Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 6, Number 3, Jul-Sep 2002 Previous Issue / Next Issue Genes CTNNB1 (Catenin, beta-1) (3p22-p21.3). Brigitte Debuire, Antoinette Lemoine, Raphael Saffroy. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 392-402. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CTNNB1ID71.html EXT1 (8q24.11-q24.13) - updated. Judith V.M.G. Bovée. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 403-408. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html EXT2 (11p11-p12) - updated. Judith V.M.G. Bovée. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 409-415. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/EXT2ID213.html GPHN (Gephyrin) (14q23.3). Brigitte David-Watine. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3):416-420. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/GPHNID317.html MLN51 (17q11-17q21.3). Sébastien Degot. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 421-424. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MLN51ID241.html NSD1 (Nuclear receptor-binding, su(var), enhancer-of-zeste and trithorax domain- containing 1) (5q35). Lyndal Kearney. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 425-429. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 I URL : http://AtlasGeneticsOncology.org/Genes/NSD1ID356.html NUP98 (nucleoporin 98 kDa) (11p15) - updated. Lyndal Kearney. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 430-437. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/NUP98.html TPR (Translocated promoter region) (1q25). Brigitte David-Watine. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3):438-442. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TPRID282.html BCL11A (B-cell lymphoma/leukemia 11A) (2p13-15). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 443-447. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/BCL11AID391.html RECQL5 (17q25.2-25.3). Mounira Amor-Guéret. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 448-451. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RECQL5ID286.html SDHB (succinate dehydrogenase complex II, subunit B, iron-sulfur protein or IP) (1p36.1- p35). Anne-Paule Gimenez-Roqueplo. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 452-456. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SDHBID388.html SDHC (succinate dehydrogenase complex II, subunit C, integral membrane protein) (1q21). Anne-Paule Gimenez-Roqueplo. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 457-460. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SDHCID389.html -3 (GPC3) (Xq26.1). Daniel Sinnett. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 461-467. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/GPC3ID156.html Leukaemias t(5;11)(q35;p15.5). Lyndal Kearney. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 468-472. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0511q35p15ID1209.html t(1;19)(p13;p13.1). Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 II Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 473-474. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0119p13p13ID1230.html t(11;14)(q23;q24). Mariko Eguchi. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 475-478. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1114q23q24ID1198.html Classification of acute myeloid leukemias. Georges Flandrin. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 479-487. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/ClassifAMLID1238.html Classification of myelodysplasic syndromes. Georges Flandrin. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 488-497. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/ClassifMDSID1239.html M0 acute non lymphocytic leukemia (M0-ANLL) - updated. Marie Christine Bene. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 498-499. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/M0ANLLID1057.html t(1;3)(p36;q21) - updated. Jay L Hess. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 500-503. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0103.html t(1;3)(p36;p21). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 504-506. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0103p36p21ID1237.html t(1;16)(q11;q11). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 507-508. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0116q11q11ID1247.html +5 or trisomy 5. Edmond Ma, Thomas Wan. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 509-512. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/tri5ID1255.html t(Y;1)(q12;q12). Thomas Wan and Edmond Ma. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3):513-515. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 III URL : http://AtlasGeneticsOncology.org/Anomalies/tY1q12q12ID1160.html Solid Tumours Bone: Chondrosarcoma - updated. Judith VMG Bovée. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 516-523. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/chondrosarcID5063.html Cancer Prone Diseases Hereditary multiple exostoses (HME) - updated. Judith VMG Bovée. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 524-529. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/HeredMultExostosID10061.html Costello syndrome. Nicole Philip. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 530-532. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/CostelloID10075.html Deep Insights Functional organization of the genome: chromatin. Patricia Ridgway, Christèle Maison, Geneviève Almouzni. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 533-546. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/ChromatinID20024.htm.html Case Reports Pentasomy 21 as a sole abnormality in an atypical CML patient in chronic phase. Shambhu K Roy, Sonal R Bakshi, Shailesh J Patel, Pina J Trivedi, Manisha M Brahmbhatt, Shwetal M Rawal, Pankaj M Shah, Devendra D Patel. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 547-550. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/21CRRoyID100004.html Educational Items Immunoglobulin Genes. Marie-Paule Lefranc, Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3):551-559. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Educ/PolyIgEng.html Chromatin. Patricia Ridgway, Christèle Maison, Geneviève Almouzni. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 560-568. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Educ/ChromatinEducEng.html Selection.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 IV Robert Kalmes. Atlas Genet Cytogenet Oncol Haematol 2002; 6 (3): 569-582. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Educ/SelectionID30040ES.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 V Atlas of Genetics and Cytogenetics in Oncology and Haematology

