx_DNA_bnd [ EBI ] CluSTr O00716 Pfam PF02319 E2F_TDP [ SRS ] PF02319 E2F_TDP [ Sanger ] pfam02319 [ NCBI-CDD ] Blocks O00716 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -565- OMIM 600427 [ map ] GENECLINICS 600427

SNP E2F3 [dbSNP-NCBI]

SNP NM_001949 [SNP-NCI]

SNP E2F3 [GeneSNPs - Utah] E2F3 [SNP - CSHL] E2F3] [HGBASE - SRS] General knowledge Family E2F3 [UCSC Family Browser] Browser SOURCE NM_001949 SMD Hs.269408 SAGE Hs.269408 Amigo component|nucleus Amigo function|protein binding Amigo process|regulation of cell cycle Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity Amigo component|transcription factor complex Amigo process|transcription initiation from Pol II promoter PubGene E2F3 Other databases Probes Probe E2F3 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography The retinoblastoma protein binds to a family of E2F transcription factors. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K. Mol Cell Biol 1993; 13(12): 7813-7825. Medline 8246996

Multiple members of the E2F transcription factor family are the products of oncogenes. Xu G, Livingston DM, Krek W. Proc Natl Acad Sci U S A 1995; 92(5): 1357-1361. Medline 7877982

Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit. Hofmann F, Livingston DM. Genes Dev 1996; 10(7): 851-861. Medline 8846921

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Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression. Lukas J, Petersen BO, Holm K, Bartek J, Helin K. Mol Cell Biol 1996; 16(3): 1047-1057. Medline 8622649

Expression patterns of the E2F family of transcription factors during mouse nervous system development. Dagnino L, Fry CJ, Bartley SM, Farnham P, Gallie BL, Phillips RA. Mech Dev 1997; 66(1-2): 13-25. Medline 9376316

Distinct roles for E2F proteins in cell growth control and apoptosis. DeGregori J, Leone G, Miron A, Jakoi L, Nevins JR. Proc Natl Acad Sci U S A 1997; 94(14): 7245-7250. Medline 9207076

E2F as a regulator of keratinocyte proliferation: implications for skin tumor development. Jones SJ, Dicker AJ, Dahler AL, Saunders NA. J Invest Dermatol 1997; 109(2): 187-193. Medline 9242506

E2F-3 accumulation is regulated by polypeptide stability. Flores AM, Kassatly RF, Cress WD. Oncogene 1998; 16(10): 1289-1298. Medline 9546430

E2F3 activity is regulated during the cell cycle and is required for the induction of S phase. Leone G, DeGregori J, Yan Z, Jakoi L, Ishida S, Williams RS, Nevins JR. Genes Dev 1998; 12(14): 2120-2130. Medline 9679057

E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation. Strom DK, Cleveland JL, Chellappan S, Nip J, Hiebert SW. Cell Growth Differ 1998; 9(1): 59-69. Medline 9438389

Upregulation of E2F transcription factors in chemically induced mouse skin tumors. Balasubramanian S, Ahmad N, Mukhtar H. InJ Oncol 1999; 15(2): 387-390. Review. Medline 10402252

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Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity. Callaghan DA, Dong L, Callaghan SM, Hou YX, Dagnino L, Slack RS. Dev Biol 1999; 207(2): 257-270. Medline 10068462

Expression of the E2F family in human gastrointestinal carcinomas. Suzuki T, Yasui W, Yokozaki H, Naka K, Ishikawa T, Tahara E. Int J Cancer 1999; 81(4): 535-538. Medline 10225440

Differential regulation of E2F transcription factors by p53 tumor suppressor protein. Vaishnav YN, Pant V. DNA Cell Biol 1999; 18(12): 911-922. Medline 10619603

Complex transcriptional regulatory mechanisms control expression of the E2F3 locus. Adams MR, Sears R, Nuckolls F, Leone G, Nevins JR. Mol Cell Biol 2000; 20(10): 3633-3639. Medline 10779353

A genetic screen to identify genes that rescue the slow growth phenotype of c- myc null fibroblasts. Berns K, Hijmans EM, Koh E, Daley GQ, Bernards R Oncogene 2000; 19(29): 3330-3334. Medline 10918589

CpG methylation as a mechanism for the regulation of E2F activity. Campanero MR, Armstrong MI, Flemington EK. Proc Natl Acad Sci U S A 2000; 97(12): 6481-6486. Medline 10823896

Deregulated E2F transcriptional activity in autonomously growing melanoma cells. Halaban R, Cheng E, Smicun Y, Germino J. J Exp Med 2000; 191(6): 1005-1016. Medline 10727462

Identification of E2F-3B, an alternative form of E2F-3 lacking a conserved N- terminal region. He Y, Armanious MK, Thomas MJ, Cress WD. Oncogene 2000; 19: 3422-3433. Medline 10918599

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E2f3 is critical for normal cellular proliferation. Humbert PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA. Genes Dev 2000; 14(6): 690-703. Medline 10733529

Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins. Leone G, Nuckolls F, Ishida S, Adams M, Sears R, Jakoi L, Miron A, Nevins JR. Mol Cell Biol 2000; 20(10): 3626-3632. Medline 10779352

Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Takahashi Y, Rayman JB, Dynlacht BD. Genes Dev 2000; 14(7): 804-816. Medline 10766737

Myc requires distinct E2F activities to induce S phase and apoptosis. Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, Giangrande P, Wu L, Saavedra HI, Field SJ, Thompson MA, Yang H, Fujiwara Y, Greenberg ME, Orkin S, Smith C, Nevins JR. Mol Cell 2001; 8(1): 105-113. Medline 11511364

E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Muller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassilli E, Prosperini E, Vigo E, Oliner JD, Helin K. Genes Dev 2001; 15(3): 267-285. Medline 11159908

The E2F1-3 transcription factors are essential for cellular proliferation. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G. Nature 2001; 414(6862): 457-462. Medline 11719808

E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Ziebold U, Reza T, Caron A, Lees JA. Genes Dev 2001; 15(4): 386-391. Medline 11230146

Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo. Cloud JE, Rogers C, Reza TL, Ziebold U, Stone JR, Picard MH, Caron AM, Bronson

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -569- RT, Lees JA. Mol Cell Biol 22(8): 2663-2672. Medline 11909960

The genetics of the E2F family of transcription factors: shared functions and unique roles. DeGregori J. Biochim Biophys Acta 2002; 1602(2): 131-150. Review. Medline 12020800

Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors. Parisi T, Pollice A, Di Cristofano A, Calabro V, La Mantia G. Biochem Biophys Res Commun 2002; 291(5): 1138-1145. Medline 11883935

E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Polager S, Kalma Y, Berkovich E, Ginsberg D. Oncogene 2002; 21(3): 437-446. Medline 11821956

Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb. Saavedra HI, Wu L, de Bruin A, Timmers C, Rosol TJ, Weinstein M, Robinson ML, Leone G. Cell Growth Differ 2002; 13(5): 215-225. Medline 12065245

Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function. Schlisio S, Halperin T, Vidal M, Nevins JR. EMBO J 2002; 21(21): 5775-5786. Medline 12411495

Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor. Giangrande PH, Hallstrom TC, Tunyaplin C, Calame K, Nevins JR. Mol Cell Biol 2003; 23(11): 3707-3720. Medline 12748276

Specificity in the activation and control of transcription factor E2F-dependent apoptosis. Hallstrom TC, Nevins JR. Proc Natl Acad Sci U S A. 2003 100(19):10848-53. Medline 12954980

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Gene expression phenotypic models that predict the activity of oncogenic pathways. Huang E, Ishida S, Pittman J, Dressman H, Bild A, Kloos M, D'Amico M, Pestell RG, West M, Nevins JR Nat Genet 2003; 34(2): 226-230. Medline 12754511

Inhibition of cell proliferation and induction of apoptosis by novel tetravalent peptides inhibiting DNA binding of E2F. Montigiani S, Muller R, Kontermann RE. Oncogene 2003; 22(32): 4943-4952. Medline 12902977

Inactivation of E2F3 results in centrosome amplification. Saavedra HI, Maiti B, Timmers C, Altura R, Tokuyama Y, Fukasawa K, Leone G. Cancer Cell 2003; 3(4): 333-346. Medline 12726860

Inhibition of retinoblastoma protein (Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention. Tyagi A, Agarwal C, Agarwal R. Mol Cancer Ther 2002; 1(7): 525-532. Medline 12479270

Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE, DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, Cordon-Cardo C, Jain AN, Waldman FM. Cancer Res 2003; 63(11): 2872-2880. Medline 12782593

Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. Zhu Y, Jin K, Mao XO, Greenberg DA. FASEB J 2003; 17(2): 186-193. Medline 12554697

E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Ziebold U, Lee EY, Bronson RT, Lees JA. Mol Cell Biol. 2003 23(18):6542-52. Medline 12944480

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -571- Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. Aslanian A, Iaquinta PJ, Verona R, Lees JA. Genes Dev 2004; 18(12): 1413-1422. Medline 15175242

Amplification and overexpression of E2F3 in human bladder cancer. Feber A, Clark J, Goodwin G, Dodson AR, Smith PH, Fletcher A, Edwards S, Flohr P, Falconer A, Roe T, Kovacs G, Dennis N, Fisher C, Wooster R, Huddart R, Foster CS, Cooper CS. Oncogene 2004; 23(8): 1627-1630. Medline 14716298

Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome. Foster CS, Falconer A, Dodson AR, Norman AR, Dennis N, Fletcher A, Southgate C, Dowe A, Dearnaley D, Jhavar S, Eeles R, Feber A, Cooper CS. Oncogene 2004; 23(35): 5871-5879. Medline 15184867

Combinatorial gene control involving E2F and E Box family members. Giangrande PH, Zhu W, Rempel RE, Laakso N, Nevins JR. EMBO J 2004; 23(6): 1336-1347. Medline 15014447

E2F3-a novel repressor of the ARF/p53 pathway. Ginsberg D. Dev Cell 2004; 6(6): 742-743. Review. Medline 15177020

Aberrant regulation of survivin by the RB/E2F family of proteins. Jiang Y, Saavedra HI, Holloway MP, Leone G, Altura RA. J Biol Chem 2004; 279(39): 40511-40520. Epub 2004 Jul 22. Medline 15271987

E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Oeggerli M, Tomovska S, Schraml P, Calvano-Forte D, Schafroth S, Simon R, Gasser T, Mihatsch MJ, Sauter G. Oncogene 2004; 23(33): 5616-5623. Medline 15122326

Mitoinhibitory effects of the tumor promoter 2-acetylaminofluorene in rat liver: loss of E2F-1 and E2F-3 expression and cdk 2 kinase activity in late G1. Ohlson LC, Koroxenidou L, Porsch-Hallstrom I. J Hepatol 2004; 40(6): 957-962.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -572- Medline 15158336

E2Fs link the control of G1/S and G2/M transcription. Zhu W, Giangrande PH, Nevins JR. EMBO J 2004; 23(23): 4615-4626. Medline 15510213

Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Denchi EL, Attwooll C, Pasini D, Helin K. Mol Cell Biol 2005; 25(7): 2660-2672. Medline 15767672

Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis. Ebelt H, Hufnagel N, Neuhaus P, Neuhaus H, Gajawada P, Simm A, Muller-Werdan U, Werdan K, Braun T. Circ Res 2005; 96(5): 509-517. Medline 15718499

HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3. Nagel S, Scherr M, Quentmeier H, Kaufmann M, Zaborski M, Drexler HG, MacLeod RAF. Leukemia 2005; 19(5): 841-846. Medline 15772702

E2F1 is crucial for E2F-dependent apoptosis. Lazzerini Denchi E, Helin K. EMBO Rep 2005; 6(7): 661-668. Medline 15976820

Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer. Wu Q, Hoffmann MJ, Hartmann FH, Schulz WA. Mol Cancer 2005; 4(1): 16. Medline 15876350

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Roderick AF MacLeod, Stefan Nagel 2005 Citation

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -573- This paper should be referenced as such : MacLeod RAF, Nagel S . E2F3 (E2F transcription factor 3). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/E2F3ID40384ch6p22.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -574- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MSH2 (human mutS homolog 2)

Identity Other COCA1 names FCC1 hMSH2 HNPCC1 Hugo MSH2 Location 2p22-p21 Between the FLJ40172 and MSH6 genes. DNA/RNA

Diagram of the MSH2 gene. Exons are represented by boxes (in scale) transcribed and untranscribed sequences in blue and yellow, with exon numbers on top and number of base pairs at the bottom. Introns are represented by black bars (not in scale) and the number of base pairs indicated. The arrows show the ATG and the stop codons respectively.

Description The MSH2 gene is composed of 16 exons spanning in a region of 80098 bp. Transcription The transcribed mRNA has 3145 bp. Protein

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -575- Diagram of the MSH2 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The boxes inside represent the DNA binding domain (red), the hMSH3/hMSH6 interaction domain (yellow) and the MutL homologs interaction domain (green); C: Carboxyl-terminal; N: Amino-terminal.

Description Aminoacids: 934. Molecular Weight: 104.7 kDa. MSH2 is a protein involved in the mismatch repair process after DNA replication. It contains a DNA binding domain and two interaction domains, one for MSH3 or MSH6 and the other for MutL homologs (MLH1 and PMS2), located in two different regions of the gene. Localisation Nuclear Function MSH2 can bind to MSH6 or to MSH3 to form the MutS alpha or the MutS beta complexes respectively. While MutS alpha complex binds to base-base and insertion-deletion mismatches, MutS beta only binds to insertion-deletion mismatches. Upon binding to the mismatch, the MutS complex associates with the MutL complex (composed of MLH1 and PMS2), and recruits the proteins needed for DNA excision and repair. (See also: Repair of DNA double-strand breaks Homology MSH2 is homologue to the bacterial MutS gene and MSH2 homologues are also present in eukaryotes. Mutations Germinal There are over 300 MSH2 germline mutations described along the gene that cause hereditary non-polyposis colorectal cancer (HNPCC, see below). Mutations do not occur in any particular hotspot or region of the gene and include either nucleotide substitutions (missense, nonsense and splicing errors) and insertions/deletions (gross or small). In most of these mutations the resulting protein is truncated. Although rare there are described some founding mutations which account for a high proportion of the HNPCC tumours in some specific populations. Some germline genetic changes have also been described in exons and introns as non pathogenic. Somatic Some sporadic mismatch repair deficient cases (sporadic MSI) with somatic MSH2 mutations are described. Implicated in Entity HNPCC (Hereditary Non Polyposis Colorectal Cancer) Disease Predisposition to develop cancer, preferentially colorectal, but also in endometrium, , urinary tract, stomach, small bowel, biliary tract and brain. Oncogenesis MSH2 mutations in HNPCC account for about 25% of the total cases approximately. These mutations are inherited in one allele and later the other allele is lost by LOH. This leads to mismatch repair deficiency in this patients, which is the cause of the accumulation of mutations along the genome, causing microsatellite instability (MSI) and promoting tumorigenesis. It has also been described that low levels of MSI characterize MLH1 and MSH2 HNPCC carriers before tumour diagnosis.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -576-

Entity MSI (MicroSatellite Instability) Note Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system. Disease This phenotype is present in 15% of colorectal, gastric and endometrial cancer, and has a lower incidence in some other tissues. Prognosis MSI tumours have better prognosis than the MicroSatellite Stable (MSS). Oncogenesis Few sporadic cases and about 25% of the HNPCC are due to different mutations in MSH2. These mutations are germline in HNPCC.

Entity Muir-Torre syndrome Disease Coincidence of at least one sebaceous adenoma, epithelioma or carcinoma and one internal malignancy. Oncogenesis Muir-Torre syndrome is mainly due to inherited MSH2 mutations.

External links Nomenclature Hugo MSH2 GDB MSH2 MSH2 4436 mutS homolog 2, colon cancer, nonpolyposis type 1 (E. Entrez_Gene coli) Cards GeneCards MSH2 Ensembl MSH2 CancerGene MSH2 Genatlas MSH2 GeneLynx MSH2 eGenome MSH2 euGene 4436 Genomic and cartography GoldenPath MSH2 - chr2:47541914-47622011 + 2p21 (hg17-May_2004) Ensembl MSH2 - 2p21 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MSH2 Gene and transcription

Genbank AF066081 [ SRS ] AF066081 [ ENTREZ ]

Genbank AY344477 [ SRS ] AY344477 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -577- Genbank AY601851 [ SRS ] AY601851 [ ENTREZ ]

Genbank U41221 [ SRS ] U41221 [ ENTREZ ]

Genbank BC001122 [ SRS ] BC001122 [ ENTREZ ]

RefSeq NM_000251 [ SRS ] NM_000251 [ ENTREZ ]

RefSeq NT_086610 [ SRS ] NT_086610 [ ENTREZ ] AceView MSH2 AceView - NCBI TRASER MSH2 Traser - Stanford

Unigene Hs.156519 [ SRS ] Hs.156519 [ NCBI ] HS156519 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P43246 [ SRS] P43246 [ EXPASY ] P43246 [ INTERPRO ]

PS00486 DNA_MISMATCH_REPAIR_2 [ SRS ] PS00486 Prosite DNA_MISMATCH_REPAIR_2 [ Expasy ]

Interpro IPR011184 MSH2 [ SRS ] IPR011184 MSH2 [ EBI ]

Interpro IPR000432 MutS_C [ SRS ] IPR000432 MutS_C [ EBI ]

Interpro IPR007860 MutS_II [ SRS ] IPR007860 MutS_II [ EBI ]

Interpro IPR007696 MutS_III [ SRS ] IPR007696 MutS_III [ EBI ]

Interpro IPR007861 MutS_IV [ SRS ] IPR007861 MutS_IV [ EBI ]

Interpro IPR007695 MutS_N [ SRS ] IPR007695 MutS_N [ EBI ] CluSTr P43246 Pfam PF01624 MutS_I [ SRS ] PF01624 MutS_I [ Sanger ] pfam01624 [ NCBI- CDD ] Pfam PF05188 MutS_II [ SRS ] PF05188 MutS_II [ Sanger ] pfam05188 [ NCBI- CDD ] Pfam PF05192 MutS_III [ SRS ] PF05192 MutS_III [ Sanger ] pfam05192 [ NCBI-CDD ] Pfam PF05190 MutS_IV [ SRS ] PF05190 MutS_IV [ Sanger ] pfam05190 [ NCBI-CDD ] Pfam PF00488 MutS_V [ SRS ] PF00488 MutS_V [ Sanger ] pfam00488 [ NCBI- CDD ]

Prodom PD001263 MutS_C[INRA-Toulouse] Prodom P43246 MSH2_HUMAN [ Domain structure ] P43246 MSH2_HUMAN [ sequences sharing at least 1 domain ] Blocks P43246 Polymorphism : SNP, mutations, diseases OMIM 120435 [ map ] GENECLINICS 120435

SNP MSH2 [dbSNP-NCBI]

SNP NM_000251 [SNP-NCI]

SNP MSH2 [GeneSNPs - Utah] MSH2 [SNP - CSHL] MSH2] [HGBASE - SRS] General knowledge

Family MSH2 [UCSC Family Browser]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -578- Browser SOURCE NM_000251 SMD Hs.156519 SAGE Hs.156519 Amigo function|ATP binding Amigo function|damaged DNA binding Amigo process|mismatch repair Amigo process|negative regulation of cell cycle Amigo component|nucleus Amigo process|postreplication repair PubGene MSH2 Other databases Probes Probe MSH2 Related clones (RZPD - Berlin) PubMed PubMed 77 Pubmed reference(s) in LocusLink Bibliography The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R. Cell 1993; 75: 1027-1038. Medline 8252616

Microsatellite instability in inherited and sporadic neoplasms. Eshleman JR, Markowitz SD. Curr Opin Oncol 1995; 7: 83-89. (REVIEW). Medline 7696368

DNA mismatch repair defects: role in colorectal carcinogenesis. Jacob S, Praz F. Biochimie 2002; 84: 27-47. (REVIEW) Medline 11900875

DNA mismatch repair and mutation avoidance pathways. Marti TM, Kunz C, Fleck O. Medline 11920679

Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. Mitchell RJ, Farrington SM, Dunlop MG, Campbell H. Am J Epidemiol 2002; 156: 885-902. (REVIEW).

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -579- Medline 12419761

A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States. Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, Lynch JF, Barrows A, Wijnen J, van der Klift H, Franken P, Wagner A, Fodde R, de la ChapelleA. JAMA 2004; 291: 718-724. Medline 14871915

A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. Mangold E, Pagenstecher C, Leister M, Mathiak M, Rutten A, Friedl W, Propping P, Ruzicka T, Kruse R. J Med Genet 2004; 41: 567-572. Medline 15235030

Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. Alazzouzi H, Domingo E, Gonzalez S, Blanco I, Armengol M, Espin E, Plaja A, Schwartz S, Capella G, Schwartz S Jr. Hum Mol Genet 2005; 14: 235-239. Medline 15563510

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Enric Domingo, Sim¢ Schwartz Jr 2005 Citation This paper should be referenced as such : Domingo E, Schwartz S Jr . MSH2 (human mutS homolog 2). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MSH2ID340ch2p22.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -580- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PAX2 (Paired box gene 2)

Identity Other Paired box homeotic gene 2 names Hugo PAX2 Location 10q24 DNA/RNA Description 12 exons, including alternative spliced exons 6 and 10 Transcription 7 alternative splicing isoforms Pseudogene No Protein

Description 416 amino acids; 44.7kD Expression PAX2 is expressed in the developing eye, ear, CNS, spinal cord, pancreas and urogenital tract. PAX2 contains a DNA binding paired domain, a truncated homeodomain, an octapeptide region and a carboxyl-terminal transactivation domain. Localisation Nuclear. Function PAX2 is a transcription factor that acts to regulate the expression of genes involved in mediating cell proliferation and growth, resistance to apoptosis, and cell migration. PAX2 null mutant mice die perinatally with absent , kidneys, ureters, oviducts, vas deferens and epididymis, also demonstrating mid- and hindbrain deficiency and defective optic nerve. Homology PAX2 shares homology through the conserved paired box domain with the other members of the nine strong PAX gene family. Mutations Germinal A number of PAX2 mutations have been reported as associated with Renal Coloboma Syndrome (see below), oligomeganephronia and isolated renal hypoplasia. These are collated on the Human PAX2 Allelic Variant Database (see below). Implicated in Entity Renal Coloboma Syndrome (RCS) Note Caused by heterozygous PAX2 mutations. Increased apoptosis arising as a result of impaired PAX2 function believed to be responsible for

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -581- disrupted nephron formation and arrested cochlear outgrowth.

External links Nomenclature Hugo PAX2 GDB PAX2 Entrez_Gene PAX2 5076 paired box gene 2 Cards GeneCards PAX2 Ensembl PAX2 CancerGene PAX2 Genatlas PAX2 GeneLynx PAX2 eGenome PAX2 euGene 5076 Genomic and cartography PAX2 - 10q24 chr10:102495322-102579687 + 10q24.31 (hg17- GoldenPath May_2004) Ensembl PAX2 - 10q24.31 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PAX2 Gene and transcription

Genbank AF515729 [ SRS ] AF515729 [ ENTREZ ]

Genbank AL138762 [ SRS ] AL138762 [ ENTREZ ]

Genbank AL589862 [ SRS ] AL589862 [ ENTREZ ]

Genbank L09747 [ SRS ] L09747 [ ENTREZ ]

Genbank U45245 [ SRS ] U45245 [ ENTREZ ]

RefSeq NM_000278 [ SRS ] NM_000278 [ ENTREZ ]

RefSeq NM_003987 [ SRS ] NM_003987 [ ENTREZ ]

RefSeq NM_003988 [ SRS ] NM_003988 [ ENTREZ ]

RefSeq NM_003989 [ SRS ] NM_003989 [ ENTREZ ]

RefSeq NM_003990 [ SRS ] NM_003990 [ ENTREZ ]

RefSeq NT_086775 [ SRS ] NT_086775 [ ENTREZ ] AceView PAX2 AceView - NCBI TRASER PAX2 Traser - Stanford

Unigene Hs.155644 [ SRS ] Hs.155644 [ NCBI ] HS155644 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -582- SwissProt Q02962 [ SRS] Q02962 [ EXPASY ] Q02962 [ INTERPRO ]

Prosite PS00034 PAIRED_BOX [ SRS ] PS00034 PAIRED_BOX [ Expasy ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ]

Interpro IPR001523 Paired_box_N [ SRS ] IPR001523 Paired_box_N [ EBI ] CluSTr Q02962

Pfam PF00292 PAX [ SRS ] PF00292 PAX [ Sanger ] pfam00292 [ NCBI-CDD ] Blocks Q02962 Polymorphism : SNP, mutations, diseases OMIM 167409 [ map ] GENECLINICS 167409

SNP PAX2 [dbSNP-NCBI]

SNP NM_000278 [SNP-NCI]

SNP NM_003987 [SNP-NCI]

SNP NM_003988 [SNP-NCI]

SNP NM_003989 [SNP-NCI]

SNP NM_003990 [SNP-NCI]

SNP PAX2 [GeneSNPs - Utah] PAX2 [SNP - CSHL] PAX2] [HGBASE - SRS] General knowledge Family PAX2 [UCSC Family Browser] Browser SOURCE NM_000278 SOURCE NM_003987 SOURCE NM_003988 SOURCE NM_003989 SOURCE NM_003990 SMD Hs.155644 SAGE Hs.155644 Amigo function|ATP binding Amigo process|CTP biosynthesis Amigo function|DNA binding Amigo function|DNA binding Amigo process|GTP biosynthesis Amigo process|UTP biosynthesis Amigo process|axonogenesis Amigo process|cell differentiation Amigo process|development Amigo function|nucleoside-diphosphate kinase activity

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -583- Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo process|transcription Amigo process|transcription from Pol II promoter Amigo process|visual perception PubGene PAX2 Other databases Other PAX2 Allelic Variant Database http://pax2.hgu.mrc.ac.uk/ database Probes Probe PAX2 Related clones (RZPD - Berlin) PubMed PubMed 21 Pubmed reference(s) in LocusLink Bibliography Pax2, a new murine paired-box-containing gene and its expression in the developing excretory system. Dressler GR, Deutsch U, Chowdhury K, Nornes HO, Gruss P. Development 1990; 109: 787-795. Medline 1977574

The paired box encodes a second DNA-binding domain in the paired homeo domain protein. Treisman J, Harris E, Desplan C. Genes Dev 1991; 5: 594-604. Medline 1672661

Expression of the PAX2 gene in human fetal kidney and Wilms' tumor. Eccles MR, Wallis LJ, Fidler AE, Spurr NK, Goodfellow PJ, Reeve AE. Cell Growth Differ 1992; 3: 279-289. Medline 1378753

Alternative messenger RNA forms and open reading frames within an additional conserved region of the human PAX-2 gene. Ward TA, Nebel A, Reeve AE, Eccles MR. Cell Growth Differ 1994; 5: 1015-1021. Medline 7819127

Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Sanyanusin P, Schimmenti LA, McNoe LA, Ward TA, Pierpont ME, Sullivan MJ, Dobyns WB, Eccles MR. Nat Genet 1995; 9: 358-364. Medline 7795640

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The mouse Pax2(1Neu) mutation is identical to a human PAX2 mutation in a family with renal-coloboma syndrome and results in developmental defects of the brain, ear, eye, and kidney. Favor J, Sandulache R, Neuhauser-Klaus A, Pretsch W, Chatterjee B, Senft E, Wurst W, Blanquet V, Grimes P, Sporle R, Schughart K. Proc Natl Acad Sci U S A 1996; 93: 13870-13875. Medline 8943028

Pax2 contributes to inner ear patterning and optic nerve trajectory. Torres M, Gomez-Pardo E, Gruss P. Development 1996; 122: 3381-3391. Medline 8951055

Pax genes and organogenesis. Dahl E, Koseki H, Balling R. Bioessays 1997; 19: 755-765. (REVIEW) Medline 14747376

Renal-coloboma syndrome: a multi-system developmental disorder caused by PAX2 mutations. Eccles MR, Schimmenti LA. Clin Genet 1999; 56: 1-9. (REVIEW) Medline 10466411

Reduced Pax2 gene dosage increases apoptosis and slows the progression of renal cystic disease. Ostrom L, Tang MJ, Gruss P, Dressler GR. Dev Biol 2000; 219: 250-258. Medline 10694420

Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of Pax2(1Neu) +/- mutant mice. Porteous S, Torban E, Cho NP, Cunliffe H, Chua L, McNoe L, Ward T, Souza C, Gus P, Giugliani R, et al. Hum Mol Genet 2000; 9: 1-11. Medline 10587573

PAX genes in development and disease: the role of PAX2 in urogenital tract development. Eccles MR, He S, Legge M, Kumar R, Fox J, Zhou C, French M, Tsai RW. Int J Dev Biol 2002; 46: 535-544. (REVIEW) Medline 12141441

Ureteric bud apoptosis and renal hypoplasia in transgenic PAX2-Bax fetal mice mimics the renal-coloboma syndrome.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -585- Dziarmaga A, Clark P, Stayner C, Julien JP, Torban E, Goodyer P, Eccles M. J Am Soc Nephrol 2003; 14: 2767-2774. Medline 14569086

The role of Pax2 in mouse inner ear development. Burton Q, Cole LK, Mulheisen M, Chang W, Wu DK. Dev Biol 2004; 272: 161-175. Medline 15242798

Rescue of defective branching nephrogenesis in renal-coloboma syndrome by the caspase inhibitor, Z-VAD-fmk. Clark P, Dziarmaga A, Eccles M, Goodyer P. J Am Soc Nephrol 2004; 15: 299-305. Medline 14747376

Pax2 mutant mice display increased number and size of islets of Langerhans but no change in insulin and glucagon content. Zaiko M, Estreicher A, Ritz-Laser B, Herrera P, Favor J, Meda P, Philippe J. Eur J Endocrinol 2004; 150: 389-395. Medline 15012626

Pax2 expression occurs in renal medullary epithelial cells in vivo and in cell culture, is osmoregulated, and promotes osmotic tolerance. Cai Q, Dmitrieva NI, Ferraris JD, Brooks HL, van Balkom BW, Burg M. Proc Natl Acad Sci U S A 2005; 102: 503-508. Medline 15623552

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Ewan Robson, Jess Whall, Michael Eccles 2005 Citation This paper should be referenced as such : Robson E, Whall J, Eccles M . PAX2 (Paired box gene 2). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PAX2ID41642ch10q24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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PDGFRB (platelet-derived growth factor receptor, beta polypeptide)

Identity Other BC032224 names J03278 M21616 JTK12 PDGFR CD140B PDGFR1 PDGF-R-beta Hugo PDGFRB Location 5q31-q32 MXI1 (MAX-interacting protein 1) is more telomeric. XPNPEP1 (X-

prolylaminopeptidase 1) is more telomeric. DNA/RNA

Genomic structure of PDGFRB. Black boxes indicate exons, small ones indicate untranslated exons.

Description 23 exons spanning 149.5 Mb on 5q31-q32. Transcription is from telomere to centromere. Transcription 1 transcript in RefSeq encoding NP_002600. 1 transcript in EnsEMBL encoding ENSP00000261799. Protein

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Schematic representation of PDGFRB. Ig-like domains: extracellular immunoglobulin- like domains involved in protein-ligand interaction, TM: transmembrane domain, Split- TK domain: RTK class III cytoplasmic kinase domain with an insertion of 70 to 100 hydrophilic residues.

Note PDGFRB; Beta platelet-derived growth factor receptor [Precursor] Description Beta platelet-derived growth factor receptor precursor (PDGF-R-beta) (CD140b antigen). Localisation Type I membrane protein. Function is receptor that binds specifically to PDGFB and has a tyrosine-protein kinase activity. Is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. The PDGFR/PDGF system includes two receptors (PDGFRA and PDGFRB) and four ligands (, B, C and D). The receptors PDGFRA and PDGFRB are related in sequence and both are members of the class III subtype of receptor tyrosine kinases (RTKs). Other class III RTKs are CSF1R, KIT and FLT3. Mature PDGFRB consist of 1067 amino acids and can bind strongly to PDGF-BB and -DD homodimers, but weakly to AB heterodimers and not to PDGF-AA homodimer. The different ligands seem to induce different signals. Homology PDGFRB presents homology in several species. It also belongs to GROWTH FACTOR RECEPTOR PRECURSOR EC_2.7.1.112 TYROSINE KINASE protein family. Mutations Germinal See SNPs at EnsEMBL (http://www.ensembl.org/Homo_sapiens/genesnpview?db=core&gene=ENSG000001137 Implicated in Note Some rare gene fusions involving PDGFRB have been described in several patients with chronic myeloproliferative disorders (CMPD), myelodysplastic/myeloproliferative syndromes (MDS/MPD) and AML, often associated with eosinophilia and splenomegaly. Transformation to acute leukemia has been observed in a minor proportion of cases. Some of them respond to imatinib mesylate.

Entity t(1;5)(q23;q33) Disease described in an 11 month old girl with myelodysplastic/myeloproliferative syndrome with eosinophilia Prognosis bad Cytogenetics t(1;5)(q23;q33) Hybrid/Mutated 5' PDE4DIP-PDGFRB 3' Gene Abnormal PDE4DIP-PDGFRB Protein

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Entity t(1;3;5)(p36;p21;q33) Note PDGFRB fusion partner unpublished. Translocation described in a patient with a chronic myeloproliferative disorder Disease CMPD Cytogenetics t(1;3;5)(p36;p21;q33) Hybrid/Mutated unidentified Gene Abnormal unidentified. Protein

Entity t(2;12;5)(q37;q22;q33) Note PDGFRB fusion partner unpublished. Disease Translocation described in a patient with a myelodysplastic syndrome Cytogenetics t(2;12;5)(q37;q22;q33) Hybrid/Mutated unidentified. Gene Abnormal unidentified. Protein

Entity t(3;5)(p21;q31) Note PDGFRB fusion partner unpublished. Disease Translocation described in a patient with an atypical CML Cytogenetics t(3;5)(p21;q31) Hybrid/Mutated unidentified. Gene Abnormal unidentified. Protein

Entity t(5;7)(q33;q11.2) Disease Described in two patients with CMML/eosinophilia and CMML Prognosis unknown. Cytogenetics t(5;7)(q33;q11.2) Hybrid/Mutated 5' HIP1-PDGFRB 3' Gene Abnormal HIP1-PDGFRB Protein

Entity t(5;10)(q33;q22)

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -589- Disease Described in five cases with atypical CML. Prognosis good, imatinib mesylate responsive disease. Cytogenetics t(5;10)(q33;q22) Hybrid/Mutated 5' H4-PDGFRB 3' Gene Abnormal H4-PDGFRB Protein

Entity t(5;12)(q33;p13) Disease Associated to atypical CML, AML, chronic myelomonocytic leukaemia (CMML), chronic eosinophilic leukaemia (CEL) or unclassified myeloproliferative disorders Prognosis Good. Cytogenetics t(5;12)(q33;p13) Hybrid/Mutated 5' ETV6-PDGFRB 3' Gene Abnormal ETV6-PDGFRB Protein

Entity t(5;14)(q33;q32) Disease Described in a patient with AML and a t(7;11)(p15;p15) at initial diagnosis, who relapsed with a prominent eosinophilia, hepatosplenomegaly and t(5;14) as an additional cytogenetic abnormality. Prognosis Good. Cytogenetics t(5;14)(q33;q32) Hybrid/Mutated 5' TRIP11-PDGFRB 3' Gene Abnormal TRIP11-PDGFRB Protein

Entity t(5;14)(q33;q24) Disease described in a patient with a chronic myeloproliferative disorder with eosinophilia Prognosis Good, imatinib mesylate responsive disease. Cytogenetics t(5;14)(q33;q24) Hybrid/Mutated 5' NIN-PDGFRB 3' Gene Abnormal NIN-PDGFRB Protein

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -590- Entity t(5;14)(q31;q32) Disease described in a patient with a chronic myeloproliferative disorder with peripheral blood monocitosis Prognosis Good, imatinib mesylate responsive disease. Cytogenetics t(5;14)(q31;q32) Hybrid/Mutated 5' KIAA1509-PDGFRB 3' Gene Abnormal 5' KIAA1509-PDGFRB 3' Protein

Entity t(5;15)(q33;q22) Disease described in a patient with a chronic myeloproliferative disorder with eosinophilia Prognosis Imatinib mesylate responsive disease but the patient described resistance was developed. Cytogenetics t(5;15)(q33;q22) Hybrid/Mutated 5' TP53BP1-PDGFRB 3' Gene Abnormal TP53BP1-PDGFRB Protein

Entity t(5;17)(q33;p11.2) Disease JMML/CMML Prognosis Good. Cytogenetics t(5;17)(q33;p11.2) Hybrid/Mutated 5' HCMOGT-PDGFRB 3' fusion described in an 18 month old boy Gene with juvenile myelomonocytic leukemia and eosinophilia Abnormal HCMOGT-PDGFRB Protein

Entity t(5;17)(q33;p13) Disease described in a patient with chronic myelomonocitic leukemia Prognosis unknown. Cytogenetics t(5;17)(q33;p13) Hybrid/Mutated 5' RABEP1-PDGFRB 3' Gene Abnormal RABEP1-PDGFRB Protein

Breakpoints

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External links Nomenclature Hugo PDGFRB GDB PDGFRB PDGFRB 5159 platelet-derived growth factor receptor, beta Entrez_Gene polypeptide Cards GeneCards PDGFRB Ensembl PDGFRB CancerGene PDGFRB Genatlas PDGFRB GeneLynx PDGFRB eGenome PDGFRB euGene 5159 Genomic and cartography PDGFRB - chr5:149473596-149515503 - 5q32 (hg17- GoldenPath May_2004) Ensembl PDGFRB - 5q32 [CytoView]

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

Genbank U33172 [ SRS ] U33172 [ ENTREZ ]

Genbank BC032224 [ SRS ] BC032224 [ ENTREZ ]

Genbank J03278 [ SRS ] J03278 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -592- Genbank M21616 [ SRS ] M21616 [ ENTREZ ]

RefSeq NM_002609 [ SRS ] NM_002609 [ ENTREZ ]

RefSeq NT_086681 [ SRS ] NT_086681 [ ENTREZ ] AceView PDGFRB AceView - NCBI TRASER PDGFRB Traser - Stanford

Unigene Hs.509067 [ SRS ] Hs.509067 [ NCBI ] HS509067 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P09619 [ SRS] P09619 [ EXPASY ] P09619 [ INTERPRO ]

Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 Prosite PROTEIN_KINASE_TYR [ Expasy ]

PS00240 RECEPTOR_TYR_KIN_III [ SRS ] PS00240 Prosite RECEPTOR_TYR_KIN_III [ Expasy ]

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

Interpro IPR003598 Ig_c2 [ SRS ] IPR003598 Ig_c2 [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ]

Interpro IPR001824 RecepttyrkinsIII [ SRS ] IPR001824 RecepttyrkinsIII [ EBI ]

Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]

Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ]

Interpro IPR009134 VEGFR [ SRS ] IPR009134 VEGFR [ EBI ] CluSTr P09619

Pfam PF00047 ig [ SRS ] PF00047 ig [ Sanger ] pfam00047 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00408 IGc2 [EMBL]

Smart SM00219 TyrKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom P09619 PGDR_HUMAN [ Domain structure ] P09619 PGDR_HUMAN [ sequences sharing at least 1 domain ] Blocks P09619

PDB 1GQ5 [ SRS ] 1GQ5 [ PdbSum ], 1GQ5 [ IMB ]

PDB 1H9O [ SRS ] 1H9O [ PdbSum ], 1H9O [ IMB ]

PDB 1LWP [ SRS ] 1LWP [ PdbSum ], 1LWP [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 173410 [ map ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -593- GENECLINICS 173410

SNP PDGFRB [dbSNP-NCBI]

SNP NM_002609 [SNP-NCI]

SNP PDGFRB [GeneSNPs - Utah] PDGFRB [SNP - CSHL] PDGFRB] [HGBASE - SRS] General knowledge Family PDGFRB [UCSC Family Browser] Browser SOURCE NM_002609 SMD Hs.509067 SAGE Hs.509067

2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG Enzyme ] 2.7.1.112 [ WIT ] Amigo function|ATP binding Amigo component|integral to membrane Amigo function|platelet activating factor receptor activity Amigo function|platelet-derived growth factor receptor activity Amigo process|protein amino acid phosphorylation Amigo function|receptor activity Amigo process|signal transduction Amigo function|transferase activity process|transmembrane receptor protein tyrosine kinase signaling Amigo pathway Amigo function|vascular endothelial growth factor receptor activity PubGene PDGFRB Other databases Probes Probe PDGFRB Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in LocusLink Bibliography Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Golub TR, Barker GF, Lovett M, Gilliland DG. Cell 1994; 77: 307-316. Medline 8168137

Fusion of the platelet-derived growth factor receptor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Abe A, Emi N, Tanimoto M, Terasaki H, Marunouchi T, Saito H. Blood 1997; 90: 4271-4277.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -594- Medline 9373237

Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Ross TS, Bernard OA, Berger R, Gilliland DG. Blood 1998; 91: 4419-4426. Medline 9616134

Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Kulkarni S, Heath C, Parker S, Chase A, Iqbal S, Pocock CF, Kaeda J, Cwynarski K, Goldman JM, Cross NC. Cancer Res 2000; 60: 3592-3598. Medline 10910073

Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Magnusson MK, Meade KE, Brown KE, Arthur DC, Krueger LA, Barrett AJ, Dunbar CE. Blood 2001; 98: 2518-2525. Medline 11588050

H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). Schwaller J, Anastasiadou E, Cain D, Kutok J, Wojiski S, Williams IR, LaStarza R, Crescenzi B, Sternberg DW, Andreasson P, Schiavo R, Siena S, Mecucci C, Gilliland DG. Blood 2001; 97: 3910-3918. Medline 11389034

Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM. N Engl J Med 2002; 347: 481-487. Medline 12181402

Myeloproliferative disorders with translocations of chromosome 5q31-35: role of the platelet-derived growth factor receptor Beta. Steer EJ , Cross NCP. Acta Haematol 2002; 107: 113-122. REVIEW. Medline 11919393

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -595- Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders. Baxter EJ, Kulkarni S, Vizmanos JL, Jaju R, Martinelli G, Testoni N, Hughes G, Salamanchuk Z, Calasanz MJ, Lahortiga I, Pocock CF, Dang R, Fidler C, Wainscoat JS, Boultwood J, Cross NC. Br J Haematol 2003; 120: 251-256. Medline 12542482

Imatinib mesylate elicits positive clinical response in atypical chronic myeloid leukemia involving the platelet-derived growth factor receptor beta. Garcia JL, Font d M, Hernandez JM, Queizan JA, Gutierrez NC, Hernandez JM, San Miguel JF. Blood 2003; 102: 2699-2700. Medline 14504072

Sensitivity to imatinib but low frequency of the TEL/PDGFRb fusion protein in chronic myelomonocytic leukemia. Gunby RH, Cazzaniga G, Tassi E, Le Coutre P, Pogliani E, Specchia G, Biondi A, Gambacorti-Passerini C. Haematologica 2003; 88: 408-415. Medline 12681968

Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA, Aguiar RC. Blood 2003; 102: 4187-4190. Medline 12907457 p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. Grand FH, Burgstaller S, Kuhr T, Baxter EJ, Webersinke G, Thaler J, Chase AJ, Cross NC. Cancer Res 2004; 64: 7216-7219.

Oncogenic derivatives of platelet-derived growth factor receptors. Jones AV, Cross NC. Cell Mol Life Sci 2004; 61: 2912-2923.REVIEW. Medline 15583853

HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic leukemia with t(5;17)(q33;p11.2). Morerio C, Acquila M, Rosanda C, Rapella A, Dufour C, Locatelli F, Maserati E, Pasquali F, Panarello C. Cancer Res 2004; 64: 2649-2651. Medline 15087372

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NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder. Vizmanos JL, Novo FJ, Roman JP, Baxter EJ, Lahortiga I, Larrayoz MJ, Odero MD, Giraldo P, Calasanz MJ, Cross NC. Cancer Res 2004; 64: 2673-2676. Medline 15087377

KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, Galinsky I, Stone RM, DeAngelo DJ, Gilliland DG, Cools J. Leukemia 2005;19: 27-30. Medline 15496975

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- José Luis Vizmanos 2005 Citation This paper should be referenced as such : Vizmanos JL . PDGFRB (platelet-derived growth factor receptor, beta polypeptide). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PDGFRBID21ch5q32.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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TBX2 (T-box 2)

Identity Note T-box proteins contain a T-domain that has roles in dimerization and DNA binding. TBX2 belongs to the Tbx2 subfamily of T-box transcription factors. Other subfamilies of T-box genes are Brachyury, T-brain1, Tbx1 and Tbx6. TBX2, TBX3, TBX4 and TBX5 belong to the Tbx2 subfamily. TBX2 and TBX3 are the only mammalian T-box factors with reported transcriptional repressor functions. Other FLJ10169 names Hugo TBX2 Location 17q23 Genes flanking TBX2 in centromere to telomere direction on 17q23 are: APPBP2, 17q21-q23, amyloid beta precursor protein (cytoplasmic tail) binding protein 2 TBX2, 17q23, T-box2 PPM1D, 17q23, protein phosphatase 1D magnesium-dependent, delta

isoform LOC440450, 17q23.2 LOC440450 LOC388407, 17q23.2, hypothetical gene supported by BC046200 LOC388406, 17q23.2, hypothetical LOC388406 MGC71999, 17q23.2, alpha-NAC protein DNA/RNA Note Genes of the same T-box subfamily are thought to have arisen from duplication and recombination of a single ancestor gene. TBX2 is most closely related to TBX3 (12q24), whereas the other members of the subfamily, TBX4 and TBX5, are more closely related to one another. It is postulated that genes of the same subfamily may have redundant expression patterns and thus potential functional redundancy.

The alignment of TBX2 mRNA (3396 bp) to its genomic sequence.

Description TBX2 gene spans 9,5kb. TBX2 gene has 7 exons and the sizes of the exons 1 to 7 are 676, 268, 147, 77, 164, 635, 1413 bps. Exon/intron

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -598- boundaries of TBX2 and a polymorphism within intron 2 of the gene have also been reported. Transcription TBX2 mRNA is 3396 bp. TBX2 mRNA is expressed in a wide variety of tissues including fetal kidney and fetal lung as well as multiple adult tissues, kidney, lung, placenta, ovary, prostate, spleen, testis and breast. Relatively reduced expression of TBX2 can be detected in heart, white blood cells, small intestine and thymus. Transcript size heterogeneity has been detected for TBX2, possibly due to alternative polyadenylation. Increased TBX2 mRNA is observed within 2 hours after addition of retinoic acid in B16 mouse melanoma cells due to the presence of a degenerate retinoic acid response element (RARE) between -186 and -163 in the promoter region of the TBX2 gene.

Transcript localisation: Human and mouse TBX2, TBX3, and TBX5 transcripts detected by riboprobes are found asymmetrically across the embryonic neural retina, with highest levels of transcripts within dorsal and peripheral retina. The dorsoventral gradient of TBX2 expression cannot be detected before the ganglion cell layer (GCL) forms and expression is found to be restricted to the inner neuroblastic retina and later to the GCL and inner nuclear layer. TBX2 transcript is also detected in the optic and otic vesicles at 9.5 dpc, and in the naso-facial mesenchyme, and later in the developing limbs and other internal organ primordia (of lungs and genitalia). Later at around 8 and 10 dpc, TBX2 is detected in allantois, inflow tract (IFT), outflow tract (OFT) and atrio-ventricular canal (AVC) of the developing mouse heart. Chick heart development is also consistent in terms of similar TBX2 expression patterns. During mammary development, TBX2 expression is detected at 11.5 dpc in the mesodermal milk lines. Pseudogene No pseudogenes have been reported for TBX2. Protein

Description Protein consists of 702 amino acids and is 74.2 kDa. Protein has the T- box DNA binding domain (corresponds to amino acids 96-279) of the T- box family of transcriptional regulators. Function In an evolutionarily diverse group of organisms including chick, Xenopus, mouse, and human, TBX2 is involved during development of widely diverse organs and tissues including limbs, kidneys, lungs, mammary glands, heart and craniofacial structures. In order to identify genes that may be regulated by Tbx2, mouse cDNA microarrays were used to analyze differential profiles, comparing stably transfected NIH3T3 cells overexpressing Tbx2 with vector-transfected controls. 107 genes were up-regulated (more than or equal to 2-fold) and 66 genes were down-regulated (more than or equal to 2-fold). Among the upregulated genes in the Tbx2-overexpressing cells were: Caveolin, Pleiotrophin, Osteoblast-specific factor-2 and Collagen Type I alpha. Cadherin 3, Tenascin C, and Insulin-like Growth

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -599- Factor Binding Protein 10/CYR61 (IBP10) were among the genes that are downregulated. In vitro reporter assays and transgenic mice studies suggest that TBX2 represses the transcription of certain cardiac genes (e.g. Connexin 40, Connexin 43, and Natriuretic Peptide Precursor A) during heart development. TBX2 and TBX3 are also thought to be regulating one another in Hedgehog related signaling pathways during chick limb development. In addition to developmental functions, evidence suggest that TBX2 also has important roles in cell cycle regulation through repressing the expression of CDKN1A (p21, cyclin-dependent kinase inhibitor) and CDKN2A (p19ARF). In BMI oncogene deficient murine embryonic fibroblasts, TBX2 is shown to repress the CDKN2A promoter and also attenuate the induction of CDKN2A by E2F1, MYC, and HRAS, providing senescence bypass and suggesting TBX2 as a potent immortalizing gene. Homology C.familiaris: Tbx2, T-box 2 transcription factor M.musculus: Tbx2, T-box 2 R.norvegicus: Tbx2_predicted, T-box 2 (predicted) D.melanogaster: bi, bifid A.gambiae: 1280927, Anopheles gambiae str. PEST ENSANGG00000011542 gene. C.elegans: tbx-2, T-box family member (47.0 kD) Mutations Germinal Despite the high frequency T-box family gene mutations identified as causes of congenital developmental disorders, there have been no mutations reported for TBX2 that cause congenital anomalies. Germline segregation of TBX2 mutations with human diseases has not been identified. Somatic CGH (comparative genomic hybridization), Southern blot, FISH, PCR based techniques and microarray analyses suggest amplification and overexpression of TBX2 in certain cancer cells. Implicated in

Entity Breast cancer Note TBX2 has been found to be amplified and overexpressed in breast cancer cell lines and primary tumors. TBX2 resides on the chromosomal band 17q23 that is frequently amplified in breast cancer cells. Evidence suggests presence of distinct proximal and distal amplicons on 17q23 with defined boundaries. TBX2 seems to be at the center of the distal amplicon. In addition to breast cancer cell line data, a study of tissue microarray of 372 primary tumors found TBX2 amplification in 8.6% of the cases. Moreover, preferential amplification and overexpression of TBX2 have been detected in BRCA1 and BRCA2 mutated breast tumors compared to sporadic controls.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -600- Entity Pancreatic Cancer Note TBX2 amplification has been detected in 50% of 20 pancreatic cancer cell lines detected by interphase FISH.

Entity Melanomas Note TBX2 overexpression in melanoma cell lines is thought to target histone deacetylase 1 to the CDKN1A initiator. Expression of a dominant- negative Tbx2 leads to displacement of histone deacetylase 1 with up- regulation of CDKN1A expression, and the induction of replicative senescence in CDKN2A-null B16 melanoma cells. In human melanoma cells, expression of the same dominant negative TBX2 results with reduced growth and induction of senescence-associated heterochromatin foci.

Note Analysis of TBX2 in other tumor types has not been widely reported.