CTNNB1 (Catenin, beta-1)

Identity Other Cadherin-associated protein, beta names Hugo CTNNB1 Location 3p22-p21.3

CTNNB1 (2p22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -392-

Description The encompasses 23.2kb of DNA ; 16 exons (the first is non- coding). Transcription 3362 nucleotides mRNA ; 2343 bp open reading frame. Alternative splicing within exon 16 produces a splice variant that is 159 bp shorter in the 3' untranslated region. Protein

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -393-

Description 781 amino acids ; 92 kDa protein. Can be phosphorylated ; contains from N-term to C-term, a phosphorylation site by the serine-threonine glycogen synthase kinase -3b(GSK-3b), an a-catenin binding site, 13 armadillo repeats and a transactivating domain. Expression Widely expressed. Localisation Cytoplasm and nucleus Function Important functions in the E-cadherin-mediated cell-cell adhesion system and also as a dowstream signaling molecule in the Wnt pathway. Cytoplasmic accumulation of b catenin allows it to translocate to the nucleus to form complexes with transcription factors of the T cell factor-lymphoid enhancer factor (Tcf-Lef) family. b-catenin is assumed to transactivate mostly unknown target genes, which may stimulate cell proliferation (acts as an oncogene) or inhibit apoptosis. The b-catenin level in the cell is regulated by its association with the adenomatous polyposis coli ( APC) tumor suppressor protein, axin and GSK-3b. Phosphorylation of b-catenin by the APC-axin-GSK-3b complex leads to its degradation by the ubiquitin-proteasome system. Homology The b-catenin protein shares 70 % amino acid identity with both plakoglobin (intracellular junction in desmosomes) and the product of the Drosphila segment polarity gene "armadillo". Mutations Somatic Two mechanisms underlying the increase in b-catenin levels by stabilizing b-catenin are known. One is inactivating mutation in the APC gene, the other is activating mutation at the GSK-3b phosphorylation sites within exon 3 of the b-catenin gene. b-catenin plays a key role in the development of colorectal cancer and has been found mutated in colorectal cancer cell lines. b-catenin aberration is a frequent event in the development of and may facilitate its development in the course of chronic hepatitis. b-catenin has also been found mutated in hepatoblastoma, ovarian carcinoma, medulloblastoma, pilomatricoma as well as in melanoma cell lines. External links

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -394- Nomenclature Hugo CTNNB1 GDB CTNNB1 Entrez_Gene CTNNB1 1499 catenin (cadherin-associated protein), beta 1, 88kDa Cards Atlas CTNNB1ID71 GeneCards CTNNB1 Ensembl CTNNB1 CancerGene CTNNB1 Genatlas CTNNB1 GeneLynx CTNNB1 eGenome CTNNB1 euGene 1499 Genomic and cartography CTNNB1 - chr3:41216016-41256938 + 3p22.1 (hg17- GoldenPath May_2004) Ensembl CTNNB1 - 3p22.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CTNNB1 Gene and transcription

Genbank AY081165 [ SRS ] AY081165 [ ]

Genbank AY463360 [ SRS ] AY463360 [ ENTREZ ]

Genbank AB062292 [ SRS ] AB062292 [ ENTREZ ]

Genbank AF130085 [ SRS ] AF130085 [ ENTREZ ]

Genbank BC058926 [ SRS ] BC058926 [ ENTREZ ]

RefSeq NM_001904 [ SRS ] NM_001904 [ ENTREZ ]

RefSeq NT_086638 [ SRS ] NT_086638 [ ENTREZ ] AceView CTNNB1 AceView - NCBI TRASER CTNNB1 Traser - Stanford

Unigene Hs.476018 [ SRS ] Hs.476018 [ NCBI ] HS476018 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P35222 [ SRS] P35222 [ EXPASY ] P35222 [ INTERPRO ]

Prosite PS50176 ARM_REPEAT [ SRS ] PS50176 ARM_REPEAT [ Expasy ]

Interpro IPR008938 ARM [ SRS ] IPR008938 ARM [ EBI ]

Interpro IPR000225 Armadillo [ SRS ] IPR000225 Armadillo [ EBI ] CluSTr P35222

Pfam PF00514 Arm [ SRS ] PF00514 Arm [ Sanger ] pfam00514 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -395- Smart SM00185 ARM [EMBL] Blocks P35222

PDB 1G3J [ SRS ] 1G3J [ PdbSum ], 1G3J [ IMB ]

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

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

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

PDB 1P22 [ SRS ] 1P22 [ PdbSum ], 1P22 [ IMB ]

PDB 1QZ7 [ SRS ] 1QZ7 [ PdbSum ], 1QZ7 [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 116806 [ map ] GENECLINICS 116806

SNP CTNNB1 [dbSNP-NCBI]

SNP NM_001904 [SNP-NCI]

SNP CTNNB1 [GeneSNPs - Utah] CTNNB1 [SNP - CSHL] CTNNB1] [HGBASE - SRS] General knowledge Family CTNNB1 [UCSC Family Browser] Browser SOURCE NM_001904 SMD Hs.476018 SAGE Hs.476018 Amigo process|Wnt receptor signaling pathway Amigo process|cell adhesion Amigo component|cytoskeleton Amigo component|intercellular junction Amigo component|nucleus Amigo component|plasma membrane Amigo function|protein binding Amigo process|regulation of transcription from Pol II promoter Amigo function|signal transducer activity Amigo function|structural molecule activity Amigo process|transcription BIOCARTA ALK in cardiac myocytes BIOCARTA Cell to Cell Adhesion Signaling Inactivation of Gsk3 by AKT causes accumulation of b-catenin in BIOCARTA Alveolar Macrophages BIOCARTA Multi-step Regulation of Transcription by Pitx2 BIOCARTA Presenilin action in Notch and Wnt signaling BIOCARTA Trefoil Factors Initiate Mucosal Healing

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -396- BIOCARTA WNT Signaling Pathway PubGene CTNNB1 Other databases Other Somatic mutation (COSMIC-CGP-Sanger) database Probes Probe Cancer Cytogenetics (Bari) Probe CTNNB1 Related clones (RZPD - Berlin) PubMed PubMed 112 Pubmed reference(s) in LocusLink Bibliography Association of the APC tumor suppressor protein with catenins. Su LK, Vogelstein B, Kinzler KW. Science 1993; 262: 1734-1737. Medline 8259519

Localization of the human beta-catenin gene (CTNN1) to 3p21 : a region implicated in tumor development. Kraus C, Liehr T, Hulsken J, Behrens J, Birchmeier W, Grzeschik KH, Ballhausen WG. Genomics 1994; 23: 272-274. Medline 7829088

Yeast artificial cloning of the beta-catenin locus on human chromosome 3p21-22. Bailey A, Norris AL, Leek JP, Clissold PM, Carr IM, Ogilvie DJ, Morrison JFJ, Meredith DM, Markham AF. Chromosome Res 1995; 3: 201-203. Medline 7780664

Signal transduction of beta-catenin. Gumbiner BM. Curr Opin Cell Biol 1995; 7: 634-640. Medline 8573337

The gene for the APC-binding protein beta-catenin (CTNNB1) maps to chromosome 3p22, a region frequently altered in human malignancies. Cytogenet Cell Genet 1995; 71: 343-344. Medline 8521721