External links Nomenclature Hugo TBX2 GDB TBX2 Entrez_Gene TBX2 6909 T-box 2 Cards Atlas TBX2ID42485ch17q23 GeneCards TBX2 Ensembl TBX2 CancerGene TBX2 Genatlas TBX2 GeneLynx TBX2 eGenome TBX2 euGene 6909 Genomic and cartography TBX2 - 17q23 chr17:56832039-56841607 + 17q23.2 (hg17- GoldenPath May_2004) Ensembl TBX2 - 17q23.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TBX2 Gene and transcription

Genbank AK001031 [ SRS ] AK001031 [ ENTREZ ]

Genbank AL832900 [ SRS ] AL832900 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -601- Genbank BC052566 [ SRS ] BC052566 [ ENTREZ ]

Genbank BC070054 [ SRS ] BC070054 [ ENTREZ ]

Genbank BM985069 [ SRS ] BM985069 [ ENTREZ ]

RefSeq NM_005994 [ SRS ] NM_005994 [ ENTREZ ]

RefSeq NT_086883 [ SRS ] NT_086883 [ ENTREZ ] AceView TBX2 AceView - NCBI TRASER TBX2 Traser - Stanford

Unigene Hs.531085 [ SRS ] Hs.531085 [ NCBI ] HS531085 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q13207 [ SRS] Q13207 [ EXPASY ] Q13207 [ INTERPRO ]

Prosite PS01283 TBOX_1 [ SRS ] PS01283 TBOX_1 [ Expasy ]

Prosite PS01264 TBOX_2 [ SRS ] PS01264 TBOX_2 [ Expasy ]

Prosite PS50252 TBOX_3 [ SRS ] PS50252 TBOX_3 [ Expasy ]

IPR008967 P53_like_DNA_bnd [ SRS ] IPR008967 Interpro P53_like_DNA_bnd [ EBI ]

Interpro IPR002070 TF_Brachyury [ SRS ] IPR002070 TF_Brachyury [ EBI ]

Interpro IPR001699 TF_T-box [ SRS ] IPR001699 TF_T-box [ EBI ] CluSTr Q13207

Pfam PF00907 T-box [ SRS ] PF00907 T-box [ Sanger ] pfam00907 [ NCBI-CDD ]

Smart SM00425 TBOX [EMBL] Blocks Q13207 Polymorphism : SNP, mutations, diseases OMIM 600747 [ map ] GENECLINICS 600747

SNP TBX2 [dbSNP-NCBI]

SNP NM_005994 [SNP-NCI]

SNP TBX2 [GeneSNPs - Utah] TBX2 [SNP - CSHL] TBX2] [HGBASE - SRS] General knowledge Family TBX2 [UCSC Family Browser] Browser SOURCE NM_005994 SMD Hs.531085 SAGE Hs.531085 Amigo process|development Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity BIOCARTA Tumor Suppressor Arf Inhibits Ribosomal Biogenesis

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -602- PubGene TBX2 Other databases Probes Probe TBX2 Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene. Campbell C, Goodrich K, Casey G, Beatty B. Genomics 1995; 28: 255-260. Medline 8530034

Identification, characterization, and localization to chromosome 17q21-22 of the human TBX2 homolog, member of a conserved developmental gene family. Law DJ, Gebuhr T, Garvey N, Agulnik SI, Silver LM. Mamm Genome 1995; 6: 793-797. Medline 8597636

Expression of the T-box family genes, Tbx1-Tbx5, during early mouse development. Chapman DL, Garvey N, Hancock S, Alexiou M, Agulnik SI, Gibson-Brown JJ, Cebra-Thomas J, Bollag RJ, Silver LM, Papaioannou VE. Dev Dyn 1996; 206: 379-390. Medline 8853987

Evidence of a role for T-box genes in the evolution of limb morphogenesis and the specification of forelimb/hindlimb identity. Gibson-Brown JJ, Agulnik SI, Chapman DL, Alexiou M, Garvey N, Silver LM, Papaioannou VE. Mech Dev 1996; 56: 93-101. Medline 8798150

Genomic structure of TBX2 indicates conservation with distantly related T-box genes. Campbell CE, Casey G, Goodrich K. Mamm Genome 1998; 9: 70-73. Medline 9434949

Expression of T-box genes Tbx2-Tbx5 during chick organogenesis. Gibson-Brown JJ, I Agulnik S, Silver LM, Papaioannou VE. Mech Dev 1998; 74: 165-169. Medline 9651516

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -603- Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. Barlund M, Monni O, Kononen J, Cornelison R, Torhorst J, Sauter G, Kallioniemi OLLI-P, Kallioniemi A. Cancer Res 2000; 60: 5340-5344. Medline 11034067

Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2. Yamada M, Revelli JP, Eichele G, Barron M, Schwartz RJ. Dev Biol 2000; 228: 95-105. Medline 11087629

Microarray analysis of Tbx2-directed gene expression: a possible role in osteogenesis. Chen J, Zhong Q, Wang J, Cameron RS, Borke JL, Isales CM, Bollag RJ. Mol Cell Endocrinol 2001; 25: 177: 43-54. Medline 11377819

Overexpressed genes/ESTs and characterization of distinct amplicons on 17q23 in breast cancer cells. Erson AE, Niell BL, DeMers SK, Rouillard JM, Hanash SM, Petty EM. Neoplasia 2001; 3: 521-526. Medline 11774034

Virtual genome scan: a tool for restriction landmark-based scanning of the . Rouillard JM, Erson AE, Kuick R, Asakawa J, Wimmer K, Muleris M, Petty EM, Hanash S. Genome Res 2001; 11: 1453-1459 Medline 11483587

Expression of Drosophila omb-related T-box genes in the developing human and mouse neural retina. Sowden JC, Holt JKL, Meins M, Smith HK, Bhattacharya SS. Invest Ophthal Vis Sci 2001; 42: 3095-3102. Medline 11726608

Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation. Habets PE, Moorman AF, Clout DE, van Roon MA, Lingbeek M, van Lohuizen M, Campione M, Christoffels VM. Genes Dev 2002; 16: 1234-1246. Medline 12023302

Frequent amplification of 8q24, 11q, 17q, and 20q-specific genes in pancreatic

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -604- cancer. Mahlamaki EH, Barlund M, Tanner M, Gorunova L, Hoglund M, Karhu R, Kallioniemi A. Genes Chromosomes Cancer 2002; 35: 353-358. Medline 12378529

TBX2 is preferentially amplified in BRCA1- and BRCA2-related breast tumors. Sinclair CS, Adem C, Naderi A, Soderberg CL, Johnson M, Wu K, Wadum L, Couch VL, Sellers TA, Schaid D, Slezak J, Fredericksen Z, Ingle JN, Hartmann L, Jenkins RB, Couch FJ. Cancer Res 2002; 62: 3587-3591. Medline 12097257

The T-box family. Wilson V, Conlon FL Genome Biol 2002; 3: REVIEWS3008. Medline 12093383

Tension-induced reduction in connexin 43 expression in cranial sutures is linked to transcriptional regulation by TBX2. Borke JL, Yu JC, Isales CM, Wagle N, Do NN, Chen JR, Bollag RJ. Ann Plast Surg 2003; 51: 499-504. Medline 14595187

T-box genes in human disorders. Packham EA, Brook JD. Hum Mol Genet 2003; 12 Spec No 1: R37-44. Review. Medline 12668595

T-box binding protein type two (TBX2) is an immediate early gene target in retinoic-acid-treated B16 murine melanoma cells. Boskovic G, Niles RM. Exp Cell Res 2004; 295: 281-289. Medline 15093729

Tbx2 represses expression of Connexin43 in osteoblastic-like cells. Chen JR, Chatterjee B, Meyer R, Yu JC, Borke JL, Isales CM, Kirby ML, Lo CW, Bollag RJ. Calcif Tissue Int 2004; 74: 561-573. Medline 15354864

T-box transcription factor Tbx2 represses differentiation and formation of the cardiac chambers. Christoffels VM, Hoogaars WM, Tessari A, Clout DE, Moorman AF, Campione M. Dev Dyn 2004; 229: 763-770. Medline 15042700

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -605-

Tbx2 directly represses the expression of the p21(WAF1) cyclin-dependent kinase inhibitor. Prince S, Carreira S, Vance KW, Abrahams A, Goding CR. Cancer Res 2004; 64: 1669-1674. Medline 14996726

The role of Tbx2 and Tbx3 in mammary development and tumorigenesis. Rowley M, Grothey E, Couch FJ. J Mammary Gland Biol Neoplasia 2004; 9: 109-118. Medline 15300007

Tbx Genes Specify Posterior Digit Identity through Shh and BMP Signaling. Suzuki T, Takeuchi J, Koshiba-Takeuchi K, Ogura T. Dev Cell 2004; 6: 43-53. Erratum in: Dev Cell. 2005; 8: 971-972. Medline 14723846

T-box genes and heart development: putting the "T" in heart. Plageman TF Jr, Yutzey KE. Dev Dyn 2005; 232: 11-20. Medline 15580613

Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation. Stennard FA, Costa MW, Lai D, Biben C, Furtado MB, Solloway MJ, McCulley DJ, Leimena C, Preis JI, Dunwoodie SL, Elliott DE, Prall OW, Black BL, Fatkin D, Harvey RP. Development 2005; 132: 2451-2462. Medline 15843414

Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Vance KW, Carreira S, Brosch G, Goding CR. Cancer Res 2005; 65: 2260-2268. Medline 15781639

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Ayse Elif Erson, Elizabeth M. Petty 2005 Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -606- Erson AE, Petty EM . TBX2 (T-box 2). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TBX2ID42485ch17q23.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -607- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TMPRSS3 (transmembrane protease, serine 3)

Identity Note Not to be confused with TMPRSS4 (11q23.3), which was originally named TMPRSS3 Other DFNB10 (deafness, autosomal recessive 10) names DFNB8 (deafness, autosomal recessive 8) TADG12 (Tumor associated differentially-expressed gene-12

protein) ECHOS1 Hugo TMPRSS3 Location 21q22.3 DNA/RNA Description 13 exons spanning 24 kb Transcription Four alternative splice isoforms have been described, producing transcripts of 1.3 kb, 2.1 kb, 2.4 kb and 2.5 kb, respectively Protein

Description Isoform A (full length) is 454 amino acids; isoforms B and C lack 127 aa at the N-terminus due to alternative splicing; isoform D is 344 aa and has a unique C-terminus due to alternative splicing. The full length isoform comprises an LDL-receptor A domain, a Scavenger receptor (Srcr) domain and a peptidase S1 S6 domain, Expression Expressed in many fetal and adult tissues Localisation Transmembrane Function Transmembrane serine protease; exact function unknown Mutations Germinal Insertion, frameshift and missense mutations in the TMPRSS3 gene have been described in familial congenital (DFNB10) and childhood onset (DFNB8) deafness. Implicated in Entity Autosomal recessive neurosensory deafness; childhood-onset deafness (DFNB8); Autosomal recessive neurosensory deafness; congenital deafness (DFNB10)

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -608- Entity Ovarian Cancer Disease Variant D of TMPRSS3 has been reported to be overexpressed in ovarian carcinomas and has been proposed as a novel diagnostic marker. Prognosis High expression of variant D is correlated with advanced clinical stages of the disease.

Entity Pancreatic Cancer Disease TMPRSS3 has been reported to be overexpressed in pancreatic cancer. No information on splice variants or prognostic value is available.

External links Nomenclature Hugo TMPRSS3 GDB TMPRSS3 Entrez_Gene TMPRSS3 64699 transmembrane protease, serine 3 Cards GeneCards TMPRSS3 Ensembl TMPRSS3 CancerGene TMPRSS3 Genatlas TMPRSS3 GeneLynx TMPRSS3 eGenome TMPRSS3 euGene 64699 Genomic and cartography TMPRSS3 - 21q22.3 chr21:42665069-42689269 - 21q22.3 GoldenPath (hg17-May_2004) Ensembl TMPRSS3 - 21q22.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TMPRSS3 Gene and transcription

Genbank AB038157 [ SRS ] AB038157 [ ENTREZ ]

Genbank AB038158 [ SRS ] AB038158 [ ENTREZ ]

Genbank AB038159 [ SRS ] AB038159 [ ENTREZ ]

Genbank AB038160 [ SRS ] AB038160 [ ENTREZ ]

Genbank AF201380 [ SRS ] AF201380 [ ENTREZ ]

RefSeq NM_024022 [ SRS ] NM_024022 [ ENTREZ ]

RefSeq NM_032401 [ SRS ] NM_032401 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -609- RefSeq NM_032404 [ SRS ] NM_032404 [ ENTREZ ]

RefSeq NM_032405 [ SRS ] NM_032405 [ ENTREZ ]

RefSeq NT_086913 [ SRS ] NT_086913 [ ENTREZ ] AceView TMPRSS3 AceView - NCBI TRASER TMPRSS3 Traser - Stanford

Unigene Hs.208600 [ SRS ] Hs.208600 [ NCBI ] HS208600 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P57727 [ SRS] P57727 [ EXPASY ] P57727 [ INTERPRO ]

Prosite PS01209 LDLRA_1 [ SRS ] PS01209 LDLRA_1 [ Expasy ]

Prosite PS50068 LDLRA_2 [ SRS ] PS50068 LDLRA_2 [ Expasy ]

Prosite PS00420 SRCR_1 [ SRS ] PS00420 SRCR_1 [ Expasy ]

Prosite PS50287 SRCR_2 [ SRS ] PS50287 SRCR_2 [ Expasy ]

Prosite PS50240 TRYPSIN_DOM [ SRS ] PS50240 TRYPSIN_DOM [ Expasy ]

Prosite PS00134 TRYPSIN_HIS [ SRS ] PS00134 TRYPSIN_HIS [ Expasy ]

Prosite PS00135 TRYPSIN_SER [ SRS ] PS00135 TRYPSIN_SER [ Expasy ]

Interpro IPR002172 LDL_receptor_A [ SRS ] IPR002172 LDL_receptor_A [ EBI ]

Interpro IPR009003 Pept_Ser_Cys [ SRS ] IPR009003 Pept_Ser_Cys [ EBI ]

Interpro IPR001254 Peptidase_S1 [ SRS ] IPR001254 Peptidase_S1 [ EBI ]

Interpro IPR001314 Peptidase_S1A [ SRS ] IPR001314 Peptidase_S1A [ EBI ]

Interpro IPR001190 Srcr_receptor [ SRS ] IPR001190 Srcr_receptor [ EBI ] CluSTr P57727

PF00057 Ldl_recept_a [ SRS ] PF00057 Ldl_recept_a [ Sanger Pfam ] pfam00057 [ NCBI-CDD ] Pfam PF00089 Trypsin [ SRS ] PF00089 Trypsin [ Sanger ] pfam00089 [ NCBI- CDD ] Blocks P57727 Polymorphism : SNP, mutations, diseases OMIM 605511 [ map ] GENECLINICS 605511

SNP TMPRSS3 [dbSNP-NCBI]

SNP NM_024022 [SNP-NCI]

SNP NM_032401 [SNP-NCI]

SNP NM_032404 [SNP-NCI]

SNP NM_032405 [SNP-NCI]

SNP TMPRSS3 [GeneSNPs - Utah] TMPRSS3 [SNP - CSHL] TMPRSS3] [HGBASE - SRS] General knowledge Family TMPRSS3 [UCSC Family Browser] Browser SOURCE NM_024022

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -610- SOURCE NM_032401 SOURCE NM_032404 SOURCE NM_032405 SMD Hs.208600 SAGE Hs.208600

Enzyme 3.4.21.- [ Enzyme-SRS ] 3.4.21.- [ Brenda-SRS ] 3.4.21.- [ KEGG ] 3.4.21.- [ WIT ] Amigo function|chymotrypsin activity Amigo component|endoplasmic reticulum Amigo function|hydrolase activity Amigo component|integral to membrane Amigo component|integral to membrane Amigo function|peptidase activity Amigo process|perception of sound Amigo process|proteolysis and peptidolysis Amigo process|proteolysis and peptidolysis Amigo function|scavenger receptor activity Amigo function|trypsin activity PubGene TMPRSS3 Other databases Probes Probe TMPRSS3 Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness. Ben-Yosef T, Wattenhofer M, Riazuddin S, Ahmed ZM, Scott HS, Kudoh J, Shibuya K, Antonarakis SE, Bonne-Tamir B, Radhakrishna U, Naz S, Ahmed Z, Riazuddin S, Pandya A, Nance WE, Wilcox ER, Friedman TB, Morell RJ. J Med Genet 2001 Jun; 38(6): 396-400. Medline 11424922

Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, Guipponi M, Wang J, Kawasaki K, Asakawa S, Minoshima S, Younus F, Mehdi SQ, Radhakrishna U, Papasavvas MP, Gehrig C, Rossier C, Korostishevsky M, Gal A, Shimizu N, Bonne- Tamir B, Antonarakis SE. Nat Genet 2001 Jan; 27(1): 59-63. Medline 11137999

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -611- Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. Wattenhofer M, Di Iorio MV, Rabionet R, Dougherty L, Pampanos A, Schwede T, Montserrat-Sentis B, Arbones ML, Iliades T, Pasquadibisceglie A, D'Amelio M, Alwan S, Rossier C, Dahl HH, Petersen MB, Estivill X, Gasparini P, Scott HS, Antonarakis SE. J Mol Med 2002 Feb; 80(2): 124-131. Medline 11907649

Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Iacobuzio-Donahue CA, Ashfaq R, Maitra A, Adsay NV, Shen-Ong GL, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH. Cancer Res 2003 Dec 15; 63(24): 8614-8622. Medline 14695172

Pathogenic mutations but not polymorphisms in congenital and childhood onset autosomal recessive deafness disrupt the proteolytic activity of TMPRSS3. Lee YJ, Park D, Kim SY, Park WJ. J Med Genet 2003 Aug; 40(8): 629-631. Medline 12920079

Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan. Ahmed ZM, Li XC, Powell SD, Riazuddin S, Young TL, Ramzan K, Ahmad Z, Luscombe S, Dhillon K, MacLaren L, Ploplis B, Shotland LI, Ives E, Riazuddin S, Friedman TB, Morell RJ, Wilcox ER. BMC Med Genet 2004 Sep 24; 5(1): 24. Medline 15447792

The transmembrane protease serine (TMPRSS3/TADG-12) D variant: a potential candidate for diagnosis and therapeutic intervention in ovarian cancer. Sawasaki T, Shigemasa K, Gu L, Beard JB, O'Brien TJ. Tumour Biol 2004 May-Jun; 25(3): 141-148. Medline 15361711

A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein. Wattenhofer M, Sahin-Calapoglu N, Andreasen D, Kalay E, Caylan R, Braillard B, Fowler-Jaeger N, Reymond A, Rossier BC, Karaguzel A, Antonarakis SE. Hum Genet 2005 Jul 14; [Epub ahead of print] Medline 16021470

REVIEW articles automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -612- Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Malte Buchholz, Thomas M Gress 2005 Citation This paper should be referenced as such : Buchholz M, Gress TM . TMPRSS3 (transmembrane protease, serine 3). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TMPRSS3ID42593ch21q22.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -613- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CIP29 (cytokine induced protein 29 kDa)

Identity Note HCC-1 is an alias for CIP29 (12q13), but also for CCL14 (17q11.2) Other HCC-1 names Hugo CIP29 Location 12q13 Protein

Description 210 amino acids, 29 kDa;contains from N term to C term a SAP domain and 2 nuclear localization domains, and also 3 possible N-glycosylation sites and 9 potential phosphorylation sites. A SAP domain is a putative DNA binding motif involved in chromosomal organization and may regulate transcription, DNA repair, RNA processing. Expression Widely expressed in fetal and adult tissues, as well as cancer cell lines; upregulated by EPO (erythropoietin), TPO (thrombopoietin), FL (FLT3 Ligand), and SCF (stem cell factor). Associated with cell cycle progression Localisation Nucleus but some staining was also found in the cytoplasm. Implicated in Entity M4 acute non lymphocytic leukaemia (ANLL) with t(11;12)(q23;q13) - -> (MLL/CIP29) Note only one case to date Prognosis unknown Hybrid/Mutated 5' MLL - 3' CIP29 including the 9 first exons of MLL, and nearly the Gene entire CIP29 Abnormal The fusion protein includes from N term to C term the AT hooks and Protein the methyltransferase domain of MLL and the SAP domain and the C term nuclear localization domains of CIP29.

External links Nomenclature Hugo CIP29 GDB CIP29 Entrez_Gene CIP29 84324 cytokine induced protein 29 kDa

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -614- Cards Atlas CIP29ID42967ch12q13 GeneCards CIP29 Ensembl CIP29 Genatlas CIP29 GeneLynx CIP29 eGenome CIP29 euGene 84324 Genomic and cartography CIP29 - 12q13 chr12:54437325-54497773 - 12q13.2 (hg17- GoldenPath May_2004) Ensembl CIP29 - 12q13.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] HomoloGene CIP29 Gene and transcription

Genbank AJ409089 [ SRS ] AJ409089 [ ENTREZ ]

Genbank AF161434 [ SRS ] AF161434 [ ENTREZ ]

Genbank AF486281 [ SRS ] AF486281 [ ENTREZ ]

Genbank BC007099 [ SRS ] BC007099 [ ENTREZ ]

RefSeq NM_033082 [ SRS ] NM_033082 [ ENTREZ ]

RefSeq NT_086796 [ SRS ] NT_086796 [ ENTREZ ] AceView CIP29 AceView - NCBI TRASER CIP29 Traser - Stanford

Unigene Hs.505676 [ SRS ] Hs.505676 [ NCBI ] HS505676 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases

SNP CIP29 [dbSNP-NCBI]

SNP NM_033082 [SNP-NCI]

SNP CIP29 [GeneSNPs - Utah] CIP29 [SNP - CSHL] CIP29] [HGBASE - SRS] General knowledge Family CIP29 [UCSC Family Browser] Browser SOURCE NM_033082 SMD Hs.505676 SAGE Hs.505676 Amigo function|DNA binding Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -615- Amigo process|regulation of translation Amigo process|transcription PubGene CIP29 Other databases Probes Probe CIP29 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Cloning and characterization of a proliferation-associated cytokine-inducible protein, CIP29. Fukuda S, Wu DW, Stark K, Pelus LM. Biochem Biophys Res Commun 2002; 292: 593-600. Medline 11922608

A novel partner gene CIP29 containing a SAP domain with MLL identified in infantile myelomonocytic leukemia. Hashii Y, Kim JY, Sawada A, Tokimasa S, Hiroyuki F, Ohta H, Makiko K, Takihara Y, Ozono K, Hara J. Leukemia 2004; 18: 1546-1548. No abstract available. Medline 15284855

Growth inhibitory effect of Hcc-1/CIP29 is associated with induction of apoptosis, not just with G(2)/M arrest. Fukuda S, Pelus LM. Cell Mol Life Sci 2005; 62: 1526-1527. Medline 15924260 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Jean Loup Huret, Sylvie Senon 2005 Citation This paper should be referenced as such : Huret JL, Senon S . CIP29 (cytokine induced protein 29 kDa). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CIP29ID42967ch12q13.html

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LASP1 (LIM and SH3 protein)

Identity Other MLN50, EVI149 names Hugo LASP1 Location 17q12-21 from centromere to telomere are: TRAF4 (alias MLN62/CART1), MLLT6 (alias AF17), LASP1, STARD3 (alias MLN64), ERBB2 (alias c-erbB2), and RARA DNA/RNA Description LASP1 encompasses 51.65 kb on the genomic level and consists of 7 exons Transcription 3845 bp mRNA, 783 bp coding sequence Protein

Description 261 amino acids; 29 kDa. LASP1 encodes a member of a LIM (Lin-11, Isl-1 and Mec-3) protein subfamily and is characterized by a LIM motif (cysteine-rich LIM/double zinc finger motif) at the N-terminus, an SH3 domain (Src homology region 3) at the C-terminus, and two actin- binding domains in the core of the protein Expression ubiquitous Localisation intracellular, cytoplasmic; associated with the F-actin rich cortical cytoskeleton Function LASP1 plays an important role in the regulation of dynamic actin-based, cytoskeletal activities and cell motility. Agonist-dependent changes in LASP1 phosphorylation may also serve to regulate actin-associated ion transport activities, not only in the parietal cell but also in certain other F-actin-rich secretory epithelial cell types. Together, (LIM-) , Lasp-1, and may play an important role in the organization of focal adhesions. Homology LASP family of proteins: actin-binding repeats similar to those in LASP1 are also present in other nebulin-related proteins such as NEBL (nebulette, 107 kD actin-binding Z-disk protein) and NRAP (nebulin- related anchoring protein); NRAP also contains an N-terminal LIM domain and NEB (nebulin) a C-terminal SH3 domain, both of which are highly homologous to the respective domains of LASP1. Implicated in Entity t(11;17)(q23;q12) --> MLL-LASP1

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -617- Disease infant AML-M4; only one case described so far Abnormal the MLL-LASP1 chimeric protein consists of the AT-hook DNA-binding Protein domain and the methyltransferase motif including the CXXC zinc-finger domain of MLL and the SH3 domain of LASP1

Entity breast carcinomas Disease 17q11-q21 amplification is found in about 25% of primary breast carcinomas; simultaneous amplification and overexpression of LASP1 and ERBB2 Prognosis poor clinical outcome; increase risk of relapse

External links Nomenclature Hugo LASP1 GDB LASP1 Entrez_Gene LASP1 3927 LIM and SH3 protein 1 Cards Atlas Lasp1ID203 GeneCards LASP1 Ensembl LASP1 CancerGene LASP1 Genatlas LASP1 GeneLynx LASP1 eGenome LASP1 euGene 3927 Genomic and cartography GoldenPath LASP1 - chr17:34279894-34331541 + 17q12 (hg17-May_2004) Ensembl LASP1 - 17q12 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene LASP1 Gene and transcription

Genbank AK095958 [ SRS ] AK095958 [ ENTREZ ]

Genbank BC007367 [ SRS ] BC007367 [ ENTREZ ]

Genbank BC007560 [ SRS ] BC007560 [ ENTREZ ]

Genbank BC012460 [ SRS ] BC012460 [ ENTREZ ]

Genbank X82456 [ SRS ] X82456 [ ENTREZ ]

RefSeq NM_006148 [ SRS ] NM_006148 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -618- RefSeq NT_086877 [ SRS ] NT_086877 [ ENTREZ ] AceView LASP1 AceView - NCBI TRASER LASP1 Traser - Stanford

Unigene Hs.334851 [ SRS ] Hs.334851 [ NCBI ] HS334851 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q14847 [ SRS] Q14847 [ EXPASY ] Q14847 [ INTERPRO ]

Prosite PS00478 LIM_DOMAIN_1 [ SRS ] PS00478 LIM_DOMAIN_1 [ Expasy ]

Prosite PS50023 LIM_DOMAIN_2 [ SRS ] PS50023 LIM_DOMAIN_2 [ Expasy ]

Prosite PS50002 SH3 [ SRS ] PS50002 SH3 [ Expasy ]

Interpro IPR001781 LIM [ SRS ] IPR001781 LIM [ EBI ]

Interpro IPR000900 Nebulin [ SRS ] IPR000900 Nebulin [ EBI ]

Interpro IPR001452 SH3 [ SRS ] IPR001452 SH3 [ EBI ] CluSTr Q14847

Pfam PF00412 LIM [ SRS ] PF00412 LIM [ Sanger ] pfam00412 [ NCBI-CDD ] Pfam PF00880 Nebulin [ SRS ] PF00880 Nebulin [ Sanger ] pfam00880 [ NCBI- CDD ]

Pfam PF00018 SH3 [ SRS ] PF00018 SH3 [ Sanger ] pfam00018 [ NCBI-CDD ]

Smart SM00132 LIM [EMBL]

Smart SM00227 NEBU [EMBL]

Smart SM00326 SH3 [EMBL]

Prodom PD000094 LIM[INRA-Toulouse] Prodom Q14847 LAS1_HUMAN [ Domain structure ] Q14847 LAS1_HUMAN [ sequences sharing at least 1 domain ]

Prodom PD000094[INRA-Toulouse] Prodom Q14847 LAS1_HUMAN [ Domain structure ] Q14847 LAS1_HUMAN [ sequences sharing at least 1 domain ] Blocks Q14847 Polymorphism : SNP, mutations, diseases OMIM 602920 [ map ] GENECLINICS 602920

SNP LASP1 [dbSNP-NCBI]

SNP NM_006148 [SNP-NCI]

SNP LASP1 [GeneSNPs - Utah] LASP1 [SNP - CSHL] LASP1] [HGBASE - SRS] General knowledge Family LASP1 [UCSC Family Browser] Browser SOURCE NM_006148 SMD Hs.334851 SAGE Hs.334851 Amigo function|SH3/SH2 adaptor protein activity

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -619- Amigo function|actin binding Amigo component|cortical actin cytoskeleton Amigo process|cortical cytoskeleton organization and biogenesis Amigo component|cytoskeleton Amigo process|ion transport Amigo function|ion transporter activity Amigo function|zinc ion binding PubGene LASP1 Other databases Probes Probe LASP1 Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in LocusLink Bibliography Lasp-1 (MLN 50) defines a new LIM protein subfamily characterized by the association of LIM and SH3 domains. Tomasetto C. Moog-Lutz C. Regnier CH. Schreiber V. Basset P. Rio MC. FEBS Lett. 1995; 373: 245-249. Medline 7589475

Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to q11-q21.3 region of . Tomasetto C, Régnier C, Moog-Lutz C, Mattei G, Chenard MP, Lidereau R, Basset P, Rio MC. Genomics 1995; 28: 367-376. Medline 7490069

Two distinct amplified regions at 17q11-q21 involved in human primary breast cancer. Bieche I, Tomasetto C, Régnier C, Moog-Lutz C, Rio MC, Lidereau R. Cancer Research 1996; 56: 3886-3890. Medline 8752152

Lasp-1 is a regulated phosphoprotein within the cAMP signaling pathway in the gastric parietal cell. Chew CS, Parente JA Jr, Zhou C, Baranco E, Chen X. Am J Physiol 1998; 275: C56-67. Medline 9688835

Chromosomal assignment and expression pattern of the murine Lasp-1 gene. Schreiber V, Masson R, Linares JL, Mattei MG, Tomasetto C, Rio MC. Gene 1998; 207: 171-175. Medline 9511759

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -620-

Lasp-1, a novel type of actin-binding protein accumulating in cell membrane extensions. Schreiber V, Moog-Lutz C, Regnier CH, Chenard MP,Boeuf H, Vonesch JL, Tomasetto C, Rio MC. Molecular Medicine 1998; 4: 675-687. Medline 9848085

The LIM and SH3 domain-containing protein, lasp-1, may link the cAMP signaling pathway with dynamic membrane restructuring activities in ion transporting epithelia. Chew CS, Parente JA Jr, Chen X, Chaponnier C, Cameron RS. J Cell Sci 2000; 113: 2035-2045. Medline 10806114

Lasp-1 binds to non-muscle F-actin in vitro and is localized within multiple sites of dynamic actin assembly in vivo. Chew CS, Chen X, Parente JA Jr, Tarrer S, Okamoto C, Qin HY. J Cell Sci 2002: 4787-4799. Medline 12432067

Actin binding of human LIM and SH3 protein is regulated by cGMP- and cAMP- dependent protein kinase phosphorylation on serine 146. Butt E, Gambaryan S, Gottfert N, Galler A, Marcus K, Meyer HE. J Biol Chem 2003; 278: 15601-15607. Medline 12571245

The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21). Strehl S, Borkhardt A, Slany R, Fuchs UE, Konig M, Haas OA. Oncogene 2003; 22: 157-160. Medline 12527918

Phosphorylation of mouse LASP-1 on threonine 156 by cAMP- and cGMP- dependent protein kinase. Keicher C, Gambaryan S, Schulze E, Marcus K, Meyer HE, Butt E. Biochem Biophys Res Commun 2004; 324: 308-316. Medline 15465019

Zyxin interacts with the SH3 domains of the cytoskeletal proteins LIM-nebulette and Lasp-1. Li B, Zhuang L, Trueb B. J Biol Chem 2004; 279: 20401-20410. Medline 15004028

Regulation of cell migration and survival by focal adhesion targeting of Lasp-1.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -621- Lin YH, Park ZY, Lin D, Brahmbhatt AA, Rio MC, Yates JR 3rd, Klemke RL. J Cell Biol 2004; 165: 421-432. Medline 15138294

Actin-binding proteins in a postsynaptic preparation: Lasp-1 is a component of central nervous system synapses and dendritic spines. Phillips GR, Anderson TR, Florens L, Gudas C, Magda G, Yates JR 3rd, Colman DR. J Neurosci Res 2004; 78: 38-48. Medline 15372503

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Marie-Christine Rio 2000 Updated 08- Sabine Strehl 2005 Citation This paper should be referenced as such : Rio MC . LASP1 (LIM and SH3 protein). Atlas Genet Cytogenet Oncol Haematol. March 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/Lasp1ID203.html Strehl S . LASP1 (LIM and SH3 protein). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/Lasp1ID203.html

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MSI2 (musashi homolog 2 (drosophila))

Identity Other MSI2H names FLJ36569 MGC3245 Hugo MSI2 Location 17q23.2 DNA/RNA Description The gene spans 424 kb.on plus strand; at least 15 exons. Transcription alternate splicing; at least 3 transcripts, of which are transcripts of 1,6 and 2,1 kb. Protein

Description 328 amino acids, 35 kDa, and 251 amino acidsThe Musashi (Msi) family genes possess 2 ribonucleoprotein (RNP or ribonucleo particle)-type RNA recognition motifs (RRMs) in the N-term; each RRM comprises 2 highly conserved sequences called RNP1 and RNP2. Heterogeneous nuclear ribonucleoparticle (hnRNP) proteins are nuclear proteins implicated in hnRNA (pre-mRNA transcript) processing; Msi2 and Msi1 have similar RNA-binding specificity. Expression Ubiquitously expressed in various tissues; expressed predominently in precursor cells in the ventricular zone and subventricular zone of the central nervous system (CNS); in CNS stem cells during embryogenesis; in the postnatal and adult CNS, the expression of Msi2 and Msi1 disappear in most post mitotic or migrating cells, but is found in cells of the astrocyte lineage; coexpressed with Msi1. Function RNA-binding protein. Some RNA-binding proteins are neural-specific. The development of neural cells from precursors may be partly regulated at the post-transcriptional level by mRNA stabilization or translational control in the cytoplasm. Msi2 may have a unique role in CNS stem cells through life. Homology MSI1

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -623- Mutations Germinal Defective MSI2 might play a role in certain dementia (although this chromosomal region also contain several loci known to be involved in neurological disorders ( NF1 and others). Somatic see below. Implicated in Entity Chronic myelogenous leukemia (CML) in accelerated phase (AP- CML) with either a t(7;17)(p15;q23) and a HOXA9 / MSI2 hybrid gene, or a t(7;17)(q32-34;q23) and a ? possible gene of the plexin family/MSI2 hybrid gene. Hybrid/Mutated 5' MSI2 - 3' HOXA9 in the t(7;17)(p15;q23) Gene Oncogenesis In the t(7;17)(p15;q23) the fusion protein contains, from N-term to C- term, the 2 RNA recognition motifs of MSI2 and the the IME and the homeobox domain of HOXA9

External links Nomenclature Hugo MSI2 GDB MSI2 Entrez_Gene MSI2 124540 musashi homolog 2 (Drosophila) Cards Atlas MSI2ID42893ch17q23 GeneCards MSI2 Ensembl MSI2 Genatlas MSI2 GeneLynx MSI2 eGenome MSI2 euGene 124540 Genomic and cartography MSI2 - 17q23.2 chr17:52688930-53112298 + 17q23.2 (hg17- GoldenPath May_2004) Ensembl MSI2 - 17q23.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MSI2 Gene and transcription

Genbank AI798817 [ SRS ] AI798817 [ ENTREZ ]

Genbank AK093888 [ SRS ] AK093888 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -624- Genbank BC001526 [ SRS ] BC001526 [ ENTREZ ]

Genbank BC017560 [ SRS ] BC017560 [ ENTREZ ]

Genbank BE836557 [ SRS ] BE836557 [ ENTREZ ]

RefSeq NM_138962 [ SRS ] NM_138962 [ ENTREZ ]

RefSeq NM_170721 [ SRS ] NM_170721 [ ENTREZ ]

RefSeq NT_086883 [ SRS ] NT_086883 [ ENTREZ ] AceView MSI2 AceView - NCBI TRASER MSI2 Traser - Stanford

Unigene Hs.134470 [ SRS ] Hs.134470 [ NCBI ] HS134470 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 607897 [ map ] GENECLINICS 607897

SNP MSI2 [dbSNP-NCBI]

SNP NM_138962 [SNP-NCI]

SNP NM_170721 [SNP-NCI]

SNP MSI2 [GeneSNPs - Utah] MSI2 [SNP - CSHL] MSI2] [HGBASE - SRS] General knowledge Family MSI2 [UCSC Family Browser] Browser SOURCE NM_138962 SOURCE NM_170721 SMD Hs.134470 SAGE Hs.134470 Amigo function|RNA binding PubGene MSI2 Other databases Probes Probe MSI2 Related clones (RZPD - Berlin) PubMed PubMed 5 Pubmed reference(s) in LocusLink Bibliography Rna-binding protein Musashi2: developmentally regulated expression in neural precursor cells and subpopulations of neurons in mammalian CNS. Sakakibara S, Nakamura Y, Satoh H, Okano H. J Neurosci. 2001; 21: 8091-8107. Medline 11588182

RNA-binding protein Musashi family: roles for CNS stem cells and a

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -625- subpopulation of ependymal cells revealed by targeted disruption and antisense ablation. Sakakibara S, Nakamura Y, Yoshida T, Shibata S, Koike M, Takano H, Ueda S, Uchiyama Y, Noda T, Okano H. Proc Natl Acad Sci U S A. 2002; 99: 15194-15199. Medline 12407178

Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel cryptic balanced translocations during disease progression. Barbouti A, Johansson B, Hoglund M, Mauritzson N, Strombeck B, Nilsson PG, Tanke HJ, Hagemeijer A, Mitelman F, Fioretos T. Genes Chromosomes Cancer. 2002; 35: 127-137. Medline 12203776

A novel gene, MSI2, encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23). Barbouti A, Hoglund M, Johansson B, Lassen C, Nilsson PG, Hagemeijer A, Mitelman F, Fioretos T. Cancer Res. 2003; 63: 1202-1206. Medline 12649177

Vertebrate 2xRBD hnRNP proteins: a comparative analysis of genome, mRNA and protein sequences. Akindahunsi AA, Bandiera A, Manzini G. Comput Biol Chem. 2005; 29: 13-23. Medline 15680582

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST

Contributor(s) Written 08- Jean Loup Huret 2005

Citation This paper should be referenced as such : Huret JL . MSI2 (musashi homolog 2 (drosophila)). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MSI2ID42893ch17q23.html

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MTHFR (5,10-Methylenetetrahydrofolate reductase)

Identity Other MTR names MTHR Hugo MTHFR Location 1p36.22 DNA/RNA Description The gene encompasses 19.3 kb of DNA; 11 exons Transcription For MTHFR, transcripts of 9.0, 7.2, 6.3, 3.0 and 2.8 kb were observed. The different-sized transcripts result from alternate transcription start sites and multiple polyadenylation signals. The total abundance is low, and the proportion of each transcript differs among tissues. Protein

MTHFR metabolic pathway

Description 656 amino acids; 74.6 kDa protein. Expression Expression is more intense in testis, intermediate in brain and kidney, and lower in other tissues. Localisation Cytosolic Function MTHFR catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -627- Homology FAD-linked oxidoreductase Mutations Germinal Two common polymorphisms 677C-T and 1298A-C have been identified. These polymorphisms are responsible for the synthesis of a thermolabile form of MTHFR. The 677TT genotype was particularly common in northern China (20%), southern Italy (26%), and Mexico (32%). The 677C>T mutation in the MTHFR gene is an important cause of mild hyperhomocysteinaemia. The second polymorphism at nucleotide position 1298, is not as well characterized. Implicated in Entity Homocystinuria due to deficiency of methylenetetrahydrofolate reductase activity Disease This form of homocystinuria is caused by mutation in the 5,10-alpha- methylenetetrahydrofolate reductase gene. This homocystinuria is autosomal recessive and shows a wide range of clinical symptoms, such as developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders. In the classic form, both thermostable and thermolabile enzyme variants have been identified.

Entity Cancer Disease In some cancers, folate and other nutrients involved in the MTHFR metabolic pathway appear to interact with MTHFR polymorphisms to further modify cancer risk. In most studies, MTHFR 677TT and 1298CC are associated with moderately reduced colorectal cancer risk, in particular in individuals who had higher folate levels. In individuals with low folate intake and/or high alcohol consumption, cancer risk may be increased. Morever, both adults and children with the variant forms of MTHFR seems to have a decreased risk of lymphoid leukemias. MTHFR polymorphisms were also associated with other cancers as breast, head and neck, liver, gastric or lung cancers. Oncogenesis Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5- methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by MTHFR. Diminution in the activity of the MTHFR enzyme increases the pool of methyleneTHF at the expense of the pool of methylTHF. Enhanced availability of methyleneTHF in the DNA synthesis pathway reduces misincorporation of uracil into DNA, which might otherwise result in double-strand breaks during uracil excision repair processes, thus increasing the risk of chromosomal aberrations. Morever, the MTHFR polymorphisms influences DNA methylation status through interaction with folate status.

Entity Coronary Artery Disease

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -628- Disease The 677TT MTHFR allele was correlated with coronary artery disease. However, the role of this polymorphism in the causation of coronary artery disease is controversial.

Entity Depression Disease Hyperhomocysteinemia and the 677TT genotype were significantly related to depression.

To be noted MTHFR polymorphisms influence the metabolism of folates and could modify the pharmacodynamics of antifolates and many other drugs whose metabolism, biochemical effects, or target structures require methylation reactions. External links Nomenclature Hugo MTHFR GDB MTHFR Entrez_Gene MTHFR 4524 5,10-methylenetetrahydrofolate reductase (NADPH) Cards GeneCards MTHFR Ensembl MTHFR CancerGene MTHFR Genatlas MTHFR GeneLynx MTHFR eGenome MTHFR euGene 4524 Genomic and cartography MTHFR - 1p36.22 chr1:11780945-11800248 - 1p36.22 (hg17- GoldenPath May_2004) Ensembl MTHFR - 1p36.22 [CytoView]

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

Genbank AF105977 [ SRS ] AF105977 [ ENTREZ ]

Genbank AF105978 [ SRS ] AF105978 [ ENTREZ ]

Genbank AF105979 [ SRS ] AF105979 [ ENTREZ ]

Genbank AF105980 [ SRS ] AF105980 [ ENTREZ ]

Genbank AF105981 [ SRS ] AF105981 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -629- RefSeq NM_005957 [ SRS ] NM_005957 [ ENTREZ ]

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

Unigene Hs.214142 [ SRS ] Hs.214142 [ NCBI ] HS214142 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P42898 [ SRS] P42898 [ EXPASY ] P42898 [ INTERPRO ]

Interpro IPR004621 Fadh2_euk [ SRS ] IPR004621 Fadh2_euk [ EBI ] Interpro IPR003171 Mehydrof_redctse [ SRS ] IPR003171 Mehydrof_redctse [ EBI ] CluSTr P42898 Pfam PF02219 MTHFR [ SRS ] PF02219 MTHFR [ Sanger ] pfam02219 [ NCBI- CDD ] Blocks P42898 Polymorphism : SNP, mutations, diseases OMIM 607093 [ map ] GENECLINICS 607093

SNP MTHFR [dbSNP-NCBI]

SNP NM_005957 [SNP-NCI]

SNP MTHFR [GeneSNPs - Utah] MTHFR [SNP - CSHL] MTHFR] [HGBASE - SRS] General knowledge Family MTHFR [UCSC Family Browser] Browser SOURCE NM_005957 SMD Hs.214142 SAGE Hs.214142 Enzyme 1.5.1.20 [ Enzyme-SRS ] 1.5.1.20 [ Brenda-SRS ] 1.5.1.20 [ KEGG ] 1.5.1.20 [ WIT ] Amigo process|amino acid metabolism Amigo process|circulation Amigo process|methionine metabolism Amigo function|methylenetetrahydrofolate reductase (NADPH) activity Amigo function|oxidoreductase activity PubGene MTHFR Other databases Probes Probe MTHFR Related clones (RZPD - Berlin) PubMed PubMed 151 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -630- Bibliography Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Kang S-S, Wong P WK, Susmano A, Sora J, Norusis M, Ruggie N. Hum Genet 1991; 48: 536-545. Medline 1998339

Methylenetetrahydrofolate reductase (MR) deficiency: thermolability of residual MR activity, methionine synthase activity, and methylcobalamin levels in cultured fibroblasts. Rosenblatt DS, Lue-Shing H, Arzoumanian A, Low-Nang L, Matiaszuk N. Biochem Med Metab biol 1992; 47: 221-225. Medline 1627352

A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer2 M, Kluijtmans LAJ, van den Heuve LP, Rozen R. Nat Genet 1995; 10: 111-113. Medline 7647779

Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. Adams M, Smith PD, Martin D, Thompson JR, Lodwick D, Samani NJ. Quart J Med 1996; 89: 437-444.

Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Goyette P, Pai A, Milos R, Frosst P, Tran P, Chen Z, Chan M, Rozen R. Mammalian Genome 1998; 9: 652-656. Medline 9680386

Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G. Proc Natl Acad Sci 1999; 96: 12810-12815. Medline 10536004

Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Schwahn B, Rozen R. Am J Pharmacogenomics 2001; 1: 189-201. Medline 12083967

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -631- Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF, United Kingdom Childhood Cancer Study Investigators. Proc Natl Acad Sci 2001; 98: 4004-4009. Medline 11274424

A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Friso S, Choi S-W, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J. Proc Natl Acad Sci 2002; 99: 5606-5611. Medline 11929966

Multiple transcription start sites and alternative splicing in themethylenetetrahydrofolate reductase gene result in two enzyme isoforms. Tran P, Leclerc D, Chan M, Pai A, Hiou-Tim F, Wu Q, Goyette P, Artigas C, Milos R, Rozen R. Mammalian Genome 2002; 13: 483-492. Medline 12370778

Folate, vitamin B12, homocysteine, and the MTHFR 677C-T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Arch Gen Psychiat 2003; 60: 618-626. Medline 12796225

A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Heijmans BT, Boer JM, Suchiman HE, Cornelisse CJ, Westendorp RG, Kromhout D, Feskens EJ, Slagboom PE. Cancer Res 2003; 63: 1249-1253. Medline 12649184

Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer. Siemianowicz K, Gminski J, Garczorz W, Slabiak N, Goss M, Machalski M, Magiera- Molendowska H. Oncol Rep 2003; 10: 1341-1344. Medline 12883704

5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Robien K, Ulrich CM. Am J Epidemiol 2003; 157: 571-582. Medline 12672676

Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -632- polymorphisms in Linxian, China. Stolzenberg-Solomon RZ, Qiao YL, Abnet CC, Ratnasinghe DL, Dawsey SM, Dong ZW, Taylor PR, Mark SD. Cancer Epidemiol Biomarkers Prev 2003; 12 : 1222-1226. Medline 14652285

The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis. Saffroy R, Pham P, Chiappini F, Gross-Goupil M, Castera L, Azoulay D, Barrier A, Samuel D, Debuire B, Lemoine A. Carcinogenesis 2004; 25: 1443-1448. Medline 15033905

Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Sharp L, Little J. Am J Epidemiol 2004 ; 159: 423-443. Medline 14977639

One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Santella RM. Cancer Res 2005; 65: 1606-1614. Medline 15735051

Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: a case-control analysis. Neumann AS, Lyons HJ, Shen H, Liu Z, Shi Q, Sturgis EM, Shete S, Spitz MR, El- Naggar A, Hong WK, Wei Q. Int J Cancer 2005; 115: 131-136. Medline 15688408

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Raphael Saffroy, Antoinette Lemoine, Brigitte Debuire 2005 Citation This paper should be referenced as such : Saffroy R, Lemoine A, Debuire B . MTHFR (5,10-Methylenetetrahydrofolate reductase). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MTHFRID41448ch1p36.html

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© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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PAX5 (paired box gene 5)

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

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

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

Breakpoints

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

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

Genbank AF074913 [ SRS ] AF074913 [ ENTREZ ]

Genbank AF268279 [ SRS ] AF268279 [ ENTREZ ]

Genbank AF386790 [ SRS ] AF386790 [ ENTREZ ]

Genbank U56835 [ SRS ] U56835 [ ENTREZ ]

Genbank U56836 [ SRS ] U56836 [ ENTREZ ]

RefSeq NM_016734 [ SRS ] NM_016734 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -636- RefSeq NT_086749 [ SRS ] NT_086749 [ ENTREZ ] AceView PAX5 AceView - NCBI TRASER PAX5 Traser - Stanford

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

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

Prosite PS00034 PAIRED_BOX [ SRS ] PS00034 PAIRED_BOX [ Expasy ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ]

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

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

Smart SM00351 PAX [EMBL] Blocks Q02548

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

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

SNP PAX5 [dbSNP-NCBI]

SNP NM_016734 [SNP-NCI]

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

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -637- PubGene PAX5 Other databases Probes Probe PAX5 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography A novel B-cell lineage-specific transcription factor present at early but not late stages of differentiation. Barberis A, Widenhorn K, Vitelli L, Busslinger M. Genes Dev 1990; 4: 849-859. Medline 90337320 t(9;14)(p13;q32) denotes a subset of low-grade non-Hodgkin's lymphoma with plasmacytoid differentiation. Offit K, Parsa NZ, Filippa D, Jhanwar SC, Chaganti RS. Blood 1992; 80: 2594-2599. Medline 93043307

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

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

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

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

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -638- Medline 9722295

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

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

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

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

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

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

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

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

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -639- Transcriptional control of early B cell development. Busslinger M. Annu Rev Immunol 2004; 22: 55-79. Review. Medline 15032574

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

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

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

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

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PAX9 (Paired box gene 9)

Identity Other Paired box homeotic gene 9 names Hugo PAX9 Location 14q12 DNA/RNA Description 4 exons Transcription 3 alternative splicing isoforms Protein

Description 341 amino acids; 36.3kD Expression PAX9 is expressed in developing somites, specifically in the posterior ventrolateral region. These cells undergo an epithelial-mesenchymal transition, gaining increased motile capability as a consequence. Subsequent migration of this population generates the lateral sclerotome, which in turn gives rise to the ribs and neural arches. PAX9 contains a DNA binding paired domain, an octapeptide region and a carboxyl-terminal transactivation domain. Localisation Nuclear. Function PAX9 is a transcription factor that regulates the expression of genes involved in mediating cell proliferation, resistance to apoptosis, and cell migration. Mice homozygous for Pax9 mutations die shortly after birth, lacking the thymus, parathyroid glands and ultimobranchial bodies derived from the third and fourth pharangeal pouches, presenting aberrant head and visceral skeleton development and a complete absence of teeth. Homology PAX9 shares homology through the conserved paired box domain with the other members of the nine strong PAX gene family. Mutations Germinal PAX9 mutations are associated with oligodontia. Implicated in Entity Oligodontia Disease Caused by missense and frameshift PAX9 mutations. Patients present normal primary dentition but lack most permanent molars.

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Entity Jarcho-Levin syndrome Disease In humans, a reduction in expression levels of Pax9, together with those of the related Pax1 gene, have been reported in vertebral column chondrocytes of autopsied foeti presenting Jarcho-Levin syndrome, a segmentation anomaly affecting thoracic and vertebral skeletal development. This syndrome shares similarities with the phenotype of the Pax9/Pax1 double mutant mouse.

External links Nomenclature Hugo PAX9 GDB PAX9 Entrez_Gene PAX9 5083 paired box gene 9 Cards GeneCards PAX9 Ensembl PAX9 CancerGene PAX9 Genatlas PAX9 GeneLynx PAX9 eGenome PAX9 euGene 5083 Genomic and cartography PAX9 - 14q12 chr14:36200656-36215621 + 14q13.3 (hg17- GoldenPath May_2004) Ensembl PAX9 - 14q13.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PAX9 Gene and transcription

Genbank AJ238381 [ SRS ] AJ238381 [ ENTREZ ]

Genbank AJ238382 [ SRS ] AJ238382 [ ENTREZ ]

Genbank AJ238383 [ SRS ] AJ238383 [ ENTREZ ]

Genbank AY338688 [ SRS ] AY338688 [ ENTREZ ]

Genbank L09745 [ SRS ] L09745 [ ENTREZ ]

RefSeq NM_006194 [ SRS ] NM_006194 [ ENTREZ ]

RefSeq NT_086806 [ SRS ] NT_086806 [ ENTREZ ] AceView PAX9 AceView - NCBI TRASER PAX9 Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -642- Unigene Hs.132576 [ SRS ] Hs.132576 [ NCBI ] HS132576 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P55771 [ SRS] P55771 [ EXPASY ] P55771 [ INTERPRO ]

Prosite PS00034 PAIRED_BOX [ SRS ] PS00034 PAIRED_BOX [ Expasy ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ]

Interpro IPR001523 Paired_box_N [ SRS ] IPR001523 Paired_box_N [ EBI ] CluSTr P55771

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

Smart SM00351 PAX [EMBL] Blocks P55771 Polymorphism : SNP, mutations, diseases OMIM 167416 [ map ] GENECLINICS 167416

SNP PAX9 [dbSNP-NCBI]

SNP NM_006194 [SNP-NCI]

SNP PAX9 [GeneSNPs - Utah] PAX9 [SNP - CSHL] PAX9] [HGBASE - SRS] General knowledge Family PAX9 [UCSC Family Browser] Browser SOURCE NM_006194 SMD Hs.132576 SAGE Hs.132576 Amigo function|DNA binding Amigo process|development Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent PubGene PAX9 Other databases Probes Probe PAX9 Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography The paired box encodes a second DNA-binding domain in the paired homeo domain protein. Treisman J, Harris E, Desplan C. Genes Dev 1991; 5: 594-604. Medline 1672661

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -643-

Pax genes and organogenesis. Dahl E, Koseki H, Balling R. Bioessays 1997; 19: 755-765. (REVIEW) Medline 14747376

Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Peters H, Neubuser A, Kratochwil K, Balling R. Genes Dev 1998; 12: 2735-2747. Medline 9732271

Pax1 and Pax9 synergistically regulate vertebral column development. Peters H, Wilm B, Sakai N, Imai K, Maas R, Balling R. Development 1999; 126: 5399-5408. Medline 10556064

Mutation of PAX9 is associated with oligodontia. Stockton DW, Das P, Goldenberg M, D'Souza RN, Patel PI. Nat Genet 2000; 24: 18-19. Medline 10615120

Haploinsufficiency of PAX9 is associated with autosomal dominant hypodontia. Das P, Stockton DW, Bauer C, Shaffer LG, D'Souza RN, Wright T, Patel PI. Hum Genet 2002; 110: 371-376. Medline 11941488

Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review. Bannykh SI, Emery SC, Gerber JK, Jones KL, Benirschke K, Masliah E. Am J Med Genet A 2003; 120: 241-246. (REVIEW) Medline 12833407

A missense mutation in PAX9 in a family with distinct phenotype of oligodontia. Lammi L, Halonen K, Pirinen S, Thesleff I, Arte S, Nieminen P. Eur J Hum Genet 2003; 11: 866-871. Medline 14571272

Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome. Rodrigo I, Hill RE, Balling R, Munsterberg A, Imai K. Development 2003; 130: 473-482. Medline 12490554

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -644- Novel mutation of the initiation codon of PAX9 causes oligodontia. Klein ML, Nieminen P, Lammi L, Niebuhr E, Kreiborg S. J Dent Res 2005; 84: 43-47. Medline 15615874

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Ewan Robson, Jess Whall, Michael Eccles 2005 Citation This paper should be referenced as such : Robson E, Whall J, Eccles M . PAX9 (Paired box gene 9). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PAX9ID41644ch14q12.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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SET (SET translocation (myeloid leukemia- associated))

Identity Other I2PP2A, I-2PP2A (Phosphatase 2A inhibitor) names TAF-IBETA (Template activating factor I) PHAPII (HLA-DR associated protein II) IGAAD (Inhibitor of granzyme A-activated Dnase) Hugo SET Location 9q34 from centromere to telomere: SET, ABL1, NUP214 (alias CAN),

NOTCH1 (alias TAN1) DNA/RNA Description SET encompasses 6.81 kb on the genomic DNA; 8 exons Transcription 2577 bp mRNA Protein

Description two isoforms; isoform 1 (TAF1 alpha) 290 amino acids, 33.5 kDa; isoform 2 (TAF1 beta) - 277 amino acids, 23.1 kDa Expression widely expressed; highly expressed in Wilms' tumor Localisation cytoplasmic and nuclear; in the cytoplasm, found both in the cytosol and associated with the endoplasmic reticulum Function multitasking protein, involved in apoptosis, transcription, nucleosome assembly, and histone binding; potent inhibitor of protein phosphatase 2A; inhibits also EP300/CREBBP and PCAF-mediated acetylation of histones (HAT) - predominantly H4 - and nucleosomes; HAT inhibition leads to silencing of HAT-dependent transcription and prevents active demethylation of DNA Homology belongs to the nucleosome assembly protein (NAP) family Implicated in Entity t(9;9)(q34;q34) --> SET-NUP214 (alias CAN) Disease acute undifferentiated leukemia (AUL); only one case described so far Cytogenetics normal karyotype; may be overlooked

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -646- Hybrid/Mutated 5' SET - 3' NUP214 Gene Abnormal the SET-NUP214 (alias CAN) fusion protein consists of almost the Protein whole SET protein fused to the C-terminus of NUP214 Oncogenesis SET-NUP214 leads to disorganization of nuclear export

External links Nomenclature Hugo SET GDB SET Entrez_Gene SET 6418 SET translocation (myeloid leukemia-associated) Cards GeneCards SET Ensembl SET CancerGene SET Genatlas SET GeneLynx SET eGenome SET euGene 6418 Genomic and cartography SET - 9q34 chr9:128531415-128538221 + 9q34.11 (hg17- GoldenPath May_2004) Ensembl SET - 9q34.11 [CytoView]

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

Genbank AL356481 [ SRS ] AL356481 [ ENTREZ ]

Genbank AY349172 [ SRS ] AY349172 [ ENTREZ ]

Genbank BC032749 [ SRS ] BC032749 [ ENTREZ ]

Genbank CR536543 [ SRS ] CR536543 [ ENTREZ ]

Genbank CR542050 [ SRS ] CR542050 [ ENTREZ ]

RefSeq NM_003011 [ SRS ] NM_003011 [ ENTREZ ]

RefSeq NT_086756 [ SRS ] NT_086756 [ ENTREZ ] AceView SET AceView - NCBI TRASER SET Traser - Stanford

Unigene Hs.436687 [ SRS ] Hs.436687 [ NCBI ] HS436687 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -647- SwissProt Q01105 [ SRS] Q01105 [ EXPASY ] Q01105 [ INTERPRO ]