Assignment of the human beta-catenin gene (CTNNB1) to 3p22-p21.3 by fluorescence in situ hybridization. Van Hengel J, Berx G, van Roy N, Speleman F, van Roy F. Cytogenet Cell Genet 1995; 70: 68-70.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -397- Medline 7736793

Functional interaction of beta-catenin with the transcription factor LEF-1. Behrens J, van Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R Birchmeier W. Nature 1996; 382: 638-642. Medline 8757136

Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Huber O, Korn R, Mc Laughlin J, Ohsugi M, Herrman BG, Kemler R. Mech Dev 1996; 59: 3-10. Medline 8892228

Genomic organization of the human beta-catenin gene (CTNNB1). Nollet F, Berx G, Molemans F, van Roy F. Genomics 1996; 32: 413-424. Medline 8838805

Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Science 1996; 272: 1023-1026. Medline 8638126

Beta-catenin is a target for the ubiquitin-proteasome pathway. Aberle H, Bqauer A, Stappert J, Kispert A, Kemler R. EMBO J 1997; 16: 3797-37804. Medline 9233789

Beta-catenin mutations in cell lines established from human colorectal cancers. Ilyas M, Tomlinson IPM, Rowan A, Pignatelli M, Bodmer WF. Proc Nat Acad Sci 1997; 94: 10330-10334. Medline 9294210

Activation of b-catenin-Tcf signaling in colon cancer by mutations in b-catenin or APC. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Clevers H. Science 1997; 275: 1787-1790. Medline 9065401

Loss of b-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. Rubinfeld B, Albert I, Porfiri E, Munemitsu S, Polakis P. Cancer Res 1997; 57: 4624-4630. Medline 9377578

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -398- Stabilization of beta-catenin by genetic defects in melanoma cell lines. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P. Science 1997; 275: 1790-1792. Medline 9065403

Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W. Science 1998; 280: 596-599. Medline 9554852

Somatic mutations of the b-catenin gene are frequent in mouse and human hepatocellular carcinomas. De la Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C. Proc Natl Acad Sci USA 1998; 95: 8847-8851. Medline 9671767

Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of beta-catenin. Fagotto F, Gluck U, Gumbiner BM. Curr Biol 1998; 8: 181-190. Medline 9501980

Downregulation of b-catenin by human axin and it's association with the APC tumor suppressor, b-catenin and GSK3b. Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P. Curr Biol 1998;8:573-581. Medline 9601641

Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK b and b -catenin and promotes GSK3b -dependent phosphorylation of b- catenin. Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. EMBO J 1998; 17: 1371-1384. Medline 9482734

Activation of the beta-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, Ishiguro S, Nakamura Y, Miyoshi Y. Cancer Res 1998; 58: 1021-1026. Medline 9500465

Mutational analysis of the APC/ b-catenin/Tcf pathway in colorectal cancer.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -399- Sparks AB, Morin PJ, Vogelstein B, Kinzler KW. Cancer Res 1998; 58: 1130-1134. Medline 9515795

Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma. Blaker H, Hofmann WJ, Rieker RJ, Penzel R, Graf M, Otto HF. Genes Cancer 1999; 25: 399-402. Medline 10398436

A common human skin tumour is caused by activating mutations in beta- catenin. Chan EF, Gat U, Mc Niff JM, Fuchs E. Nature Genet 1999; 21: 410-413. Medline 10192393

The metalloproteinase matrilysin is a target of b-catenin transactivation in intestinal tumors. Crawford HC, Fingleton BM, Rudolph-Owen LA, Heppner Goss KJ, Rubinfeld B, Polakis P, Matrisian LM. Oncogene 1999; 18: 2883-2891. Medline 10362259

Intestinal polyposis in mice with a dominant stable mutation of the b-catenin gene. Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M, Taketo MM. EMBO J 1999; 18: 5931-5942. Medline 10545105

Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene. Koch A, Denkhaus D, Albrecht S, Leuschner I, von Schweinitz D, Pietsch T. Cancer Res 1999; 59: 269-273. Medline 9927029