Interpro IPR002164 NAP_family [ SRS ] IPR002164 NAP_family [ EBI ] CluSTr Q01105

Pfam PF00956 NAP [ SRS ] PF00956 NAP [ Sanger ] pfam00956 [ NCBI-CDD ] Blocks Q01105 Polymorphism : SNP, mutations, diseases OMIM 600960 [ map ] GENECLINICS 600960

SNP SET [dbSNP-NCBI]

SNP NM_003011 [SNP-NCI]

SNP SET [GeneSNPs - Utah] SET [SNP - CSHL] SET] [HGBASE - SRS] General knowledge Family SET [UCSC Family Browser] Browser SOURCE NM_003011 SMD Hs.436687 SAGE Hs.436687 Amigo process|DNA replication Amigo component|endoplasmic reticulum Amigo function|histone binding Amigo process|negative regulation of histone acetylation Amigo process|nucleocytoplasmic transport Amigo process|nucleosome assembly Amigo process|nucleosome disassembly Amigo component|nucleus Amigo component|perinuclear region Amigo function|protein phosphatase inhibitor activity Amigo function|protein phosphatase type 2A regulator activity BIOCARTA Granzyme A mediated Apoptosis Pathway PubGene SET Other databases Probes Probe SET Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography Can, a putative oncogene associated with myeloid leukemogenesis, may be activated by fusion of its 3' half to different genes: characterization of the set

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -648- gene. von Lindern M, van Baal S, Wiegant J, Raap A, Hagemeijer A, Grosveld G. Mol Cell Biol 1992; 12: 3346-3355. Medline 1630450

Identification of in vivo phosphorylation sites of SET, a nuclear phosphoprotein encoded by the translocation breakpoint in acute undifferentiated leukemia. Adachi Y, Pavlakis GN, Copeland TD. FEBS Lett 1994; 340: 231-235. Medline 8131851

Identification and characterization of SET, a nuclear phosphoprotein encoded by the translocation break point in acute undifferentiated leukemia. Adachi Y, Pavlakis GN, Copeland TD. J Biol Chem 1994; 269: 2258-2262. Medline 8294483

Replication factor encoded by a putative oncogene, set, associated with myeloid leukemogenesis. Nagata K, Kawase H, Handa H, Yano K, Yamasaki M, Ishimi Y, Okuda A, Kikuchi A, Matsumoto K. Proc Natl Acad Sci USA 1995; 92: 4279-4283. Medline 7753797

The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. Li M, Makkinje A, Damuni Z. J Biol Chem 1996; 271: 11059-11062. Medline 8626647

Expression of SET, an inhibitor of protein phosphatase 2A, in renal development and Wilms' tumor. Carlson SG, Eng E, Kim E-G, Perlman EJ, Copeland TD, Ballermann BJ. J Am Soc Nephrol 1998; 9: 1873-1880. Medline 9773788

HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Fan Z, Beresford PJ, Zhang D, Lieberman J. Mol Cell Biol 2002; 22: 2810-2820. Medline 11909973

Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL- mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -649- Cell 2003; 112: 659-672. Medline 12628186

Effects of SET and SET-CAN on the differentiation of the human promonocytic cell line U937. Kandilci A, Mientjes E, Grosveld G. Leukemia 2004; 18: 337-340. Medline 14671643

Aberrant intracellular localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export. Saito S, Miyaji-Yamaguchi M, Nagata K. Int J Cancer 2004; 111: 501-507. Medline 15239126

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Sabine Strehl 2005 Citation This paper should be referenced as such : Strehl S . SET (SET translocation (myeloid leukemia-associated)). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SETID42272ch9q34.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -650- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TAL2 (T-cell acute lymphoblastic leukemia 2)

Identity Hugo TAL2 Location 9q31 from centromere to telomere: CSDUFD1, MGC45564, FCMD, TAL2,

C9ort87, ZNF462 DNA/RNA Description exons 1a, 2, 3, and 1b located 5-8 kb upstream of exon 4; coding region in exon 4 (326 bp) Transcription various mRNA isoforms were found in SUP-T3 and in the mouse, which also encompass upstream exons; gene products, however, always corresponded to the TAL2 protein encoded by exon 4 Protein

Description 108 amino acids; basic Helix Loop Helix motif for protein dimerization and DNA-binding Expression in adult testes; in developing midbrain, dorsal diencephalon, rostroventral diencaphalic/telencephalic boundary, and anterior pons; pivotal role in the development of the mature central nervous system; not expressed during normal hematopoietic development Function transcription factor; TAL2 dimerizes with members of the class A subgroup of bHLH proteins (ie E47, E12, E2-2, HEB), as well as LIM- only proteins LMO1 and LMO2; heterodimers are formed intracellularly through stable interaction between bHLH domains of TAL2 and E47; TAL2/E47 heterodimers bind DNA in a sequence-specific manner that is dependent on the E-box element; TAL2/E12 heterodimers also have DNA-binding activity; TAL2 does not bind DNA in absence of E2A proteins; a significant fraction (60%) of TAL2 polypeptides from SUP-T3 exist in phosphorylated form, the rest is unphosphorylated; serine residue 100 of TAL2 is the potential site of phosphorylation by MAP kinases. Homology TAL1 at 1p31, LYL1 at 19p13; TAL2, TAL1, and LYL1 share more than 85% amino acid identity in the bHLH domain and are thus more related to one other than to other bHLH proteins, for instance c-myc Implicated in Entity t(7;9)(q34;q32) -->TAL2-TCRB Disease T cell acute lymphoblastic leukemia found in < 1% of ALL, in 1-2% of

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -651- T-ALL, rare but recurrent Hybrid/Mutated Translocation of part of TCRB locus to a breakpoint 33 kb Gene downstream of TAL2 mediated by the V(D)J recombinase via a fortuitous recombination signal sequence (YRSS) on chromosome 9; the translocation results in a signal joint fusion of TAL2 YRSS with the Db1 23-RSS; this gene product was detected in 6 of 10 thymus samples of healthy children with an estimated frequency of 1 in 10 million thymic cells; only upon secondary rearrangement of the TAL2/Db signal joint to the Jb2.6 segment, and deletion of the intervening sequence, the typical TAL2/Jb2.6 T-ALL junctions could be observed which presumably lead to overexpression of TAL2 and development of leukemia. Abnormal TAL2 placed under control of TCRB enhancer leading to Protein overexpression of TAL2 in T-cells and development of leukemia

External links Nomenclature Hugo TAL2 GDB TAL2 Entrez_Gene TAL2 6887 T-cell acute lymphocytic leukemia 2 Cards GeneCards TAL2 Ensembl TAL2 CancerGene TAL2 Genatlas TAL2 GeneLynx TAL2 eGenome TAL2 euGene 6887 Genomic and cartography TAL2 - 9q31 chr9:105504333-105504659 + 9q31.2 (hg17- GoldenPath May_2004) Ensembl TAL2 - 9q31.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TAL2 Gene and transcription

Genbank M81078 [ SRS ] M81078 [ ENTREZ ]

Genbank S69377 [ SRS ] S69377 [ ENTREZ ]

Genbank BC069422 [ SRS ] BC069422 [ ENTREZ ]

RefSeq NM_005421 [ SRS ] NM_005421 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -652- RefSeq NT_086754 [ SRS ] NT_086754 [ ENTREZ ] AceView TAL2 AceView - NCBI TRASER TAL2 Traser - Stanford

Unigene Hs.247978 [ SRS ] Hs.247978 [ NCBI ] HS247978 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q16559 [ SRS] Q16559 [ EXPASY ] Q16559 [ INTERPRO ]

Prosite PS50888 HLH [ SRS ] PS50888 HLH [ Expasy ]

Interpro IPR001092 HLH_basic [ SRS ] IPR001092 HLH_basic [ EBI ] CluSTr Q16559

Pfam PF00010 HLH [ SRS ] PF00010 HLH [ Sanger ] pfam00010 [ NCBI-CDD ] Blocks Q16559 Polymorphism : SNP, mutations, diseases OMIM 186855 [ map ] GENECLINICS 186855

SNP TAL2 [dbSNP-NCBI]

SNP NM_005421 [SNP-NCI]

SNP TAL2 [GeneSNPs - Utah] TAL2 [SNP - CSHL] TAL2] [HGBASE - SRS] General knowledge Family TAL2 [UCSC Family Browser] Browser SOURCE NM_005421 SMD Hs.247978 SAGE Hs.247978 Amigo function|DNA binding Amigo function|protein binding Amigo process|regulation of transcription, DNA-dependent PubGene TAL2 Other databases Probes Probe TAL2 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Consistent breakage between consensus recombinase heptamers of chromosome 9 DNA in a recurrent chromosomal translocation of human T cell leukemia. Tycko B, Reynolds TC, Smith SD, Sklar J. J Exp Med 1989; 169: 369-377. Medline 2536065

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -653-

TAL2, a helix-loop-helix gene activated by the (7;9)(q34;q32) translocation in human T-cell leukemia. Xia Y, Brown L, Yang CYC, Tsan JT, Siciliano MJ, Espinosa R, Le Beau MM, Baer RJ. Proc Natl Acad Sci U S A 1991; 88: 11416-11420. Medline 1763056

TAL1, TAL2 and LYL1: a family of basic helix-loop-helix proteins implicated in T cell acute leukaemia. Baer R. Sem Cancer Biol 1993; 4: 341-347. Medline 8142619

Products of the TAL2 oncogene in leukemic T cells: bHLH phosphoproteins with DNA-binding activity. Xia Y, Hwang LY, Cobb MH, Baer R. Oncogene 1994; 9: 1437-1446. Medline 8152805

The leukemic oncogene Tal2 is expressed in the developing mouse brain. Mori S, Sugawara S, Kikuchi T, Tanji M, Narumi O, Stoykova A, Nishikawa SI, Yokota Y. Mol Brain Res 1998; 64: 199-210. Medline 9931488

The T cell oncogene Tal2 is necessary for normal development of the mouse brain. Bucher K, Sofroniew MV, Pannell R, Impey H, Smith AJH, Torres EM, Dunnett SB, Jin Y, Baer R, Rabbitts, TH. Dev Biol 2000; 227: 533-544. Medline 11071772

V(D)J-mediated translocations in lymphoid neoplasms: a functional asessment of genomic instability by cryptic sites. Marculescu R, Le T, Simon P, Jaeger U, Nadel B. J Exp Med 2002; 195: 85-98. Medline 11781368

Distinct t(7;9)(q34;q32) breakpoints in healthy individuals and T-ALL patients: signal joint reactivity as a novel pathway of V(D)J-mediated oncogene activation. Marculescu R, Vanura K, Le T, Simon P, Jaeger U, Nadel B. Nat Gen 2003; 33: 342-344. Medline 12567187

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -654- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Katrina Vanura 2005 Citation This paper should be referenced as such : Vanura K . TAL2 (T-cell acute lymphoblastic leukemia 2). Atlas Genet Cytogenet Oncol Haematol. August 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TAL2ID28ch9q31.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -655- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(X;21)(p22;q22)

Clinics and Pathology Disease Acute myeloid leukemia with maturation (AML M2) in one case only. Phenotype / CD13+, CD33+, CD34+, and CD117+ blast population consistent with cell stem AML-M2 by FAB subtype. origin Etiology Unknown. Epidemiology Single case involving 74 year old male. Clinics A 74-year-old Caucasian male patient with progressive weakness and fatigue without any ³B symptoms². Evolution Despite intensive induction chemotherapy with Ara-C, Mitoxantrone, Topotecan and Mylotarg, no remission was obtained. The patient developed prolonged pancytopenia and remained transfusion- dependent. Prognosis The patient died five months after diagnosis from an episode of febrile neutropenia. Genes involved and Proteins Gene PRDX4 Name Location Xp22 Dna / Rna About 24.4 kb in size and contains 7 exons. Protein PRDX4 is one of six peroxiredoxin-family genes, all of which are highly conserved in eukaryotes and prokaryotes and are ubiquitously expressed, being highest in pancreas, liver, heart and lowest in small intestine, thymus, spleen, and brain, and undetectable in peripheral- blood leukocytes. They use redox-active cysteines to reduce peroxides. In contrast to the intracellular localization of other family members, PRDX4 exists uniquely in the plasma, where the reduced form binds as a homodimer to heparan sulfate on endothelial cell surfaces. PRDXs are also implicated in a number of cellular functions such as cell proliferation and differentiation, enhancement of natural killer cell activity, protection of free radical sensitive proteins, hemoglobin metabolism, and intracellular signaling. PRDX4 plays a regulatory role in the activation of the transcription factor NF-kB by modulating IkB - alpha phosphorylation in the cytoplasm, and thus it is an immediate regulator of H2O2-mediated activation of NF-kB. In addition, PRDX1 or

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -656- PRDX2 null mice have hemolytic anemia and several malignancies including lymphoma, indicating the essential role of these genes in erythrocyte antioxidant defense and in tumor suppression. Gene RUNX1/AML1 Name Location 21q22 Dna / Rna Transcription from telomere to centreomere. Protein Contains the RUNT binding domain at 5' portion and the transactivation domain at 3' portion. Forms heterodimers; widely expressed; nuclear localization; a transcription factor and critical regulator of hematopoietic- cell development. Result of the chromosomal anomaly Hybrid AML1 is fused to PRDX4 in-frame. Two in-frame AML1-PRDX4 fusion gene transcripts were detected with alternative splicing of exon 6 of AML1. Description One was the fusion between exon 5 of AML1 and exon 2 of PRDX4; the other was between exon 6 of AML1 and PRDX4. Transcript No PRDX4-AML1 fusion transcript was detected.

Fusion Contains the RUNT binding domain of AML1 at 5' portion and two Protein highly conserved cysteine residue motifs of PRDX4 in 3' portion. The Description first exon of the PRDX4 gene codes for a signal peptide that allows the secretion of the PRDX4. The first exon is lost as a result of the translocation. Oncogenesis The hybrid gene could function with a dominant-negative effect on the normal AML1. The hybrid gene contains two cysteine residue motifs of the PRDX4 at the 3' portion, but not the signal peptide which allows the secretion of PRDX4, thus resulting in loss of at least one function of PRDX4 due to non-secretion. Recently, microarray studies on leukemia samples showed PRDX4 was down-regulated in APL with t(15;17) compared with all other AML samples.

External links Other t(X;21)(p22;q22) Mitelman database (CGAP - NCBI) database Other t(X;21)(p22;q22) 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

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -657- section. Bibliography PRDX4, a member of the peroxiredoxin family, is fused to AML1(RUNX1) in an acute myeloid leukemia patient with t(X;21)(p22;q22) translocation. Zhang Y, Emmanuel N, Kamboj G, Chen J, Shurafa M, Van Dyke D, Wiktor A, Rowley JD. Genes Chromosomes Cancer 2004; 40: 365-370. Medline 15188461

Contributor(s) Written 06- Yanming Zhang, Janet D Rowley 2005 Citation This paper should be referenced as such : Zhang Y, Rowley JD . t(X;21)(p22;q22). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/tx21p22q22ID1377.html

© Atlas of Genetics and Cytogenetics in Oncology and indexed on : Mon Aug 8 10:20:22 MEST Haematology 2005

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -658- Atlas of Genetics and Cytogenetics in Oncology and Haematology

12p rearrangements in ALL

Clinics and Pathology Disease acute lyphocytic leukemia (ALL) Phenotype / lack of specificity for particular immunophenotype, although more stem cell stem origin frequent in B-lineage cases origin Epidemiology approximately 10-15% of pediatric ALL cases, and 5% of adult ALL Prognosis recent data indicate no difference in overall outcome between childhood ALL cases with versus without 12p abnormalities, although there was an improved outcome for pseudodiploid patients with versus without a cytogenetic 12p abnormality; although a dic(9;12) has been reported to be associated with an excellent outcome, in a recent study, there was no difference in outcome between those patients with a dic(9;12) versus patients lacking an abnormal 12p. Cytogenetics Cytogenetics various aberrations result in an abnormal 12p; these include Morphological morphological balanced translocations with 12p breakpoints, del(12p), add(12p), monosomy 12, der(12)t(V;12)(V;p), and dic(V;12)(V;p); an abnormal 12p usually occurs as part of a more complex karyotype, and occurs as the sole aberration in less than 20% of cases with an abnormal 12p; in greater than 10% of cases both 12p homologues are abnormal; few cases with an abnormal 12p have more than 50 chromosomes Additional del(6q), del(13q) or monosomy 13, acquired +21; few recurring anomalies anomalies Genes involved and Proteins Note approximately half of patients with an abnormal 12p have a rearranged TEL gene Gene TEL (or ETV6) Name Location 12p13 Protein TEL proteins belong to the ETS family transcription factors; important in the vitelline angiogenesis and in the bone marrow hematopoiesis Bibliography

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -659- Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group. Behrendt H, Charrin C, Gibbons B, Harrison CJ, Hawkins JM, Heerema NA, Horschler-Botel B, Huret JL, Lai JL, Lampert F, et al Leukemia 1995 Jan;9(1):102-6 Medline 7845002

Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A Collaborative Studyof the Group Francais de Cytogenetique Hematologique. GFCO Blood 1996 Apr 15;87(8):3135-42 Medline 8605327

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia Chessels JM, Swansbury GJ, Reeves B, Bailey CC, Richards SM Br J Haematol 1997 Oct;99(1):93-100 Medline 9359508

12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia. Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew S, Hancock M, Pui CH, Rivera GK, Grosveld GC, Behm FG Blood 1997 Dec 1;90(11):4559-66 Medline 9373267

Contributor(s) Written 02- Nyla A. Heerema 2000 Citation This paper should be referenced as such : Heerema NA . 12p rearrangements in ALL. Atlas Genet Cytogenet Oncol Haematol. February 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/12pALLID1074.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -660- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(3;14)(p14;q32)

Clinics and Pathology Disease Extra-nodal Marginal Zone B-cell lymphoma (MZBCL) of mucosa- associated lymphoid tissue (MALT) type, also called MALT lymphoma Note MALT lymphomas without the t(3;14) are frequently associated with either a t(1;14)(p22;q32) ( BCL10 / IGH), a t(11;18)(q21;q21) ( API2 / MALT1, or a t(14;18)(q32;q21) (IGH/MALT1) Epidemiology 9 cases detected to date Clinics MALT lymphoma is an indolent disease involving most often the stomach, the lung, the thyroid, the salivary gland, the orbit, and the skin, with a non random anatomic distribution according to the translocation. The t(3;14) is frequently found in MALT lymphomas of the thyroid, the orbit, and the skin. Cytogenetics Additional +3 is found in half cases anomalies Genes involved and Proteins Gene FOXP1 Name Location 3p14.1 Protein Transcription factor; member of the FOXP subfamily, characterized by a DNA binding forkhead. Gene IGH Name Location 14q32 Result of the chromosomal anomaly Hybrid gene Breakpoint upstream the first 5' non coding exon of FOXP1 Description

External links

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -661- Other t(3;14)(p14;q32) Mitelman database (CGAP - NCBI) database Other t(3;14)(p14;q32) 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 T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. Leukemia 2005; 19: 652-658.

Contributor(s) Written 07- Jean Loup Huret 2005 Citation This paper should be referenced as such : Huret JL . t(3;14)(p14;q32). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0314p14q32ID1398.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -662- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(9;14)(q34;q32)

Clinics and Pathology Disease T cell acute lymhoblastic leukemia (T-ALL) Epidemiology only 1 case to date: a 16 yr old female patient Cytology high leukocytosis with 99% blasts with the phenotype of cortical thymocytes Prognosis yet unknown; the patient was in complete remission at 15 mths+. Cytogenetics Cytogenetics cryptic translocation: the karyotype appeared normal Morphological Cytogenetics FISH is needed Molecular Genes involved and Proteins Gene ABL1 Name Location 9q34 Gene EML1 Name Result of the chromosomal anomaly Hybrid gene 5' EML1 - 3' ABL1, fuses in frame exon 17 of EML1 to exon 2 of ABL1; Description

Fusion 190 kDa hybrid NH2 EML1 - COOH ABL1 protein, containing the Protein coiled-coil domain of EML1 and the kinase domain of ABL1. Description Oncogenesis EML1-ABL1 tyrosine kinase activity constitutively activated.

External links Other t(9;14)(q34;q32) Mitelman database (CGAP - NCBI)

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -663- database Other t(9;14)(q34;q32) 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 Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). De Keersmaecker K, Graux C, Odero MD, Mentens N, Somers R, Maertens J, Wlodarska I, Vandenberghe P, Hagemeijer A, Marynen P, Cools J. Blood. 2005; 105: 4849-4852. Medline 15713800

Contributor(s) Written 07- Jean Loup Huret 2005 Citation This paper should be referenced as such : Huret JL . t(9;14)(q34;q32). Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0914q34q32ID1399.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -664-

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Breast tumors : an overview

Classification Benign epithelial lesions with no significant tendency to malignant transformation include : adenoma:

o ductal o lactating o tubular

adenosis:

o apocrine o blunt duct o microglandular o sclerosing

fibroadenoma radial scar/complex sclerosing lesions Invasive breast carcinomas are divided into two major categories on the basis of their cytoarchitectural features: Invasive ductal carcinoma :

o acinic cell carcinoma o adenoid cystic carcinoma o apocrine carcinoma o cribriform carcinoma o glycogen-rich/clear cell o inflammatory carcinoma o lipid-rich carcinoma o medullary carcinoma o metaplastic carcinoma o micropapillary carcinoma o mucinous carcinoma o neuroendocrine carcinoma o oncocytic carcinoma o papillary carcinoma o sebaceous carcinoma o Secretory Breast Carcinoma o tubular carcinoma

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -665- lobular carcinoma

o pleomorphic o signet ring cell

The recognized precursor lesions of invasive breast carcinoma are : intraductal proliferative lesions:

o atypical ductal hyperplasia o ductal carcinoma in situ o florid o usual

lobular neoplasia/atypical lobular The terminology Invasive ductal/lobular carcinoma does not imply an origin form ducts and lobules, respectively, but the presence of cytoarchitectural and phenotypical features of ductal-type and lobular- type, respectively. Ductal adenocarcinoma is the most common. Lobular carcinoma is the second malignant breast tumour. Medullary carcinoma is rare. Hyperplasia is a proliferation without criteria of malignancy. Fibroadenomas are benign breast tumours. Clinics and Pathology Etiology The etiology is multifactorial. It involves diet, genetic and reproductive factors, and related hormone imbalances. Epidemiology The annual incidence of breast cancer is about 43/100 000 per year in France, and the mortality rate is about 18/100 000 per year. Invasive breast cancer is the most common carcinoma in women, accounting for 22% of all female cancers. One million women worldwide are diagnosed with breast cancer every year. The main factors of risk are: gender : women's risk for the development of invasive breast carcinoma is approximately 400 times that of men. age : breast cancer incidence increases rapidly with age. The mean age at diagnosis is around 60 yrs genetic factors : rare (3 to 5% of cancers and 1/500-800 women) but highly predictive of the disease. The areas of higher risk are the affluent populations of North America, Europa and Australia, where 6% of women develop invasive breast carcinoma before age 75. Pathology The most common histologic type of invasive breast carcinoma is designated as ductal, NOS (not otherwise specified). It comprises about 80% of all cases. It is a proliferation of epithelial cells from galactophoral ducts; it may be preceded and accompanied by an in situ component characterized by a proliferation of cells within the ducts without interuption of the basal membrane; when this membrane is

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -666- altered, the carcinoma is invasive. It can be graded on the basis of the architecture (amount of tubule formations), nuclear atypia and mitotic activity. The score resulting from the sum of these criteria (NottinghamÕs score) has been show to be an important prognostic indicator. A 3-grade system has been developed for in situ ductal carcinoma. Grade III in situ ductal carcinoma corresponds to the classic comedocarcinoma, whereas Grade I in situ ductal carcinoma merges with atypical ductal hyperplasia, to the point that some authors regard the two process as one and the same. Recently, a proposal has been made to embrace all of the various types of intraductal proliferative lesions under the term ductal intraepithelial neoplasia (DIN) and to divide this into 3 grades, having increasingly higher risk for the development of invasive carcinoma.

Many morphologic variants of invasive ductal carcinoma exist, some of them extremely rare. They include: tubular, cribriform, medullary, mucinous, neuroendocrine, papillary, micropapillary, apocrine, metaplastic, lipid-rich, secretory, oncocytic, adenoid cystic, acinic cell, glycogen-rich (clear cell), sebaceous, and inflammatory carcinoma. The prognosis of these subtypes varies, some of them having a better and some a worse outcome than invasive ductal carcinoma, NOS.

Invasive lobular carcinoma is the second major type (5-10%) of breast cancer. Like its ductal counterpart, it may be preceded or accompanied by an in situ component. It is histologically more homogeneous than ductal carcinoma, but some morphologic variation exist, such as pleomorphic and signet ring cell. Medullary carcinoma, already mentioned above as a rare subtype of invasive ductal carcinoma (1%) with a better prognosis, it has a very distinctive form: sharply circumscribed, accompanied by a heavy lymphoid infiltrate, of high nuclear grade, with a syncytial pattern of growth, and lacking in situ or microglandular features. When one of these features is lacking, the tumor is referred to as Òatypical medullary carcinoma". A high frequency of medullary carcinoma has been reported in patients with BRCA1 germ line mutation. The different steps in the progression of breast cancer are not well individualized. Hyperplasia is a proliferation of ductal or lobular epithelial cells, without criteria of malignancy; in contrast, atypical hyperplasia has incomplete malignant features and can be difficult to distinguish from in situ carcinoma. Fibroadenomas are the most common form of benign breast tumors.

These different forms of breast cancer may occur with (hereditary or familial forms) or without (sporadic forms) a familial background. Prognosis There are over 100 factors that have been identified as having prognostic significance in breast carcinoma , but only a minority of them will retain this property when subjected to a multivariate analysis.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -667- The most important prognostic factors are: presence and number of positive lymph nodes; tumor size; microscopic grade; and presence of lymphovascular invasion. Other parameters examined pathologically - such as hormone receptors and ERBB2/Neu - have more of a predictive than a prognostic value, in the sense of anticipating a certain type of response to specific forms of therapy. Upon diagnosis, the different presentations are classified upon morphological study, and the gravity and prognosis of the disease is estimated with several parameters that are : tumor size, tumor grade: it is calculated from assessment of tubular differentiation, number of mitoses, and nuclear polymorphism, the absence of estrogen and progesterone receptors, the presence of lymph node metastasis, peritumoral vascular invasion. Other parameters such as the proliferating index (Ki 67, S-phase), the ploidy, and the presence of P53 or ERBB2 alteration may also be useful for prognostic evaluation or as predictive factors for therapeutic response. Genetics Note Familial breast cancers are thought to represent about 5 to 10% of all breast cancers. Cytogenetics Cytogenetics Many of the chromosomal aberrations observed in breast carcinomas Morphological are not specific of this type of tumour; karyotypes of breast tumours frequently show multiclonality, suggesting the existence of a high degree of intratumoural heterogeneity.

Alterations of chromosome arms 1q, 3p, 6q, 8p are often present; i(1q) and der t(1;16) are frequent as sole anomalies; +7, +8 and +20 are also frequent; cytogenetic signs of DNA amplification, such as homogeneously staining regions (HSR), are commonly observed in breast carcinomas and seem preferentially associated to 8p. Cytogenetics LOH studies : loss of heterozygosity (LOH) has been associated with Molecular physical deletion of large genomic segments containing tumour suppressor genes; common regions of LOH in breast cancer are located on several chromosomes: 1p, 1q, 3p, 6q, 8p, 11q, 13q, 16q, 17p, 17q; almost all breast tumours show LOH in one or several regions; some regions are lost in more than 50% of tumors: 8p, 16q, 17p; precancerous lesions also show LOH.

CGH : Comparative genomic hybridization (CGH) is a molecular cytogenetics method designed to detect and map chromosomal regions showing abnormal copy numbers in tumors; theoretically, it is possible to detect equally copy number gains (DNA amplification or polyploidies) or losses using this approach; it appears, however, that CGH has a greater sensitivity for gains than for losses; this could be related to the fact that gains are generally of higher magnitude than losses and that losses can be obscured by intratumoral heterogeneity;

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -668- Overall CGH data show that breast tumor genomes undergo severe rearrangements; on average, breast tumors show 5-7 copy number changes/tumor; less than 10% of the tumors analyzed by CGH show neither gains nor losses; almost every chromosome presents at least one site with aberrant copy numbers, however, gains or losses are not evenly distributed throughout the genome.

Hot spots for gains are routinely observed at 1q (50-55% of the tumors), 8q (60%), 17q (25-30%), 20q (20-25%); gains generally involve subregions of each chromosomal arm and most prevalent regions are 1q31-q32, 8q12 and 8q24 (with MYC and other genes), 17q12 (ERBB2) and 17q23-q24, and 20q13; other regions of recurrent gains are 11q13 (20%, with CCND1), 8p12 (10-15%, and FGFR1), 16p (10-15%); recurrent losses are observed at 1p, 6q, 8p, 11q23- qter, 13q, 16q, 17p and 22q

CGH has revealed that copy number gains are common in breast tumors and involve 26 (!) chromosomal arms; these data somewhat contradict karyotypical analysis and LOH studies which indicate that losses are more frequent that gains; furthermore, it appears from CGH data that the number of events (gains and losses) increases in advanced cancer. Genes involved and Proteins Gene HRAS Name Location 11p15.5

Gene KRAS Name Location 12p12.1

Gene NRAS Name Location 1p13.2 Protein H, K, and NRAS genes are a subfamily of the huge RAS/RHO/RAB superfamily and encode ubiquitous cytoplasmic GTP binding p21 proteins involved in signal transduction. Somatic RAS genes are mutated at codons 12, 13 and 61in different types of mutation cancers; the frequency of mutations in breast cancer is rather low (<10%) compared to colorectal cancer or pancreatic cancer for instance.

Gene P53 Name Location 17p13

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -669- Dna / Rna 11 exons Protein The tumor suppressor gene P53 encodes an ubiquitous nuclear protein involved in the control of genome integrity by preventing cells from dividing before DNA damage is repaired; it has 5 conserved regions containing a transactivation domain, a DNA-binding domain, a tetramerization domain. Somatic 20-25% of breast cancers show P53 mutations and these correspond mutation to aggressive breast tumors (loss of estrogen receptor expression). 90% of P53 mutations are found within exons 5 through 9, portions correspondig to codons 165-185 (exon 5) and 235-252 (exon 7) concentrating 50% of the mutations (mutational hot spots); most frequently involved are codons 175, 248 and 273; mutations affecting residues 165-185 and 235-252 bear worse prognostic significance than others; these amino acid residues are located in the L2 and L3 domains of the p53 protein; both these domains bind a Zinc atom and convey contact to DNA; it may thus be of greater phenotypic significance. The majority of P53 mutations (80%) in breast cancer are missense, while nonsense mutations, deletions, insertions or, splice site mutations, which result in the truncation of the protein, make the rest (20%). Prolonged half-life of the protein can also be detected by immunohistochemistry and shows correlation with missense mutations.

Gene ERBB2 Name Location 17q21.2 Protein The ERBB2 (also called HER2 or NEU) gene encodes an integral type I protein of 185 kDa with a cysteine-rich extracellular region, a transmembrane domain and an intracellular region endowed with a tyrosine kinase activity. Somatic HER2 somatic mutations are reported in lung cancer, glioblastoma and mutation ovarian tumor. No somatic mutations in human breast carcinoma are described. Amplification : the ERBB2 gene is amplified and overexpressed in 20- 25% of breast tumors; tumors showing ERBB2 amplification have predominantly lost estrogen receptor expression (ER-) and are of ductal invasive type; interestingly, 70% of intraductal comedo carcinomas show ERBB2 expression, suggesting a role of this gene in the etiology of this breast tumor subtype ; Although ERBB2 amplification and overexpression are related to a worsened course of the disease, they do not represent independent prognostic indicators; However, the p185-ERBB2 protein being a transmembrane receptor with low levels of expression in normal tissues has turned out to be a very interesting target for therapeutical approaches; several protocols using engineered anti-ERBB2 antibodies have shown a good success rate.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -670- Gene CCND1 Name Location 11q13.3 Protein The CCND1 gene codes for a cell cycle protein specifically acting in the G1 phase; upon interaction with cyclin dependent kinases (CDK4 or CDK6) cyclin D1 phosphorylates the p105-RB protein and thereby promotes progression in late G1 thus favoring entry into S phase; ectopic overexpression of CCND1 has been shown to result in shortened G1 phase and increased genetic instability, possibly due to a bypass of cell cycle checkpoints. Somatic Amplification : the CCND1 gene is amplified in approximately 15% mutation breast cancers; CCND1 amplification is strongly correlated to expression of ER and is prevalent in invasive lobular carcinomas; univariate analysis and Cox model studies show that CCND1 amplification is an independent prognostic factor, however, it bears greatest significance in node positive patients.

Gene FGFR1 Name Location 8p11-12 Protein The FGFR1 gene encodes an integral type I protein of 145 kDa with an extracellular region made of three immunoglobulin-like domains, a transmembrane domain and an intracellular region endowed with a tyrosine kinase activity; alternative splicing create a large number of isoforms; it is a receptor for different members of the fibroblast growth factor family (FGF), which has about 20 members known to date. Somatic Amplification : the 8p11-12 region is amplified in about 10% of breast mutation carcinomas; the FGFR1 gene is overexpressed as a consequence of the amplification, and is a good candidate for being the driver gene of the 8p11-12 amplicon; FGFR1 is frequently amplified concomitantly with CCND1 (40% of FGFR1 amplified tumors also show CCND1 amplification); this coamplification of FGFR1 and CCND1 chromosomal regions results in the formation of a hybrid chromosomal structure in which amplified FGFR1 and CCND1 sequences are sequentially arranged.

Gene BRCA1 Name Location 17q21 Dna / Rna Large gene of 22 coding exons spaning more than 70 kb of genomic DNA; exon 11 corresponds to almost 50% of the total coding sequence (5592 nucleotides); the BRCA1 mRNA has a size of 7.8 kb, and a complex pattern of alternative splicing has been reported; it is expressed in numerous tissues (breast, ovary, testis, spleen, thymus ...). Protein the corresponding protein has 1863 amino acids, and 190-220 kDa;

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -671- BRCA1 is not a member of any known gene family; there is only two stretches of evolutionary conserved sequences between humans and mice: at the N-terminus (the RING finger motif), and at the C-terminus (the BRCT domain); the function of BRCA1 is still unknown but it seems to act as a tumor suppressor gene with transcriptional activity; it is involved in cell proliferation processes of mammary epithelial cells in response to hormonal stimulation, in apoptosis, control of recombination and genome integrity after binding to proteins involved in these activities. Germinal more than 300 sequence variations at the germline level have been mutation reported; a list is available on the BIC website:

the germline mutations are dispersed throughout the coding sequence; although a majority of these variations are unique, recurrent mutations such as 185delAG and 5382insC are observed; they were initially described in the Ashkenazy Jewish population; more than 80% of the sequence variants lead to a truncated protein; in contrast, the majority of missense mutations are of unknown clinical significance, excepted those in the RING finger region; in the BRCA1 families, an excess of breast, ovarian, and prostate cancers are seen; all mutations combined, penetrance at age 70 years works out at 56% to 87% in the case of breast cancer, and 16% to 63% in that of ovarian cancer

BRCA1-associated breast cancers have specific morphological features; they are more frequently of histoprognostic grade 3, highly proliferating and poorly differentiated tumors with a very pleomorphotic nuclear pattern; high frequencies of P53 alterations and negativity of steroid receptors are found in these tumors; a high rate of medullary breast carcinomas is observed among BRCA1-associated breast cancers; evidence for possible genotype-phenotype correlations have been provided concerning the tumor spectrum (breast/ovarian cancer incidence rate), the penetrance, and the proliferation rate of tumors Somatic in contrast, somatic mutations of BRCA1 coding sequence are rare in mutation breast/ovarian cancers

Gene BRCA2 Name Location 13q12-13 Dna / Rna like BRCA1 it is a large gene spanning more than 70 kb of genomic DNA; the coding sequence comprises 26 exons (10254 nucleotides) with three large ones (exons 10, 11, 27); the mRNA is of 11-12 Kb long; like BRCA1, it is expressed in various tissues. Protein The coresponding protein has 3418 amino acid residues (384 kDa), and is poorly conserved, exepted for the BRC repeats region in exon 11 (8 copies of 20-30 aa); like BRCA1, its function remains unknown; however, it acts as a tumor suppressor gene; transcriptional activation properties have been reported as well as involvement in the DNA repair system.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -672- Germinal more than 100 unique germ-line mutations are reported and are mutation dispersed throughout the coding sequence (cf the BIC website, address above); recurrent mutations are seen: 6174delT (of Ashkenazy Jewish origin), 999del5 (Icelandic), and 6503delTT (in France and in the UK); the majority lead to a truncated protein and are considered as disease- associated mutations, except for a polymorphic stop codon in exon 27; missense mutations are of uncertain clinical significance

BRCA2 germline mutations are associated with a high risk of male and female breast cancer; initially, the breast cancer risk was considered as equivalent to that of BRCA1, but in a recent work based only on the Icelandic recurrent BRCA2 999del5 mutation, the estimated risk of breast cancer at age 70 years is considered of only 37%; the ovarian cancer risk is lower than that of BRCA1; in addition, an excess of prostate and pancreas cancers is also seen

at the morphological level, BRCA2 breast cancers seem to be different from both BRCA1-associated breast cancers and sporadic cases, with a poor differentiation but no high proliferation rate; evidence for possible genotype-phenotype correlation has been provided concerning the tumor spectrum (breast/ovarian cancer incidence rate) Somatic somatic mutations of BRCA2 coding sequence are rare in mutation breast/ovarian cancers.

Gene BRCA3 Name Location An important breakthrough in the understanding of breast carcinogenesis came with the identification of the two major genes BRCA1 and BRCA2, correponding to 52% and 32% of hereditary breast cancer families, respectively; however, the germline mutations of these genes do not account for all familial cases; additional genes may be involved.

One such gene might be located on chromosome arm 8p; a positive linkage has first been found in a small set of French families, and then a lod score of almost 3 was obtained in one German family; in addition, the chromosome 8p12-22 region seems to be frequently involved in breast carcinogenesis as well as in different types od tumors (lung, prostate, ovarian); while the 8p12-22 region remain a strong candidate locus, whole-genome linkage studies are in progress to identify the other gene(s) that predispose to breast cancer.

Gene PTEN Name Location 10q23 Dna / Rna 9 exons Protein The PTEN protein (also called MMAC1) is an evolutionary conserved

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -673- dual-specificity phosphatase sharing extensive similarity with the cytoskeletal protein tensin; PTEN appears to be a tumor suppressor since biallelic inactivations are observed in several types of tumors; inactivating germline mutations are responsible for a cancer prone syndrome, the Cowden disease (see below); also, PTEN -/- ES cells are highly tumorigenic in syngeneic mice whereas PTEN +/- are not. Germinal Heterozygous germline mutations are responsible for the Cowden mutation disease, a cancer prone syndrome with high susceptibility to breast carcinoma, and, to a lesser degree, to thyroid carcinoma; most of the mutations are inactivating mutations, either by leading to protein truncation, or by introducing alterations in the phosphatase catalytic domain; germline mutations are also seen in the Bannayan-Riley- Ruvalcaba syndrome Somatic In spite of the initial description of PTEN homozygous deletion in two mutation breast tumor xenografts and biallelic inactivation of PTEN in two breast carcinoma cell lines, very few PTEN mutations have been observed in sporadic breast carcinoma (1 described mutation in more than 100 analyzed tumors).

Gene ATM Name Location 11q23 Dna / Rna The ATM gene covers 150 kb of DNA and is spread over 64 exons. It codes for a 13.000 bp transcript, translated into a 3500 aa protein. Protein Nuclear protein showing homology at its carboxy terminus with PI-3 kinase; belongs to a family of DNA damage signaling proteins characterized in either yeast or Drosophila; ATM interacts with the ABL protein and is known to transmit a signal to the P53 protein. ATM activity seems restricted to double strand DNA breaks induced by ionising radiations or radio-mimetics; it is noteworthy that the phenotype of Atm KO mice is very similar to that of ATM patients, but that heterozygous Atm +/- mutant mice do not show an increased incidence of cancer. Germinal The ATM gene is the genetic determinant to ataxia telangiectasia, a rare mutation recessive disorder, which among other clinical signs, is characterized by an extreme sensitivity to ionising radiations; it has been hypothesized that ATM could play a role in cancer predisposition because AT patients show a 100 fold increased risk of cancer, particularly hematological malignancies; furthermore, epidemiological studies have suggested that AT heterozygotes were also at increased risk of developing cancer, specially breast cancer in women; this, added to the fact that the ATM gene maps to 11q23, a region frequently affected by losses of heterozygosity, suggested that heterozygous mutations in the ATM gene may favor breast cancer development; ATM heterozygotes have been estimated to represent 1% of the total population. Most mutations reported in ATM kindreds result in the truncation of the protein.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -674- Gene Mismatch repair genes : MSH2 (2p21), MLH1 (3p21), PMS1 (2q31-33), Name PMS2 /GTBP/MSH6 (7p22), MSH3 (5q) Protein The proteins encoded by the mismatch repair genes are analogues of the bacteria Mut HLS system which is involved in the reparation of DNA replication errors; their defect leads to genomic instability, the most visible consequence of which is the presence of additional alleles at microsatellite markers; the latter are prone to replication errors; their alteration is a hallmark of genomic instability, also called RER (replication error) or MSI (microsatellite instability) phenotype. Somatic Frequencies of genomic instability varies from 0 to 40% in breast mutation cancer, depending on studies; however, mutations of mismatch repair genes are uncommon in breast cancer; thus, the high frequencies observed may be due to unknown genes involved in the control of DNA integrity.

Gene E-Cadherin Name Location 16q22.1 Somatic Mutations and loss of expression of the E-cadherin gene, located on mutation chromosome arm 16q, is very frequentlly observed in breast lobular carcinomas.

External links Orphanet Breast cancer, familial Other On-Line Breast Cancer Mutation DataBase database

Bibliography FGFR1 and PLAT genes and DNA amplification at 8p12 in breast and ovarian cancers. Theillet C, Adelaide J, Louason G, Bonnet-Dorion F, Jacquemier J, Adnane J, Longy M, Katsaros D, Sismondi P, Gaudray P, Birnbaum D. Genes Chromosom Cancer 1993; 7: 219-226. Medline 94031964

E-cadherin is a tumour/invasion suppresor gene mutated in human lobular bbreast cancers Berx G, Cleton-Jansen AM, Nollet F, de Leeuw JF, Van de Vijver M, Cornelisse C, Van Roy F. EMBO J 1995; 14: 6107-6115. Medline 96134909

Genetic alterations in breast cancer. Bieche I and Lidereau R.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -675- Genes Chromosom Cancer 1995; 14: 227-251. Medline 96187122

Tumors of the breast. Heim S and Mitelman F. Cancer Cytogenetics, Wiley-Liss, 1995.

Loss of heterozygosity and linkage analysis in breast carcinoma : indication for a putative third susceptibility gene on the short arm of chromosome 8. Kerangueven F, Essioux L, Dib A, Noguchi T, Allione F, Geneix J, Longy M, Lidereau R, Eisinger F, Pebusque MJ, et al. Oncogene 1995; 10: 1023-1026. Medline 95206771

Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors : definition of phenotypic groups. Courjal F, Cuny M, Simony-LafontaineJ, Louason G, Speiser P, Zeillinger R, Rodriguez C, Theillet C. Cancer Res 1997; 57: 4360-4367. Medline 97470639

Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Kerangueven F, Noguchi T, Coulier F, Allione F, Wargniez V, Simony-Lafontaine J, Longy M, Jacquemier J, Sobol H, Eisinger F, Birnbaum D. Cancer Res 1997; 57: 5469-5474. Medline 98069841

Chromosomal imbalance maps of malignant solid tumors. Mertens F, Johansson B, H–glund M, Mitelman F. Cancer Res 1997; 57: 2765-2780. Medline 97349085

Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Rhei E, Bogomolniy F, Federici M, Borgen P, Boyd J. Cancer Res 1997; 57: 3657-3659. Medline 97433097

CCND1 and FGFR1 coamplification results in the colocalization of 11q13 and 8p12 sequences in breast tumor nuclei. Bautista S and Theillet C. Genes Chromosom Cancer 1998; 22: 268-277. Medline 98332327

Characterization of recurrent homogeneously staining regions in 72 breast

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -676- carcinomas. Bernardino J, Apiou F, Gerbault-Seureau M, Malfoy B, Dutrillaux B. Genes Chromosom Cancer 1998; 23: 100-108. Medline 98409392

Functions of the BRCA1 and BRCA2 genes. Bertwistle D and Ashworth A. Curr Op Genet Develop 1998; 8: 14-20. Medline 98190437

Recent advances in breast cancer biology. Eisen A and Weber B. Curr Op Oncol 1998; 10: 486-491. Medline 99035631

Mutations at BRCA1: the medullary breast carcinoma revisited. Eisinger F, Jacquemier J, Charpin C, Stoppa-Lyonnet D, Bressac-de Paillerets B, Peyrat JP, Longy M, Guinebretiere JM, Sauvan R, Noguchi T, Birnbaum D, Sobol H. Cancer Res 1998; 58: 1588-1592. Medline 98222929

Pathology and Genetics of Tumours the Breast and Female Genital Organs F.Tavassoli and P.Devilee . "World Health Organisation Classification of Tumours". IARC Press, Lyon,2003

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Daniel Birnbaum, Francois Eisinger, Jocelyne Jacquemier, 1999 Michel Longy,Hagay Sobol and Charles Theillet Updated 05- Maria Luisa Carcangiu, Patrizia Casalini, Sylvie Ménard 2005 Citation This paper should be referenced as such : Birnbaum D, Eisinger F, Jacquemier J, Longy M, Sobol H, Theillet C . Breast tumors : an overview. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://AtlasGeneticsOncology.org/Tumors/breastID5018.html Carcangiu ML, Casalini P, Ménard S . Breast tumors : an overview. Atlas Genet Cytogenet Oncol Haematol. May 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/breastID5018.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Pituitary Adenomas

Identity Note Pituitary adenomas are common benign monoclonal neoplasms accounting for approximately 15% of intracranial tumors, while occult adenomas are discovered in as many as 25% of unselected autopsies. Pituitary tumors are usually benign, but cause significant morbidity due to their critical location, expanding size, and/or inappropriate pituitary hormone expression. True malignant behaviour with metastatic spread is very rare. Classification

Note The relative incidence of the different pituitary adenomas subtypes is diagrammed in Fig.1

Various subtypes have been recognized on the basis of clinical presentation, as well as immunocytological and ultrastructural characteristics. About one-third of pituitary adenomas are not associated with clinical hypersecretory syndromes, but with symptoms of an intracranial mass such as headaches, hypopituitarism, or visual field

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -678- disturbances, and are classified as nonfunctioning pituitary adenomas (NFPAs). Clinically non-functioning adenomas (NFPA) are actually a diverse group of tumors that include LH-, FSH- secreting adenomas, null cell adenoma and oncocytoma.

The clinical features of all other pituitary adenomas are linked to the hypersecreted hormone(s) which mark the specific cell origin, allowing the tumors to be classified as:

Prolactinomas or PRL-secreting PA, the most common of all functional pituitary adenomas. The patients usually present with amenorrhea, infertility, and galactorrhea (females), impotence or infertility (males). Tumors expressing both PRL and GH are thought to originate from a common mammosomatotroph precursor cell. Somatotropinomas or GH-secreting PA, which cause acromegaly in adults, with bony acral changes in soft tissues and bone, and increased risk of hypertension, cardiac disease, and diabetes. Corticotropinomas or ACTH-secreting PA, leading to Cushing disease and adrenal steroid overstimulation. Features of hypercortisolism include truncal obesity, striae, muscle wasting, hirsutism, cardiovascular complications, osteoporosis, and psychiatric disturbances. Pure gonadotropinomas secreting intact FSH or LH are rarely encountered and may cause sexual dysfunction and hypogonadism. Thyrotropinomas cause a mild increase in thyroxine levels with inappropriate TSH levels. Clinics and Pathology Treatment PRL: medical therapy to reduce prolactin secretion and tumor size by using dopamine agonists such as bromocriptine, cabergoline and quinagolide. Trans-sphenoidal surgery may be required for drug resistant tumours or drug-intolerant individuals. NFPA: in the presence of clinical signs,the primary treatment is trans- sphenoidal surgery. Medical and radiation therapy are considered following incomplete tumor resection. Patients without clinical signs are followed-up by MRI scans and visual field checks GH: treatment depends on the adenoma size/activity and patient's age. Trans-sphenoidal surgery is the treatment of choice in most cases and can be dramatically effective, especially for microadenomas. Following surgery some patients may need radiotherapy and medical treatment with bromocriptine or somatostatin analogues to reduce prolactin secretion or inhibiting GH release from the pituitary. ACTH: the usual treatment is trans-sphenoidal surgery which leads to rapid disappearance of cortisol from the blood. When surgery is unsuccessful, radiotherapy is administered. Drugs such as metyrapone, ketoconazole and o,p'DDD are used to control cortisol levels, particularly before surgery. Evolution is dependent on adenoma subtype. A significantly higher frequency of multiple allelic deletions were found in invasive tumors compared to non-invasive tumors. Prognosis Usually favourable. Truly malignant metastatic behaviour is extremely

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -679- rare. The unresponsiveness to pharmacological treatment is associated with more aggressive behaviour. Genetics Note Little is known about the genetic defects leading to pituitary tumor formation, which likely involves multiple initiating and promoting factors. With the exception of activating mutations of GNAS1 which have been associated with 40% of somatotrophic adenomas and 10% of NFPAs, none of the candidate cell cycle, receptor, second messenger or related genes examined thus far appears to be responsible individually for more than a few percent of sporadic pituitary adenomas. Inactivation of p27kip1 and RB1 has been associated with the development of pituitary adenomas in mice, but no similar evidence has been achieved in human. MEN1A mutations, commonly found in patients affected by the MEN- 1 syndrome, are rarely found in sporadic pituitary adenomas, despite a menin variably diminished expression has been demonstrated. Increased expression of pituitary tumor transforming gene (PTTG) has been found in sporadic pituitary adenomas, and a role for this gene in pituitary cell proliferation is supported by development of multifocal plurihormonal focal pituitary adenomas in transgenic male mice overexpressing PTTG. A role for HMGA2 gene in pituitary oncogenesis has been pointed out by development of PRL adenomas in HMGA2 transgenic mice and the finding of HMGA2 expression, which is switched off in the adult pituitary gland, in human prolactinomas. Amplification and/or rearrangement of the HMGA2 gene, mapping to 12q14, was observed in most of the PRLs analyzed. Increased dosage of chromosome 12 appears to be a condition predisposing to selective overrepresentation of the 12q14 region and/or rearrangement of the HMGA2 gene. Expression of HMGA2 has been recorded also in human NFPA, which rarely harbor trisomy 12, suggesting a mechanism of activation different from that mainly operating in PRLs (Figure 2).

It remains to be determined which of the many oncogenes/growth factors and oncosuppressors reported overexpressed or underexpressed contribute to pituitary oncogenesis to identify the pathogenetic pathways which are altered in pituitary adenomas. Cytogenetics Note Cytogenetic analysis failed for some time to identify recurrent chromosomal anomalies which might correlate with a clinical adenoma subtype or with a defined tumor stage. Technical difficulties related to the size of the samples available after surgery and the low proliferative rate of pituitary cells account for the limited cytogenetic findings. Despite these constraints a small fraction of pituitary adenomas showed an abnormal karyotype characterized by hyperdiploid or near triploid modal chromosome numbers and rare random structural abnormalities. Microsatellite and interphase FISH studies indicated that trisomy of chromosome 12 is pathogenetically important, and represents the

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -680- most frequent cytogenetic alteration in human PRL. Chromosomes 5, 8 and X were also found to be preferentially overrepresented (Figure 3). Combined gains of the above chromosomes appear a non random pattern in pituitary adenoma. Comparative genomic hybridization (CGH) studies confirmed the cytogenetic and FISH evidence, but did not provide significant clues to specific subchromosomal regions.

Figure 2. Interphase and metaphase FISH of HMGA2 dosage in human pituitary adenomas. Dual-color FISH of 669g18 +698i6 BACs(targeting the entire HMGA2 genomic region, red) and pBR12 (alphoid-specific probe of chromosome 12,D12Z3locus, green) showing: (a) disomy of both regions in a NFPA tumor expressing HMGA2 and (b) increased number of signals given by HMGA2-specific BACs as compared to that given by the alphoid probe on a NFPA expressing HMGA2. Note one HMGA2 signal on a marker chromosome (arrowed). Figure 3. Interphase dual-color FISH of probes pBR12 (D12Z3 locus, green fluorescence) and pDMX1 (DXZ1 locus, red) showing trisomic and disomic dosage of chromosomes 12 and X respectively, in a PRL pituitary adenoma.

Bibliography Incidence, pathology, and recurrence of pituitary adenomas: study of 647 unselected surgical cases. Terada T, Kovacs K, Stefaneanu L, Horvath E. Endocr Pathol 1995; 6: 301-310. Medline 12114812

Cytogenetic study of pituitary adenomas. Bettio D, Rizzi N, Giardino D, Persani L, Pecori-Giraldi F, Losa M, Larizza L. Cancer Genet Cytogenet 1997; 98: 131-136. Medline 9332478

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The cytogenesis and pathogenesis of pituitary adenomas. Asa SL, Ezza S. Endocrine 1998; 19: 798-827. (REVIEW) Medline 9861546

Simple numerical chromosome aberrations Characterize Pituitary Adenomas. Larsen JB, Schroder HD, Sorensenb A-G, Bjerre P, Heim S. Cancer Genet Cytogenet 1999; 114: 144-149. Medline 10549272

Non random trisomies of chromosomes 5, 8 and 12 in the prolactinoma subtype of pituitary adenomas: conventional cytogenetics and interphase FISH study. Finelli P, Giardino D, Rizzi N, Buiatiotis S, Virduci T, Franzin A, Losa M, Larizza L. Int Journal of Cancer 2000; 86: 344-350. Medline 10760821

The epidemiology of endocrine tumours. Monson JP. Endocr Relat Cancer 2000; 7: 29-36. Medline 10808194

Pituitary tumors: pathophysiology, clinical manifestations and menagement. Arafah BM and Nasrallah MP. Int J Cancer 2001; 91: 809-814. Medline 11275984

Chromosomal aberrations in sporadic pituitary tumors. Trautman K, Thakker RV, Ellison DW, Ibrahim A, Lees PD, Harding B, Fischer C, Popp S, Bartram CR, Jauch A. Endocrine_Related Cancer 2001; 8: 287-305. Medline 11733226

The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas Finelli P, Pierantoni GM, Giardino D, Losa M, Rodeschini O, Fedele M, Valtorta E, Mortini P, Croce CM, Larizza L, Fusco A. Cancer Res 2002; 62: 2398-2405. Medline 11956103

Molecular defects in the pathogenesis of pituitary tumours Levy A, Lightman S. Front Neuroendocrinol 2003; 24: 94-127. (REVIEW) Medline 12763000

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -682- Pituitary disease: presentation, diagnosis, and menagement. Levy A. J Neurol Neurosurg Psychiatry 2004; 74: iii47-iii52. (REVIEW) Medline 15316045

Early Multipotential Pituitary Focal Hyperplasia in {alpha}GSU-driven Pituitary Tumor Transforming Gene (PTTG) Transgenic Mice. Abbud RA, Takumi I, Barker EM, Ren SG, Chen DY, Wawrowsky K, Melmed S. Mol Endocrinol 2005; 19: 1383-1391. Medline 15677710

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 05- Palma Finelli, Lidia Larizza 2005 Citation This paper should be referenced as such : Finelli P, Larizza L . Pituitary Adenomas. Atlas Genet Cytogenet Oncol Haematol. May 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/PituitAdenomID5051.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Noonan syndrome Identity Other Male Turner syndrome names Pseudo-Turner syndrome Inheritance Noonan syndrome is an autosomal dominant disorder. Rare cases with parental consanguinity have been described, but it is not clear that these represent true instances of autosomal recessive inheritance. Like many autosomal dominant disorders, a significant, but not precisely determined, percentage of cases represent de novo mutagenesis. The prevalence of Noonan syndrome has not been determined accurately to date. Most authors cite the figure of 1 in 1,000-2,500 live births. However, that estimate was not based on a population study. Fetal loss occurs for Noonan syndrome so disease incidence is higher than prevalence, but no estimate of the magnitude of this discrepancy is available. Clinics Phenotype Noonan syndrome is a clinically variable developmental disorder and clinics defined by short stature, facial dysmorphism and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high-arched palate and low-set, posteriorly rotated ears. Cardiovascular abnormalities, primarily pulmonic stenosis and hypertrophic cardiomyopathy, are present in up to 85% of affected individuals. Additional relatively frequent features are multiple skeletal defects (spine and chest), webbed neck, mental retardation, cryptorchidism and bleeding diathesis.