Beta-catenin mutations in hepatocellular carcinoma correlate with a low rate of loss of heterozygosity. Legoix P, Bluteau O, Bayer J, Perret C, Balabaud C, Belghiti J, Franco D, Thomas G, Laurent-Puig P, Zucman-Rossi J. Oncogene 1999; 18: 4044-4046. Medline 10435629

Mutational analysis of beta-catenin gene in Japanese ovarian carcinomas : frequent mutations in endometrioid carcinomas. Sagae S, Kobayashi K, Nishioka Y, Sugimura M, Ishioka S, Nagata M, Terasawa K, Tokino T, Kudo R.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -400- Jpn J Cancer Res 1999; 90: 510-515. Medline 10391090

The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A. Proc Natl Acad Sci USA 1999; 96: 5522-5527. Medline 10318916

APC mutations in sporadic medulloblastomas. Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H. Am J Path 2000; 156: 433-437. Medline 1066372

Gastrin is a target of the b-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. Koh TJ, Bulitta CJ, Fleming JV, Docray GJ, Varro A, Wang TC. J Clin Invest 2000; 106: 533-539. Medline 10953028

Mutations in AXIN2 cause colorectal cancer with defective mismatch repair, by activating b-catenin-Tcf signaling. Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, Christensen E, Schmidt SS, Roche PC, Smith DI, Thibodeau SN. Nature Genet 2000; 26: 146-147. Medline 11017067

Frequent b-catenin aberration in human hepatocellular carcinoma. Fujie H, Moriya K, Shintani Y, Tsutsumi T, Takayama T, Makuuchi M, Kimura S, Koike K. Hepatology Res 2001; 20: 39-51. Medline 11282485

The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin. Miravet S, Piedra J, Miro F, Itarte E, Garcia de Herreros A, Dunach M. J Biol Chem 2002; 277: 1884-1891 Medline 11711551

Oncogenic beta-catenin and MMP-7 (matrilysin) cosegregate in late-stage clinical colon cancer. Ougolkov AV, Yamashita K, Mai M, Minamoto T. Gastroenterology 2002; 122: 60-71. Medline 11781281

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -401- Possible association between higher beta-catenin mRNA expression and mutated beta-catenin in sporadic desmoid tumors : real-time semiquantitative assay by Taqman polymerase chain reaction. Saito T, Oda Y, Kawaguchi Ki K, Tanaka K, Matsuda S, Tamiya S, Iwamoto Y, Tsuneyoshi M. Lab Invest 2002; 82: 97-103. Medline 11796830

Frizzled-10, up-regulated in primary colorectal cancer, is a positive regulator of the Wnt - beta - catenin - TCF signaling pathway. Terasaki h, Saitoh T, Shiokawa K, Katoh M. Int J Mol Med 2002; 9: 107-112. Medline 11786918

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Brigitte Debuire, Antoinette Lemoine and Raphaël Saffroy 2002 Citation This paper should be referenced as such : Debuire B, Lemoine A, Saffroy R. . CTNNB1 (Catenin, beta-1). Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CTNNB1ID71.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -402- Atlas of Genetics and Cytogenetics in Oncology and Haematology

EXT1

Identity Hugo EXT1 Location 8q24.11-q24.13 DNA/RNA

Description 11 exons, spans approximately 350 kb of genomic DNA Transcription 3.4 kb Protein

Description 746 amino acids, 86.304 kDa Expression mRNA is ubiquitously expressed (also in chondrocytes), highest level of expression in . Localisation endoplasmic reticulum Function a tumour suppressor function is suggested; EXT1 is an endoplasmic reticulum (ER) resident type II transmembrane glycoprotein whose expression in cells alters the synthesis and display of cell surface heparan sulfate, and EXT1 was suggested to be involved in chain polymerization of heparan sulphate; an EXT1 homologue in Drosophila melanogaster (tout-velu, Ttv) was demonstrated to be involved in heparan sulphate proteoglycan biosynthesis controlling diffusion of an important segment polarity protein called Hedgehog (Hh) Homology human EXT2, EXTL1, EXTL2 and EXTL3, mouse Ext1, Drosophila tout velu Mutations Germinal germline mutations in EXT1 are causative for hereditary multiple exostoses, a genetically heterogeneous autosomal dominant disorder; mutations include nucleotide substitutions (54%), small deletions (27%) and small insertions (16%), of which the majority is predicted to result in a truncated or non-functional protein Somatic no somatic mutations were found in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas tested Implicated in Entity hereditary multiple exostoses