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Clinical features in Noonan syndrome. (A) Prenatal echography showing nuchal cystic hygroma; (B) dysmorphic facial features; (C) pectus deformities and cubitus valgus; (D) webbed neck; (E) schematic representation of major cardiac defects: 1, pulmonic stenosis; 2, hypertrophic cardiomyopathy; 3, atrial septal defects; 4, ventricular septal defects; 5, patent ductus arteriosus. (Figures kindly provided by G. Zampino, MD, Università Cattolica del Sacro Cuore, Rome, Italy).

Neoplastic Children with Noonan syndrome are predisposed to malignancies, risk juvenile myelomonocytic leukemia (JMML) most commonly. JMML, formerly termed juvenile chronic myeloid leukemia or chronic myelomonocytic leukemia, is a myeloproliferative/myelodysplastic disorder of childhood characterized by excessive proliferation of immature and mature myelomonocytic cells that originate from a pluripotent stem cell. In childhood, JMML accounts for approximately 30% of cases of myelodysplastic and myeloproliferative syndromes and 2% of leukemias. It typically presents in infancy and early childhood, and is often lethal. Recent studies have provided strong evidence that hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), due to a selective inability to down-regulate the RAS/MAPK cascade, plays a central role in the clonal cell growth characteristic of JMML. In approximately 15-30% of JMML cases, the pathological activation of the RAS/MAPK cascade results from oncogenic NRAS or KRAS2 mutations that specifically affect GTP hydrolysis, leading to the accumulation of RAS in the GTP-bound active conformation. JMML has been reported in children with neurofibromatosis type 1 (NF1), an

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -685- autosomal dominant disorder resulting from germline loss-of-function mutations of the NF1 tumor suppressor gene. In children with NF1 and JMML, the proliferative advantage of the leukemic cells results from a second hit, the somatic loss or inactivation of the normal NF1 allele. Since the NF1 gene product, neurofibromin, is a negative modulator of RAS function, this loss is associated with RAS hyperactivity. Remarkably, deregulated RAS function appears to be restricted to GM- CSF signaling in hematopoietic cells. More recently, somatic activating mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase (PTP) SHP-2, have been documented in approximately 35% of cases with JMML. Mutations in the PTPN11, RAS and NF1 genes are largely mutually exclusive in JMML, and their combined prevalence accounts for approximately 85% of cases. Acute lymphoblastic leukemia and solid tumors, particularly neuroblastoma and rhabdomyosarcoma, have also been documented with a relatively higher prevalence respect to the general population. Evolution In children with Noonan syndrome JMML may regress without treatment or follow an aggressive clinical course. By contrast, cases of JMML that arise in children without Noonan syndrome have a poor prognosis without hematopoietic stem cell transplantation. Other findings Note A significant percentage of Noonan syndrome cases arise from de novo PTPN11 mutations. Among fourteen informative families, each consisting of an affected individual heterozygous for a PTPN11 mutation and unaffected parents, the paternal origin of mutation has been demonstrated in all cases. Consistent with this finding, advanced paternal age was noted among fathers of sporadic Noonan syndrome cases, compared with fathers of the reference population. Moreover, when a parent is affected with Noonan syndrome and harbors a PTPN11 mutation, a sex-ratio bias is operative for offspring who inherit the defect. This bias favors males by a factor of 2:1. The available data point to this bias being attributable to sex-specific developmental effects of PTPN11 mutations that favor survival of affected male embryos compared to female ones. Genes involved and Proteins

Gene PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11) Name 12q24.1 Location centromere - FLJ34154 - RPL6 - PTPN11 - RPH3A - OAS1 - telomere DNA/RNA

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The PTPN11 gene and SHP-2 domain characterization. The coding exons are shown as numbered filled boxes. The functional domains of the protein, comprising two amino- terminal, tandemly arranged SH2 domains (N-SH2 and C-SH2) followed by a protein tyrosine phosphatase (PTP) domain, are shown below. Numbers below the domain structure indicate the amino-acid boundaries of those domains.

Description The PTPN11 gene counts 16 exons. Exon 1 contains the 5'-UTR and the translation initiation ATG, and a few additional codons. Exon 15 contains the stop codon and exon 16 contains a major portion of the 3'-UTR. Other features of the PTPN11 gene, such as the promoter region and enhancer elements have not been delineated. Pseudogene/TD> A number of speudogenes, sharing more than 92% nucleotide identity with PTPN11 cDNA (including the untranslated regions), have been documented in the human genome. All the pseudogenes harbour frameshift mutations and multiple stop codons. Three of the five pseudogenes are likely to be expressed but with distinct tissue distribution and expression level. Protein

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Figure 3: Three-dimensional structure of SHP-2 in its catalytically inactive conformation, as determined by Hof and co-workers. Residues involved in catalysis are shown (space fill). Figure 4: Location of SHP-2 mutated residues in human disease. (A) Noonan syndrome and LEOPARD syndrome (germ-line origin; N=224); (B) Noonan syndrome with juvenile myelomonocytic leukemia (germ-line origin; N=11); (C) hematologic malignancies, including juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia (somatic origin; N=97). The pictures show the Ca trace of SHP-2 in its catalytically inactive conformation. Affected residues are indicated with their side chains as black sticks.

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Description SHP-2 is a member of a small subfamily of cytoplasmic Src homology 2 (SH2) domain-containing protein tyrosine phosphatases. The amino- terminal SH2 (N-SH2 and C-SH2) domains selectively bind to short amino acid motifs containing a phosphotyrosyl residue and promote SHP-2 association with cell surface receptors, cell adhesion molecules and scaffolding adapters. Crystallographic data indicate that the N-SH2 domain also interacts with the PTP domain using a separate site. As these subdomains show negative cooperativity, the N-SH2 domain functions as an intramolecular switch controlling SHP-2 catalytic activation. Specifically, the N-SH2 domain interacts with the PTP domain basally, blocking the catalytic site. Binding of the N-SH2 phosphopeptide-binding site to the phosphotyrosyl ligand promotes a conformational change of the domain that weakens the auto-inhibiting intramolecular interaction, making the catalytic site available to substrate, thereby activating the phosphatase. Expression Widely expressed in both embryonic and adult tissues. Localisation Cytoplasmic. It binds to activated cell surface receptors, cell adhesion molecules and scaffolding adapters. Phosphorylation of two tyrosine residues at the C-terminus by activated tyrosine kinase receptors creates binding sites for other SH2 domain-containing signal transducers. Function SHP-2 functions as a intracellular signal transducer. It positively modulates signal flow in most circumstances, but can also function as negative regulator depending upon its binding partner and interactions with downstream signaling networks. SHP-2 positively controls the activation of the RAS/MAPK cascade induced by several growth factors, and negatively regulates JAK/STAT signaling. In most cases, SHP-2's function in intracellular signaling appears to be immediately proximal to activated receptors and upstream to RAS. The mechanisms of SHP-2's action and its physiological substrates are still poorly defined. However, both membrane translocation and PTPase activity are required for SHP- 2 function. SHP-2 is required during development. Embryos nullizygous for Shp-2 have defects in gastrulation and mesodermal patterning resulting in severe abnormalities in axial and paraxial mesodermal structures. Shp-2 function is also required for development of terminal and skeletal structures, semilunar valvulogenesis in the heart, and hematopoiesis. Homology PTPN6 (protein tyrosine phosphatase, non-receptor type, 6) previously known as SHP1 or SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase, 1). Mutations Note Studies reported PTPN11 mutation detection rates ranging between 33% to 60%. Differences in inclusion criteria stringency and recruiting strategies are likely to responsible for such variable mutation detection rate. It should also be emphasized that the mutation prevalence detected in any Noonan syndrome cohort is sensitive to its composition in terms of relative abundance of sporadic and familial cases, as

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -689- PTPN11 mutations appear to be more prevalent among families transmitting the trait compared to sporadic cases. With those issues stipulated, the contribution of PTPN11 mutations to the etiology of Noonan syndrome appears to be approximately 50%. A statistically significant association with pulmonary valve stenosis and lower incidence of hypertrophic cardiomyopathy was found among the group with PTPN11 mutations. Overall, a large percentage of PTPN11 mutation-negative individuals tended to exhibit fewer or mild clinical features of NS, even though approximately half of the Noonan syndrome patients without a PTPN11 mutation appeared clinically indistinguishable from typical PTPN11 mutation-positive patients. Germinal The vast majority of mutations affect residues residing at or close to the interface between the N-SH2 and PTP domains. Increasing evidence supports that a number of Noonan syndrome-causative mutations promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway in a ligand-dependent manner. Selection: 124A>G (T42A), 182A>G (D61G), 184T>G (Y62D), 188A>G (Y63C), 214G>T (A72S), 215C>G (A72G), 218C>T (T73I), 228G>T,C (E76D), 236A>G (N79R), 317A>C (D106A), 922A>G (N308D). Two specific missense mutations (836A>G, Y279C; 1403C>T, T468M) have been identified to recur in LEOPARD syndrome, a developmental disorder closely related to Noonan syndrome. A mouse model bearing the NS-causative Asp61Gly mutation in the Ptpn11 gene has been recently generated and characterized. The Ptpn11D61G/D61G genotype is embryonic lethal. At day E13.5, these embryos are grossly edematous and hemorrhagic, and have diffuse liver necrosis. A number of severe cardiac defects are also observed. Heterozygous embryos exhibit cardiac defects, proportionate growth failure and perturbed craniofacial development. Hematologic anomalies include a mild myeloproliferative disease. Ptpn11D61G/+ embryonic fibroblasts are characterized by a three-fold increased Shp-2 activity and increased association of Shp-2 with Gab1 after stimulation with EGF. Cell culture and whole embryo studies reveal that increased RAS/MAPK signaling is variably present, appearing to be cell-context specific. Somatic Somatic activating mutations in PTPN11 have been documented in a heterogeneous group of hematologic malignancies and pre-leukemic disorders, and rarely in certain solid tumors. Selection: 181G>T (D61Y), 182A>T (D61V), 205G>A (E69K), 214G>A (A72T), 215C>T (A72V), 226G>A (E76K), 226G>C (E76Q), 227A>T (E76V), 227A>G (E76G), 227A>C (E76A), 1471C>T (P491S), 1472C>T (P491L), 1504T>C (S502P), 1504T>G (S502A), 1520C>A (T507K), 1528C>A (Q510K).

External links Other GeneTests, Noonan syndrome database

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Other Sindrome di Noonan (Italian) database

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Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment of 118 patients. Burch M, Sharland M, Shinebourne E, Smith G, Patton M, McKenna W. J Am Coll Cardiol 1993; 22: 1189-1192. Medline 8409059

Mapping a gene for Noonan syndrome to the long arm of chromosome 12. Jamieson CR, van der Burgt I, Bradsy AF, van Reen M, Elsawi MM, Hol F, Jeffery S, Patton MA, Mariman E. Nat Genet 1994; 8: 357-360. Medline 7894486

Abnormal mesoderm pattering in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. Saxton TM, Henkemeyer M, Gasca S, Shen R, Rossi DJ, Shalaby F, Feng G-S, Pawson T. EMBO J 1997; 16: 2352-2364. Medline 9171349

Crystal structure of the tyrosine phosphatase SHP-2. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Cell 1998; 92: 441-450. Medline 9491886

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -691- Fine mapping of Noonan/cardio-facio-cutaneous syndrome in a large family. Legius E, Schollen E, Matthijs G, Fryns J-P. Eur J Hum Genet 1998; 6: 32-37. Medline 9781012

Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal. Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B. J Pediatr 1999; 135: 703-706 Medline 10586172

Mice mutants for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Chen B, Bronson RT, Klaman LD, Hampton TG, Wang J-F, Green PJ, Magnuson T, Douglas PS, Morgan JP, Neel BG. Nat Genet 2000; 24: 296-299. Medline 10700187

The SH2 tyrosine phosphatase Shp2 is required for mammalian limb development. Saxton TM, Ciruna BG, Holmyard D, Kulkarni S, Harpal K, Rossant J, Pawson T. Nat Genet 2000; 24: 420-423. Medline 10742110

Genetic heterogeneity in Noonan syndrome: Evidence for an autosomal recessive form. van der Burgt I, Brunner H. Am J Med Genet 2000; 94: 46-51. Medline 10982482

Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells. Qu C-K, Yu W-M, Azzarelli B, Cooper S, Broxmeyer HE, Feng G-S. Mol Cell Biol 2001; 18: 6075-6082. Medline 9742124

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD. Nat Genet 2001; 29: 465-468. Medline 11704759

Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 Gene.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -692- Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Am J Hum Genet 2002; 71: 389-394. Medline 12058348

PTPN11 mutations in LEOPARD syndrome. Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. J Med Genet 2002; 39: 571-574. Medline 12161596

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype- phenotype correlation, and phenotypic heterogeneity. Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD. Am J Hum Genet 2002; 70: 1555-1563. Medline 11992261

The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Neel BG, Gu H, Pao L. Trends Biochem Sci 2003; 28: 284-293. (Review) Medline 12826400

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Tartaglia M, Niemeyer CM, Fragale A. Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Nat Genet 2003; 34: 148-150. Medline 12717436

Mouse model of Noonan syndrome reveals cell type- and gene dosage- dependent effects of Ptpn11 mutation. Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL, Yang W, Pao LI, Gilliland DG, Epstein JA, Neel BG. Nat Med 2004; 10: 849-857. Medline 15273746

Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Bentires-Alj M, Paez JG, David FS, Keilhack H, Halmos B, Naoki K, Maris JM, Richardson A, Bardelli A, Sugarbaker DJ, Richards WG, Du J, Girard L, Minna JD, Loh ML, Fisher DE, Velculescu VE, Vogelstein B, Meyerson M, Sellers WR, Neel BG. Cancer Res 2004; 64: 8816-8820. Medline 15604238

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -693- Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Fragale A, Tartaglia M, Wu J, Gelb BD. Hum Mutat 2004; 23: 267-277. Medline 14974085

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Meshinchi S. Leukemia 2004; 18: 1831-1834. Medline 15385933

Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon KM. Blood 2004; 103: 2325-2331. Medline 14644997

Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome. Tartaglia M, Cordeddu V, Chang H, Shaw A, Kalidas K, Crosby A, Patton MA, Sorcini M, van der Burgt I, Jeffery S, Gelb BD. Am J Hum Genet 2004; 75: 492-497. Medline 15248152

Genetic evidence for lineage- and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M, Palmi C, Carta C, Pession A, Arico M, Masera G, Basso G, Sorcini M, Gelb BD, Biondi A. Blood 2004; 104: 307-313. Medline 14982869

SHP-2 and myeloid malignancies. Tartaglia M, Niemeyer CM, Shannon KM, Loh ML. Curr Opin Hematol 2004; 11: 44-50. (Review) Medline 14676626

Genotype-phenotype correlations in Noonan syndrome. Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A. J Pediatr 2004; 144: 368-374. Medline 15001945

Genotypic and phenotypic characterization of Noonan syndrome: New data

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -694- and review of the literature. Jongmans M, Sistermans EA, Rikken A, Nillesen WM, Tamminga R, Patton M, Maier EM, Tartaglia M, Noordam K, van der Burgt I. Am J Med Genet 2005; 134A: 165-170. Medline 15723289

Phenotypic and genotypic characterization of Noonan-like/multiple giant cell lesion syndrome. Lee JS, Tartaglia M, Gelb BD, Fridrich K, Sachs S, Stratakis CA, Muenke M, Robey PG, Collins MT, Slavotinek A. J Med Genet 2005; 42: e11. Medline 15689434

Germ-line and somatic PTPN11 mutations in human disease. Tartaglia M, Gelb BD. Eur J Med Genet 2005; 48: 81-96. (Review)

Noonan Syndrome and related disorders: Genetics and Pathogenesis. Tartaglia M, Gelb BD. Ann Rev Gen Hum Genet 2005; 6: 45-68.

Somatic PTPN11 mutations in childhood acute myeloid leukaemia. Tartaglia M, Martinelli S, Iavarone I, Cazzaniga G, Spinelli M, Giarin E, Petrangeli V, Carta C, Masetti R, Aricï M, Locatelli F, Basso G, Sorcini M, Pession A, Biondi A. Br J Haematol 2005; 129: 333-339. Medline 15842656

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Marco Tartaglia, Bruce D Gelb 2005 Citation This paper should be referenced as such : Tartaglia M, Gelb BD . Noonan syndrome. Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/NoonanID10085.html

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Genomic Imprinting: Parental differentiation of the genome

Keith Killian

July 2005

Overview: a mark about parental origin

Genomic imprinting is the biological process whereby a gene or genomic domain exists in a state of epigenetic differentiation that depends upon its parent of origin. Importantly, the establishment and propagation of these parent-specific genomic conformations does not alter the primary DNA sequence comprised of A, C, G, and T nucleotides. Genomic imprints may be covalent (DNA methylation) or non-covalent (DNA-protein and DNA-RNA interactions, genomic localization in nuclear space), and the process of imprinting encompasses the specialized nuclear enzymatic machinery that maintains parental epigenetic markings throughout the cell cycle. Because of genomic imprinting, the parent of origin of homologous genetic alleles in diploid individuals can be determined in the absence of DNA sequence polymorphisms and without recourse to parental DNA samples. As illustrated in Figure 1, alleles of imprinted genes look and behave differently, as determined by parent of origin.

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Figure 1 : Genomic imprinting results in parent-specific epigenetic differentiation and monoallelic gene expression. Parental imprints are established during gametogenesis as homologous DNA passes uniquely through sperm or egg; subsequently during embryogenesis and into adulthood, alleles of imprinted genes are maintained in two "conformational"/epigenetic states: paternal or maternal. The gamete-specific epigenotypes observed in egg and sperm may go through metamorphosis during embryogenesis into their somatic forms. While Gregor Mendel did not provide details of the anatomy of genes, a fundamental tenet of Mendelian principles of inheritance is that a gene's parent of origin does not influence its or recessiveness in phenotype determination. However, in sexually reproductive organisms including plants, insects, invertebrates, and chordates, the parental origin of genetic alleles often determines their fates. Mammals have diverged from other sexually reproductive organisms through the imprinting of a distinct family of genes involved in embryogenesis. For these imprinted genes, the diploid offspring distinguishes between maternally-inherited and paternally-inherited alleles, and selectively expresses only one of them while inactivating the other. Allelic parental discrimination and silencing at imprinted loci is imperative in the procreation of wild type mammalian progeny. The life history of these genes- including when in the past, why, and how they became imprinted- remains a mystery which fascinates evolutionary and developmental biologists, as well as clinicians seeking answers and remedies for "non-Mendelian" inherited human genetic disorders. Most studies of mammalian imprinting have investigated the phenomenon in mice or humans, but recent studies of a wide variety of mammals, including monotreme (egg-laying), marsupial (altricial offspring carried in a pouch), and eutherian ("placental") mammals are helping unravel the origins and mechanisms of the unique family of imprinted genes. Recent focus on the physical structure and biochemisty of imprinted chromatin domains also is providing an image of parental differentiation within the genome. The historical recognition, evolution, physical chromatin basis, and pathologic consequences of parental genomic imprinting will be reviewed in this article.

Historical discovery of parental genomic differences

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -697- An ancient puzzle for naturalists was the observation that parthenogenetic reproduction-asexual female reproduction- occurs naturally in many vertebrates such as birds and fishes but not mammals. However, in 1937 the renowned reproductive biologist and endocrinologist Gregory Pincus reported that he had successfully achieved "fatherless rabbits" via parthenogenesis. Such reports of parthenogenesis discount the need for sperm or male contributions to reproduction. Partly attributable to Pincus' parthenogenetic rabbit, and the powerful dual influences of Gregor Mendel's laws of genetic inheritance and the Watson-Crick model of the DNA double helix, epigenetic memory and inheritance were not initially widely recognized. That genes could exist in parent-specific conformations, and that these conformations could be self-templating from one cell division to the next, simply was not a mainstream viewpoint until recently. Following the initial report of successful parthenogenesis in rabbits, early experimental attempts by developmental biologists to produce parthenogenetic mice consistently failed to develop normally, but the "embryoids" did show various degrees of development and differentiation along embryonic lineages. It was therefore believed that successful parthenogenesis was more a matter of technical optimization of the procedure, and a fundamental need for sperm-derived nuclear genome is even discounted in some reports. Instead, the possible explanations included: asynchrony between the parthenogenone developmental stage and the uterine lining at the time of implantation; alterned nucleus:cytoplasmic ratio; failure due to absence of a sperm cytoplasmic factor; the expression of recessive lethal mutations; an incomplete zona reaction; or gene dosage effect related to X-chromosome imbalance (Graham, 1974). In parallel with such deliberate experimental manipulations to improve failing parthenogenesis attempts in mice, human pathologists were serendipitously approaching an explanation for failed mammalian parthenogenesis from a different realm of investigation, namely female germ cell tumors. Pathologic analysis of two peculiar human germ cell tumors provided the conceptual breakthrough for recognizing the fundamental functional difference between the maternal and paternal genomes during cell growth and differentiation (Linder et al., 1975; Kajii and Ohama, 1977; Wake et al., 1978). The histopathologic phenotype of ovarian teratomas reveals well-differentiated fetal structures of all three germinative layers (ectoderm, mesoderm, endoderm), while the hydatidiform mole contains no such elements, only extra-embryonic trophoblast elements. Both of these tumors arise from ovarian germ cells, and typically have a 46,XX normal karyotype. However, the teratoma is gynogenetic in origin (Figure 2) while the hydatidiform mole is androgenetic (Figure 3). Thus, as recognized in the mid 1970's, the developmental potential of ovarian germ cells is determined by the parental origin of the genome driving its development, indicating a fundamental distinction between the nuclear genomes of sperm and egg. Further analyses of pathologic specimenes ruled out a contributory role for parental origin of mitochondrial DNA or cytoplasmic factors in the differentiation of germ cell tumors.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -698- Figure 2 : Chromosomal studies of tri-embryo-lineage (endoderm, mesoderm, ectoderm) teratomas reveal a uniquely gynogenetic constitution.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -699- Figure 3 : Chromosomal studies of mono-extraembryonic-lineage (trophoblast) hydatidiform moles reveal a uniquely androgenetic constitution. As discussed by Wake, Takagi, and Sasaki (J Natl Cancer Inst, 1978): "In contrast to androgenetic ova producing only hydropic villi, parthenogenetic oocytes in the ovary produce several mature tissues. Remarkable differences in the end products of both types of conceptuses are of special interest with regard to the possible physiologic difference between maternally and paternally derived genome in the egg cytoplasm, influence of implantation site (ovary versus uterus), and interaction between mother and conceptus in early mammalian embryogenesis. Parthenogenetic or gynogenetic conceptuses developing in uteri, if existent, would help resolve these problems." As pointed out by Wake et al., analysis of human tumors could not control for potential effects of local environment in guiding developmental programming, for the teratomas develop with the ovary while hydatidiform moles develop in utero following passage through the oviduct; furthermore, various endocrinologic and developmental parameters obviously cannot be controlled for when studying human pathologic specimens. Nevertheless, pathologic human germ cell tumor analysis provided an early conceptual framework in the recognition of the different agendas of paternal versus maternal genomes during development.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -700- Figure 4 : Correlation of developmental end product with parental chromosome constitution described by Wake et al., 1978, and discussed above in the text.

Mouse pronuclear transplantation studies

Further mouse parthenogenesis and androgenesis experiments of the early 1980's provided functional evidence of heritable differences between the maternal and paternal programming of their germ cell genomes while controlling for many potential confounding factors. The pronuclear transplantation studies by McGrath and Solter (McGrath and Solter, 1984) and Surani and colleagues (Surani et al., 1984) provided the requisite parthenogenetic/gynogenetic conceptuses developing in uteri referred to by Wake et al. The series of pronuclear transplantation experiments directly confirmed that male and female parent-derived genomes direct fundamentally different developmental programs in developing embryos. In these experiments, a mature oocyte is devoided of its pronucleus while leaving the cytoplasm along with the mitochondria and other organelles intact; then this empty egg is reconstituted with either one sperm and one oocyte pronucleus (normal complement), two sperm pronuclei and no oocyte pronucleus (androgenetic complement), or two oocyte pronuclei and no sperm pronuclei (gynogenetic complement). After intrauterine implantation of the embryo or embryoids in pseudo pregnant mice, they differentially develop along lines remarkably homologous to the germ cell tumors in humans according to parental origin of nuclear genome (Figure 5).

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -701- Figure 5 : Mouse germ cell pronuclear transplant experiments convincingly demonstrate a different agenda for sperm- versus egg-derived nuclear genomes during development. Development in the absence of a sperm-derived genome (middle column) shows fairly good development of the embryo proper but failed development of the trophoblast lineage. Development in the absence of an egg-derived genome (right column) shows failed development of the embryo proper but exuberant trophoblast growth. Figure by permission, Nature.

First recognized human clinical syndromes related to genomic imprinting Clinical diseases

Following neoplastic teratoma and hydatidiform mole, the first human clinical syndromes recognized to result from imprinted loci were Prader-Willi syndrome and Angelman syndrome as reported in 1989 (Nicholls et al., 1989). These studies revealed that identical genetic deletions as well as uniparental disomy for a domain on 15q resulted in markedly different clinical phenotypes depending on the parental origin of the deletion/disomy.

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Figure 6: Recognition of imprinted inheritance of Prader-Willi and Angelman syndromes. Nicholls et al. reasoned that parentally imprinted gene(s) reside in human 15q11-13.

First identified specific imprinted genes

The idea that maternally-and paternally-derived alleles of certain genes function differently in the cell was further confirmed when the first distinct imprinted genes were identified. These were the genes coding for insulin like growth factor 2 (IGF2) and for its receptor, the mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) (Barlow et al., 1991; Dechiara et al., 1991). IGF2 is a critical fetal growth factor, while the M6P/IGF2R targets IGF2 for degradation and therefore suppresses fetal growth. Heterozygous mice that harbor null alleles of these genes have different phenotypes, depending on the sex of the parent from which they inherited the null allele. Genetic and molecular analyses in mice showed that IGF2 is expressed uniquely from the paternally-inherited allele, while M6P/IGF2R is expressed from the maternally- inherited allele.

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Figure 7: A mutant maternally-derived allele of Igf2r results in a malformed mouse embryo with placental overgrowth. Image from Wylie et al., AJP, 2003. The monoallelic expression of these and other imprinted genes, in a parent-of-origin- dependent manner, differs from the post-zygotic monoallelic expression of certain genes involved in olfaction and immunity. At present, some 4 score genes are known to be imprinted, and it is estimated that mammalian genomes may contain several hundred imprinted genes in total (Luedi PP et al., 2005.). In addition to identifying and validating the various imprinted genes, a major focus of current research in this field is to understand how and why some alleles "remember" their parental lineage long after pronuclear fusion in the zygote, while the majority of alleles "forget" from which parent they were inherited. This entails dissecting the unique physical chromatin structure and epigenetic DNA modifications, as well as the enzymatic processes that propagate them.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -704- Figure 8. Human imprinting map, showing genomic distribution of known imprinted genes and clinical syndromes. Figure from http://greallyoffice.aecom.yu.edu/. The relative diminished expression from one parental locus is sufficient to create a pathologic phenotype in heterozygous mutant animals in which the imprint gene null allele is inherited through the dominant/expressing parent. Similarly, in human uniparental disomies that encompass imprinted loci, diminished expression from imprinted loci is often syndromic. In fact, one strategy for identifying imprinted genes is based upon UPD genotype-phenotype correlations. Thus, the diminished gene expression from the stifled parental allele is biologically insufficient to support a healthy phenotype, and imprinted gene mutations are usually dominant when they affect the expressed allele. Feedback regulation of transcription at imprinted loci does not allow sufficient upregulation of transcription from the silenced allele, and organisms do not have recourse to the silenced otherwise wild- type allele in the event that the expressed allele is null.

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Figure 9: Pedigree of imprinted maternally expressed phenotype. The phenotype is expressed only when the mutant allele is inherited from the mother. Thus, mutant imprinted alleles can remain masked when they are paternally inherited, but clinically re-appear in one-half of children of carrier daughters. Clinical human diseases and syndromes stemming from the unique vulnerabilities of imprinted loci include : gestational trophoblastic disease, teratomas, Beckwith- Wiedemann syndrome, Prader-Willi syndrome, Angelman syndrome, Silver-Russell syndrome, transient neonatal diabetes, social-cognitive defects in Turner syndrome, and multiple neoplasias associated with loss of imprinting at oncogene loci. OMIM (On-line Mendelian (!) Inheritance in Man) database of the NCBI (United States National Center for Biotechnology Information) contains detailed entries on many imprinted genes and syndromes. In summary therefore, a mammalian individual's DNA contains information about the parental origin of numerous genes and, for these parentally-differentiated loci, improper balancing of allelic sex may have pathological effects.

Physical examination of imprinted chromosome domains

Epigenetic programming loosely refers to any modification to DNA that is imposed after DNA polymerase assembles the primary DNA sequence. Heritable epigenetic modifiers include physical as well as spatio-temporal programming of DNA, and candidate epigenetic markings capable of gene imprinting include cytosine methylation (Reik et al., 1987; Mayer et al., 2000; Figure 10), histone acetylation and other modifications, replication timing asynchrony, chromatin structure and nuclear localization. Molecular dissection of the Prader-Willi/Angelman syndrome imprinted domain on 15q provides a good example of the physical epigenetic modifications that can regulate an imprinted domain (reviewed by Soejima and Wagstaff, 2005; Figures 11 and 12).

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Figure 10: Immunostaining for 5-methyl cytosine in zygotes reveals a remarkable global methylation differentiation between the maternally- versus paternally- inherited chromosomes following fertilization. In particular, the paternally inherited chromosomes appear nearly completely demethylated beginning 6-8 hours after fertilization, while the maternal chomosome methylation persists.

Figure 11: 15mat imprinted domain: Physical examination of the imprinted domain on maternally inherited chromosome 15 reveals DNA cytosine methylation histone H3 tail methylation at lysine 9 recruitment of histone

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -707- deacetylating enzymes, and deacetylated histones. These features are typical of closed, transcriptionally inactive chromatin, creating a functional knockout of multiple genes in the domain (center panel), including an antisense transcript to UBE3A. Silencing of asUBE3A permits expression of UBE3A from the maternally inherited chromosome.

Figure 12: 15pat: The physical structure of the chromosome 15 PWS/AS domain inherited from the father is distinct from that from the mother. There is absent DNA cytosine 5-methylation, and tails of histones H3 and H4 are lysine 4- methylated and acetylated (H3-K4me and H4-Ac), respectively. There is recruitment of histone acetyltransferase (HAT) to the domain on the paternal chromosome. These features are typical of open, transcriptionally active chromatin. There is a "virtual" deletion of some genes in cis, including UBE3A and ATP10C.

Life cycle of an imprinted gene

The behavior/expression of imprinted genes does not depend on the sex of the individual in which those genes reside, but on the sex of the parent from which the particular allele was inherited. In diploid somatic cells of an individual mammal, maternal and paternal alleles co-exist, but in the case of an imprinted gene, normally only one allele is functionally active. Propagation of this situation means that each DNA replication must be followed by self-templated imprint maintenance. The alternate stage in the life cycle of imprinted alleles occurs in the germ line. Here the imprints manifest in somatic cells are erased and an appropriate sperm-specific or egg-specific imprint is established on all gametic alleles, presumably by gonad- specific factors that reprogram the alleles. The testis-specific transcription factor BORIS regulates imprint establishment in the male germ line, while a female germ line specific imprint regulatory molecule has yet to be identified. When a new individual is generated by fusion of an egg and a sperm, the situation found in the

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -708- parents is recreated. Thus, imprints cycle between periods of maintenance and establishment.

Mendel, Lamarck, and epigenetic inheritance

Genomic imprinting represents a violation of Mendelian principles of inheritance, one of which stipulates that the dominance of one genetic allele over another is an inherent function of the alleles themselves, and does not depend upon the parent of origin of the allele. For example, Mendel observed the patterns of dominance and recessiveness for such traits as flower color and seed shape were independent of whether the dominant trait derived from pollen or ovum. Such observations may indicate a resistance of genetic alleles to environmental influences, such as the different climatic or cellular environments in which the male and female germ cells are propagated. While parental imprinting does not invalidate the results of Mendel's work, it does constitute a significant inheritance mechanism not observed by Mendel (Figure 6). By contrast, genomic imprinting provides positive evidence that genomes can show heritable functional plasticity dependent on allele environment; such a concept of genetic inheritance was favored by Lamarck and discredited through much of the Twentieth Century.

Figure 13: Genomic imprinting, in which some genetic traits are determined by the parent-specific germ cell milieu, violates Gregor Mendel's (left panel) principles of inheritance; by contrast imprinting supports, or at least takes the edge off some of the anathema heaped on Jean-Baptiste Lamarck's (right panel) concept of inheritance.

Selection pressure for genomic imprinting

The consequences of imprinting are potentially disastrous since, for imprinted genes, animals have effectively abandoned the 'safety net' provided by diploidy and have shut-off a perfectly good gene copy. This drawback has spawned much philosophical debate over why imprinting could have possibly evolved, and furthermore, why it has been maintained throughout the mammalian radiation. One model proposes that

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -709- imprinting evolved precisely to prevent parthenogenesis, and that the imprinting of a few loci is a small price to pay to guarantee functional diploidy in all other genes. A second model proposes that imprinting evolved as a consequence of the action of the host defense system against parasitic foreign DNA and that the presence of imprinted genes in mammalian genomes represents the shutting-off of "innocent by- standers". Note that these two models suggest that imprinting is an adaptive mechanism beneficial to the survival of the species. They also assign an insignificant role to imprinting as a mechanism to control gene dosage. One prediction of the conflict hypothesis that - that imprinting is limited to viviparous animals - has been tested and the results support the hypothesis. Probably the most widely accepted model of imprinting evolution is known as the conflict hypothesis (Haig and Graham, 1991; Moore and Haig, 1991). The conflict hypothesis views imprinting not as a beneficial adaptation of the species but as the deleterious consequence of a reproductive scenario involving polygamy, viviparity, and substantial maternal investments in the offspring, in the absence of a similar level of investment by the father. According to the conflict model, once viviparity arose among mammalian ancestors, natural selection acting upon asymmetric parental investments in diploid offspring operates on two conflicting strategies. On the one hand it is to the male's advantage that his offspring extract a maximum amount of nutrients from the mother, for he is unlikely to mate with that female again, and this should maximize his reproductive success and that of his offspring. On the other hand it is to the female's advantage to ration her investment in any given offspring, thereby conserving her resources for herself and her future offspring. According to the conflict hypothesis, therefore, imprinting arose due to a genetic tug- of-war between the parents that is played out in the offspring, through antagonistic efforts to control gene dosage.

Figure 14: According the conflict hypothesis, genomic imprinting results from an interparental tug-of-war over the resources allocated the fetus by the mother during intrauterine gestation. The potential for conflicts between polygamous viviparous mammals is highlighted by the killing of lion young by non-paternal males (left). From the epigenomic perspective, the paternal epigenome can conflict with the maternal epigenome over offspring nutrient availability during intrauterine gestation Such conflicts are insufficient in oviparous animals such as monotreme mammals to drive the deleterious imprinted silencing of genes.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -710- Other predictions of this hypothesis are that imprinting occurs principally at fetal growth regulatory loci, that paternal epigenotypes drive expression of pro-growth genes while maternal epigenotypes suppress growth, and that such interparental conflicts exist especially under the reproductive physiology of viviparity.

Figure 15: The phylogenetic distribution of genomic imprinting of IGF2R in birds, egg-laying mammals, marsupial mammals, and placental mammals (Killian et al., 2001). Black lines: not imprinted, ancestors not imprinted; green: imprinted, maternally expressed; red: imprinting lost. Blue lines refer to presence or absence (dashed) of putative IGF2R intron 2 imprint control element, for more information please see original paper.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -711- Figure 16: The potential roles of placentation and viviparity in the evolution of imprinting have been investigated through the phyloepigenetic analysis of IGF2 and M6P/IGF2R imprinting in birds, monotreme mammals, and marsupials. To date, genomic imprinting has only been demonstrated in viviparous mammals, supporting the conflict hypothesis.

Mules, hinnies, and George Washington

Elucidating the phenomenon of imprinting has provided much insight into epigenetic regulation of development and cancer, but also helps explain centuries-old biological observations. Mule breeders 3 millennia ago observed that a horse mare crossed with a jack donkey yields a mule, whereas a horse stallion crossed with a jennet donkey produces a hinny, which has shorter ears, a thicker mane and tail, and stronger legs than the mule; thus indicating parental sex-dependent influence on phenotype. Although ancestral donkey crossers would likely have no problem with the concept and reality of parental genomic imprinting, imprinting more recently carries an iconoclastic aura, evidence of the powerful influence exerted by Gregor Mendel's writings; indeed, the phenomenon of imprinting has been classified within the realm of non-Mendelian genetics, as if Mendel's laws represent the Platonic ideal of genetic behavior.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -712-

Figure 17: No hinnies in Washington. Following is an account of the origin of the mule industry in the United States, as per the archives of the U.S. Library of Congress. In the late Eighteenth Century there were no mules in the United States, but George Washington had become interested in them after learning of their unique attributes as work animals. The requisite male donkeys needed to breed mules must have also been scarce, for Spain had a virtual monopoly on the ass industry and it was illegal to export ass from the Spanish territories. Washington made an inquiry with the U.S. ambassador to Spain, and in 1785 King Charles III of Spain sent a large jack donkey to George Washington as a gift. The donkey was named "Royal Gift" and became the father of the mule industry in the U.S. It is interesting to note the male sex of the donkey sent to Washington, which is required in order to breed a true mule. Thus, technically speaking, because of genomic imprinting, there were no hinnies only mules in early Washington. Of course, female donkeys must have been eventually obtained in order to propagate a breeding donkey population.

References

Barlow DP, Stoger R, et al. "The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus." Nature 1991; 349(6304): 84-87. PMID : 1845916 DeChiara TM, Robertson EJ, et al. "Parental imprinting of the mouse insulin-like growth factor II gene." Cell 1991; 64(4): 849-859. PMID : 1997210 Graham CF. "The production of parthenogenetic mammalian embryos and their use in biological research." Biol Rev Camb Philos Soc 1974; 49(3): 399-424. PMID : 4607224 Haig D, Graham C. "Genomic imprinting and the strange case of the insulin-like growth factor II receptor." Cell 1991; 64(6): 1045-1046. PMID : 1848481

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -713- Kajii T, Ferrier A, et al. "Anatomic and chromosomal anomalies in 639 spontaneous abortuses." Hum Genet 1980; 55(1): 87-98. PMID : 7450760 Kajii T, Ohama K. "Androgenetic origin of hydatidiform mole." Nature 1977; 268(5621): 633-634. PMID : 561314 Killian JK, Nolan CM, et al. "Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary." Hum Mol Genet 2001; 10(17): 1721-1728. PMID : 11532981 Knoll JH, Nicholls RD, et al. "On the parental origin of the deletion in Angelman syndrome." Hum Genet 1989; 83(2): 205-207. PMID : 2777263 Knoll JH, Nicholls RD, et al. "Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion." Am J Med Genet 1989; 32(2): 285-290. PMID : 2564739 Linder D, McCaw BK, et al. "Parthenogenic origin of benign ovarian teratomas." N Engl J Med 1975; 292(2): 63-66. PMID : 162806 Luedi PP, Hartemink AJ, et al. "Genome-wide prediction of imprinted murine genes." Genome Res 2005; 15(6): 875-884. PMID : 15930497 Mayer W, Niveleau A, et al. "Demethylation of the zygotic paternal genome." Nature 2000; 403(6769): 501-502. PMID : 10676950 McGrath J and Solter D. "Completion of mouse embryogenesis requires both the maternal and paternal genomes." Cell 1984; 37(1): 179-183. PMID : 6722870 Moore T and Haig D. "Genomic imprinting in mammalian development: a parental tug-of-war." Trends Genet 1991; 7(2): 45-49. PMID : 2035190 Nicholls RD, Knoll JH, et al. "Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome." Nature 1989; 342(6247): 281-285. PMID : 2812027 Reik W, Collick A, et al. "Genomic imprinting determines methylation of parental alleles in transgenic mice." Nature 1987; 328(6127): 248-251. PMID : 3600805 Surani MA, Barton SC, et al. "Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis." Nature 1984; 308(5959): 548-550. PMID : 6709062 Wake N, Takagi N, et al. "Androgenesis as a cause of hydatidiform mole." J Natl Cancer Inst 1978; 60(1): 51-57. PMID : 628023 Wylie AA, Pulford DJ, et al. "Tissue-specific inactivation of murine M6P/IGF2R." Am J Pathol 2003; 162(1): 321-328. PMID : 12507915

Contributor(s) Written 07- J Keith Killian 2005 Citation This paper should be referenced as such : Killian JK . Genomic Imprinting: Parental differentiation of the genome. Atlas Genet Cytogenet Oncol Haematol. July 2005 . URL : http://AtlasGeneticsOncology.org/Deep/GenomImprintID20032.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -714- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Neonatal Screening

I - INTRODUCTION

1- Neonatal screening for a metabolic disease must address a frequent pathology for which there is an efficient treatment and only if this treatment is applied early in life. 2- The screening must be universal 3- Urine sample screening test

II - PHENYLKETONURIA

1- Epidemiology 2- Physiopathology 3- Hyperphenylalaninemia 4- Dihydropteridin reductase deficiency 5- Hyperphenylalaninemia can be detected after a few of days of normal feeding 6- Clinical forms, differential diagnosis 7- Treatment 8- Dihydropteridine reductase deficiency version pdf III - CONGENITAL HYPOTHYROIDISM

1-Epidemiology 2-Neonatal screening 3-Dosage methods 4- Treatment

IV COROLLARY

1- Overview of international practices 2- Overview of diagnosable diseases 3- Treatment 4- Diseases with apparent symptoms during the post natal period 5- Genetic counselling / informed consent 6- Development *

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -715- I - INTRODUCTION

1- Neonatal screening for a metabolic disease must address a frequent pathology for which there is an efficient treatment and only if this treatment is applied early in life.

The universal screening of phenylketonuria and hypothyroidism are good examples of this concept. Those are diseases that affect approximately 1 out of 10,000 neonates,

• leading to a serious encephalopathy during the neonatal period if no efficient treatment is applied and for which there are screening tests that are: • specific, • sensitive, • not costly and to which there is a good response, • this leads to the establishment of regional and national infrastructures, • including accredited specialized laboratories.

2- The screening must be universal

• unless otherwise specified all newborns must have access to the program • the laboratory personnel and the clinicians analyse results, control positive and dubious results, carry on the necessary investigations and establish a treatment, • in practice: these tests are performed at the time of discharge of the mother from the maternity, (between the 2nd and 7th day after delivery, • the metabolic disorder is then diagnosable, • before any clinical sign appears in the newborn, • the blood is drawn by heel prick on a filter paper identified with the newborn hospital card vital information.

3- Urine sample screening test

• a few health services have adopted the urinary screening that is done around the 3rd week of life from a filter paper containing a urine spot taken from a damp diaper. The dried filter paper is mailed to the screening centre by the parents. • this urinary screening test was initiated in the Province of Quebec in the early seventies; it is one of the few programs that exist in the world. It allows the early detection of organic acid disorders, or other disorders which could have been missed by the blood tests done during the first week of life if the protein intake was insufficient to reveal a metabolic block.

II - PHENYLKETONURIA

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -716- 1- Epidemiology

• autosomal recessive disease, • risk of recurrence : ¼, • q gene frequency = 1%, • frequency of affected homozygotes: q2 = 0.06 to 0.1%.

2- Physiopathology

• phenylalanine hydroxylase deficiency, • a classical form that is treatable.

3- Hyperphenylalaninemia

• increase in number of catabolites of Phenylalanine (Phe), • deficit of metabolites downstream to the enzyme (tyrosine, dopa, melanin…).

4- Dihydropteridin reductase deficiency

• severe form with: • hyperphenylalaninemia, and hypertyrosinemia, • serotonine and norepinephrenine deficiency downstream to this enzyme • evolution without treatment: within a few weeks digestive problems, skin lesions and convulsions are observed, with a delay in psychomotor development, deteriorated general health leading to death in absence of treatment. One must obtain blood and urine samples and a liver biopsy for a post mortem diagnosis and early treatment of a close relative, undiagnosed brother or sister. If the treatment was instituted too late the child will develop a profound psychomotor retardation (IQ= 29 to 50) a with a number of neurological disorders and hypopigmentation.

5- Hyperphenylalaninemia can be detected after a few of days of normal feeding

• normal Phenylalanine level < 4mg/100 ml (Other ref: <300mM), • the test result is available within 15 days, • automated fluorometric blood dosage of phenylalanine.

Note : the tests will detect hyperphenylalaninemia but not its cause: it could be a true enzymatic deficiency or transitory, (prematurity manifested by hyperphenylalaninemia and hypertyrosinemia or excess nutritional phe intake). The diagnosis must be confirmed by more precise blood tests.

6- Clinical forms, differential diagnosis

• Deficit in dihydropteridine reductase: hyperphenylalaninemia, • <20mg/100ml; rapid lowering of Phe level with the diet but unpreventable neurological deterioration.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -717- 7- Treatment

• Phenylketonuria. Hypoprotein diet with a low Phe content to assure the child will have the intake needs in Phe (to avoid overloading or deficit…..biological control: 3mg/100ml < Phe < 10mg/100ml (other ref: 100mM to 300mM) • Neonatal diet Low Phe diet during infancy and if possible kept during adulthood; strict control of mother's Phe level: if it is to high during pregnancy there is an increased risk of foetal demise.

8- Dihydropteridine reductase deficiency

Treatment : substitution by tryptophane and serotonine, close follow up, genetic counselling and psychological aid.

III - CONGENITAL HYPOTHYROIDISM

1-Epidemiology: 0. 03 to 0.06 % births

2-Neonatal screening

In most programs TSH is measured on filter papers. If TSH is elevated the diagnosis must be confirmed with plasma measurements ( TSH, free T4, total T3)

3-Dosage methods

• Dosage of TSH (thyroid stimulating hormone), normal level < 12µU/ml ; pathological level> 30µU/ml ; intermediate level 15- 30µU/ml : control indicated. • Dosage of T4 (thyroxine or Tetraiodothyronine) by radioimmunology. • Identifies all thyroid primary and secondary deficits but presence of false positive, (3% of positive results are detected by this method). • Hypothalamo-hypophysary disorders are not detected by this method • Confirmation by complementary tests: scintigraphy and measure of maternal thyroid antibodies and dosage of thyroglobulin.

4- Treatment :

Initially 10µg/kg de L Thyroxine with periodical controls of thyroid function every 3 months until one year of age then every 6 months until three years of age and thereafter every year.

IV COROLLARY

1- Overview of international practices

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -718- An overview of measures taken throughout the world confirms that neonatal screening was initiated in several countries in different ways and in most cases in relation to the populations more at risk to develop a metabolic disease like phenylketonuria hypothyroidism and / or cystic fibrosis (mucoviscidosis). This is particularly true for blood dyscrasias such as sickle cell anemia and thalassemia, two diseases that are more frequent in the Mediterranean countries, Africa and Asia. Tyrosinemia is frequent in Finland and the Quebec Saguenay region. This implies that specific screening tests are developed according to the mutant gene frequencies found in certain populations that often live in isolates. Neonatal screening programs have been adopted by several countries. For instance neonatal screening for phenylketonuria and hypothyroidism are current practice in several countries of North America, Europe, in Japan New Zeland, Australia, Israel and more recently in China and South America (WB Hanley, personal communication). TANDEM MASS SPECTROMETRY The development of tandem mass spectrometry (MS/MS) has allowed in recent years the detection, confirmation of diagnosis and the follow up of newborns affected with phenylketonuria, hepatorenal tyrosinemia and MCAD (medium-chain acyl co-enzyme A dehydrogenase) deficiency and will probably be a screening tool for several metabolic disorders such as organic acidurias and urea cycle defects.

2- Overview of diagnosable diseases

Approximately 2 to 40 metabolic diseases can be detected in the neonatal period. The majority are in need of medical intervention, some will need a close surveillance.

• Hereditary metabolic diseases :Phenylketonuria, hepatorenal tyrosinemia, organic aciduria, fatty acid oxidation defects,…. • Blood dyscrasias : Thalassemia, sickle cell anemia • Endocrine diseases : Hypothyroidism, adrenal hyperplasia • Infectious diseases : Human immuno deficiency virus (HIV) • Others: o Hearing deficit o Cystic fibrosis ( mucoviscidosis) o Duchenne muscular dystrophy

i- Hearing deficit

It is generally accepted that neonatal screening can apply to non metabolic diseases like hearing deficits. A number of health services have initiated hearing evaluation by otoacoustic emissions in the neonatal period for newborns aged from 30 months of gestation to full term. This neonatal screening for hearing has the same goal as the screening programs for cystic fibrosis and Duchenne muscular dystrophy(DMD) that is to minimize secondary effects of evolutive diseases.

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -719- ii-Cystic fibrosis

In cystic fibrosis a diagnosis made in the early infancy allows the introduction of a special diet: studies have shown an improvement in the general health and growth of the patient. The incidence of cystic fibrosis being between 1 in 2000 to 1 in 4000 births, this screening program has been adopted by several health authorities. A family study and genetic counselling are applied.

iii-Duchenne Muscular dystrophy (DMD)

In muscular dystrophy the advantage of an early treatment does not seem as efficient since the age of onset of the disease is variable and often the motor symptomatology is non specific and may be similar to certain orthopedic disorders. In the future an improved detection method, reducing positive and negative results, would allow to reconsider the indication to screen for DMD in the neonatal period.

iv-Immunodeficiency virus (HIV)

The screening for the immunodeficiency virus (HIV) in the neonate is controversial on ethic and clinical grounds. Although the early treatment of the newborn who is a virus carrier seems to prevent the acquired immunodeficiency syndrome several groups contest the universal neonatal screening for the virus since there is an elevated risk of individual and ethnic discrimination.

3- Treatment

Following biochemical, enzymatic and molecular studies that confirm the diagnosis a treatment is applied :

i- Dietary restrictions, special products, supplements….., food banks

As shown in phenylcetonuria the alimentary restrictions and special foods will prevent overloading of catabolites deleterious to the child development. Protein or specific amino acid restrictions are indicated in most metabolic diseases. Food banks are generally under the state supervision and are responsible for the availability of special foods to the patient.

ii- Replacement therapy

• organs: the patient may be in need of an organ replacement like the liver transplantation in hepatorenal tyrosinemia in addition to a special diet. However in this particular disease the introduction of NTBC ((2-(2nitro-4- trifluoromethylbezoyle-1,3-cyclohexamedione)) stops an enzyme in the tyrosine metabolism leading to the decrease of succinylacetone that is toxic for the liver and responsible for severe neurological effects. This therapeutic approach has totally change the treatment of this disease in addition to

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -720- eliminating a risky and costly liver transplant, and improving the patient well being and survival. • enzymes,proteins: the replacement of enzymes and proteins is under development and evaluation of its therapeutic potential. For example a small number of patients suffering from Hurler or Hunter diseases, two mucopolysaccharidoses with a severe prognosis have been treated with synthetic enzymes but the beneficial effects of this procedure are limited. The enzyme replacement therapy combined with the recombinant human a-L- iduronidase in Hurler syndrome is nevertheless encouraging and further trials are planned. The enzyme replacement thererapy can be done with normal bone marrow transplantation from a compatible donor. Replacement of proteins like globulins and insulin are also good examples of replacement therapy.

iii-Gene therapy

The introduction of a gene in a patient, with an appropriate vector to correct an abnormal metabolism. This domain is under sustained research particularly in cancerology and in the study of hereditary degenerative diseases

4- Diseases with apparent symptoms during the post natal period

• hypertrophic cardiopathy • acyl-COA deficiency • hyperammonemia • intermittent leucinosis • others….

One may identify among hereditary diseases those for which the symptomatology is absent in the neonatal period but appears later during infancy or in adolescence and those that have a true late age of onset during adulthood. Among metabolic diseases with late manifestations one notes the intermittent leucinosis that has a residual enzymatic activity enough to delay the appearance of symptoms if there is no increase in intake of food containing branched chain aminoacids. An infectious disease in the child may trigger typical manifestations of this disease commonly called maple syrup urine disease because of the urine odour.

5- Genetic counselling / informed consent

Access to neonatal screening in a modern society is primordial. However for economical reasons or expertise disponibility all newborns will not be tested. The number of diagnosable diseases has increased in recent years and this stresses the importance at least to identify populations that are more at risk to develop a disease. Parents' consent for the screening test is not obligatory in all states. There are a number of policies regarding the access to the test. According to countries and regions a neonatal screening test informed consent may be:

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -721- i. mandatory, ii. mandatory with option to refuse the test or iii. optional.

If the screening test is positive a genetic counselling is offered to parents in view of a future pregnancy and, if they agree, to other family members identified as individuals at risk. A prenatal diagnosis can also be offered if a diagnosis can be reached by studying amniotic fluid or cells.

6- Development

Who will assume the development cost of these programs ? In general the state is responsible and must also see to the follow up of patients who had a positive screening test, to the long or short term appropriate treatment, and the genetic counselling to be offered to the parents of the positively screened individuals. The institution or other accredited organism is also responsible to the development of screening techniques and their validation. The use of tandem mass spectrometry leads to new therapeutic approaches, increase the survival of children for whom a diagnosis is made early who will eventually rely on the take over by adult medicine services. Ethics committees and the scientific community may be invited to study the merit of new disease screening methods developed and proposed by research groups: it is then the duty of ethic committee members to formulate an advice in consultation with the population on the pertinence of introducing new screening tests.

Contributor(s) Written 05- Louis Dallaire, Jean-Loup Huret 2005 Citation This paper should be referenced as such : Dallaire L, Huret JL . Neonatal Screening. Atlas Genet Cytogenet Oncol Haematol. May 2005 . URL : http://AtlasGeneticsOncology.org/Educ/NeonatID30056ES.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2005; 4 -722-