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -403- Prognosis the main complication in hereditary multiple exostoses is malignant transformation of an osteochondroma (exostosis) into chondrosarcoma, which is estimated to occur in 1-5% of the HME cases Cytogenetics clonal aberrations were found at band 8q24.1 in sporadic and hereditary osteochondromas using cytogenetic analysis; loss of heterozygosity was almost exclusively found at the EXT1 locus in 5 out of 14 osteochondromas Oncogenesis two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild type allele in three osteochondromas, supporting the Knudson's two hit model for tumour suppressor genes in osteochondroma development; these results indicate that in cartilaginous cells of the growth plate inactivation of both copies of the EXT1-gene is required for osteochondroma formation in hereditary cases

External links Nomenclature Hugo EXT1 GDB EXT1 Entrez_Gene EXT1 2131 exostoses (multiple) 1 Cards Atlas EXT1ID212 GeneCards EXT1 Ensembl EXT1 CancerGene EXT1 Genatlas EXT1 GeneLynx EXT1 eGenome EXT1 euGene 2131 Genomic and cartography EXT1 - chr8:118880787-119193239 - 8q24.11 (hg17- GoldenPath May_2004) Ensembl EXT1 - 8q24.11 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene EXT1 Gene and transcription

Genbank U70539 [ SRS ] U70539 [ ENTREZ ]

Genbank AK130054 [ SRS ] AK130054 [ ENTREZ ]

Genbank BC001174 [ SRS ] BC001174 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -404- Genbank S79639 [ SRS ] S79639 [ ENTREZ ]

RefSeq NM_000127 [ SRS ] NM_000127 [ ENTREZ ]

RefSeq NT_086743 [ SRS ] NT_086743 [ ENTREZ ] AceView EXT1 AceView - NCBI TRASER EXT1 Traser - Stanford

Unigene Hs.492618 [ SRS ] Hs.492618 [ NCBI ] HS492618 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q16394 [ SRS] Q16394 [ EXPASY ] Q16394 [ INTERPRO ]

Interpro IPR004263 Exostosin [ SRS ] IPR004263 Exostosin [ EBI ] CluSTr Q16394 Pfam PF03016 Exostosin [ SRS ] PF03016 Exostosin [ Sanger ] pfam03016 [ NCBI-CDD ] Blocks Q16394 Polymorphism : SNP, mutations, diseases OMIM 608177 [ map ] GENECLINICS 608177

SNP EXT1 [dbSNP-NCBI]

SNP NM_000127 [SNP-NCI]

SNP EXT1 [GeneSNPs - Utah] EXT1 [SNP - CSHL] EXT1] [HGBASE - SRS] General knowledge Family EXT1 [UCSC Family Browser] Browser SOURCE NM_000127 SMD Hs.492618 SAGE Hs.492618

2.4.1.224 [ Enzyme-SRS ] 2.4.1.224 [ Brenda-SRS ] 2.4.1.224 [ KEGG Enzyme ] 2.4.1.224 [ WIT ] Amigo component|Golgi apparatus function|N-acetylglucosaminyl-proteoglycan 4-beta- Amigo glucuronosyltransferase activity Amigo component|endoplasmic reticulum membrane Amigo process|glycosaminoglycan biosynthesis Amigo component|integral to membrane Amigo process|negative regulation of cell cycle Amigo process|signal transduction Amigo process|skeletal development Amigo function|transferase activity, transferring glycosyl groups KEGG Chondroitin / Heparan Sulfate Biosynthesis PubGene EXT1

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -405- Other databases Probes Probe Cancer Cytogenetics (Bari) Probe EXT1 Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Ahn J, Ludecke H, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE. Nature Gen 1995; 11: 137-143.

Tout-velu is a drosophila homologue of the putative tumour suppressor EXT1 and is needed for Hh diffusion. Bellaiche Y, The I, Perrimon N. Nature 1998; 394: 85-88.

EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Bovee JVMG, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AHM, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PCW. Am J Hum Genet 1999; 65: 689-698.

Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Bovee JVMG, Cleton-Jansen AM, Kuipers-Dijkshoorn N, Van den Broek LJCM, Taminiau AHM, Cornelisse CJ, Hogendoorn PCW. Genes Chromosom Cancer 1999; 26: 237-246.

Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Cancer 1998; 82: 1657-1663.

Genetic heterogeneity in families with hereditary multiple exostoses. Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G, et al. Am J Hum Genet 1993; 53: 71-79.

Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8. Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M. Am J Hum Genet 1995; 56: 1125-1131.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -406- The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N- acetylhexosaminyltransferase that transfers N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. Kitagawa H, Shimakawa H, Sugahara K. J Biol Chem 1999; 274: 13933-13937.

Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene. Lin X, Gan L, Klein WH, Wells DE. Biochem Biophys Res Commun 1998; 248: 738-743.

Isolation of the mouse cDNA homologous to the human EXT1 gene responsible for hereditary multiple exostoses. Lin X, Wells D. DNA seq 1997; 7: 199-202.

The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. J Biol Chem 1998; 273: 26265-26268.

The murine Ext1 gene shows a high level of sequence similarity with its human homologue and is part of a conserved linkage group on chromosome 15. Lohmann DR, Buiting K, Ludecke H, Horsthemke B. Cytogenet Cell Genet 1997; 76: 164-166.

Genomic organization and promotor structure of the human EXT1 gene. Ludecke H, Ahn J, Lin X, Hill A, Wagner MJ, Schomburg L, Horsthemke B, Wells DE. Genomics 1997; 40: 351-354.

New perspectives on the molecular basis of hereditary bone tumours. McCormick C, Duncan G, Tufaro F. Mol Med Today 1999; 5: 481-486.

The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F. Nature Genet 1998; 19: 158-161.

Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Mertens F, Rydholm A, Kreicbergs A, Willen H, Jonsson K, Heim S, Mitelman F, Mandahl N. Genes Chromosom Cancer 1994; 9: 8-12.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -407- Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Raskind WH, Conrad EU, Chansky H, Matsushita M. Am J Hum Genet 1995; 56: 1132-1139.

A direct interaction between EXT and glycosyltransferases is defective in hereditary multiple exostoses. Simmons AD, Musy MM, Lopes CS, Hwang L, Yang Y, Lovett M. Hum Mol Genet 1999; 8: 2155-2164.

Hedgehog movement is regulated through tout velu -dependant synthesis of a heparan sulfate proteoglycan. The I, Bellaiche Y, Perrimon N. Mol Cell 1999; 4: 633-639.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Judith V.M.G. Bovée 2000 Updated 03- Judith V.M.G. Bovée 2002 Citation This paper should be referenced as such : Bovée JVMG . EXT1. Atlas Genet Cytogenet Oncol Haematol. January 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/EXT1ID212.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -408- Atlas of Genetics and Cytogenetics in Oncology and Haematology

EXT2 (updated: old version not available)

Identity Hugo EXT2 Location 11p11-p12

EXT2 (11p12) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA

Description Sixteen exons across the EXT2 locus were identified, two of which (1a and 1b) are alternatively spliced; spans approximately 108 kb of genomic DNA Transcription 3.5 and 3.7 kb Protein

Description 718 amino acids; 82.2 kDa Expression mRNA is ubiquitously expressed. In mouse embryo's, a high level of expression of Ext2 mRNA has been found in developing limb buds and expression was demonstrated to be confined to the proliferating and prehypertrophic chondrocytes of the growth plate. Localisation endoplasmic reticulum Function a tumour suppressor function is suggested; exostosin-2 (EXT2) is an endoplasmic reticulum localized type II transmembrane glycoprotein

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -409- which together with exostosin-1 (EXT1) forms a Golgi-localized hetero- oligomeric complex that catalyzes heparan sulphate (HS) polymerization. It is thus hypothesized that EXT controls HSPG synthesis and display at the cell surface, which in turn is involved in FGF and IHh/PTHrP signalling within the normal growth plate. Homology human EXT1, EXTL1, EXTL2 and EXTL3, mouse Ext2 Mutations Germinal germline mutations in EXT2 are causative for hereditary multiple exostoses, a heterogeneous autosomal dominant disorder; mutations include nucleotide substitutions (57%), small deletions (19%) and small insertions (24%), of which the majority is predicted to result in a truncated or non-functional protein Somatic no somatic mutations were found in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas tested Implicated in Entity hereditary multiple exostoses Prognosis the main complication in hereditary multiple exostoses is malignant transformation of an osteochondroma (exostosis) into chondrosarcoma, which is estimated to occur in 1-3% of the HME cases Cytogenetics 11p rearrangement was found in 1 sporadic osteochondroma (exostosis) using cytogenetic analysis; loss of heterozygosity at the EXT2 locus was absent in 14 osteochondromas

External links Nomenclature Hugo EXT2 GDB EXT2 Entrez_Gene EXT2 2132 exostoses (multiple) 2 Cards Atlas EXT2ID213 GeneCards EXT2 Ensembl EXT2 CancerGene EXT2 Genatlas EXT2 GeneLynx EXT2 eGenome EXT2 euGene 2132 Genomic and cartography EXT2 - chr11:44073675-44223555 + 11p11.2 (hg17- GoldenPath May_2004)

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -410- Ensembl EXT2 - 11p11.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene EXT2 Gene and transcription

Genbank U67354 [ SRS ] U67354 [ ENTREZ ]

Genbank U67355 [ SRS ] U67355 [ ENTREZ ]

Genbank U67368 [ SRS ] U67368 [ ENTREZ ]

Genbank BC010058 [ SRS ] BC010058 [ ENTREZ ]

Genbank BC013050 [ SRS ] BC013050 [ ENTREZ ]

RefSeq NM_000401 [ SRS ] NM_000401 [ ENTREZ ]

RefSeq NM_207122 [ SRS ] NM_207122 [ ENTREZ ]

RefSeq NT_086780 [ SRS ] NT_086780 [ ENTREZ ] AceView EXT2 AceView - NCBI TRASER EXT2 Traser - Stanford

Unigene Hs.368404 [ SRS ] Hs.368404 [ NCBI ] HS368404 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q93063 [ SRS] Q93063 [ EXPASY ] Q93063 [ INTERPRO ]

Interpro IPR004263 Exostosin [ SRS ] IPR004263 Exostosin [ EBI ] CluSTr Q93063 Pfam PF03016 Exostosin [ SRS ] PF03016 Exostosin [ Sanger ] pfam03016 [ NCBI-CDD ] Blocks Q93063 Polymorphism : SNP, mutations, diseases OMIM 608210 [ map ] GENECLINICS 608210

SNP EXT2 [dbSNP-NCBI]

SNP NM_000401 [SNP-NCI]

SNP NM_207122 [SNP-NCI]

SNP EXT2 [GeneSNPs - Utah] EXT2 [SNP - CSHL] EXT2] [HGBASE - SRS] General knowledge Family EXT2 [UCSC Family Browser] Browser SOURCE NM_000401 SOURCE NM_207122 SMD Hs.368404 SAGE Hs.368404

2.4.1.224 [ Enzyme-SRS ] 2.4.1.224 [ Brenda-SRS ] 2.4.1.224 [ KEGG Enzyme ] 2.4.1.224 [ WIT ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -411- Amigo component|Golgi apparatus function|N-acetylglucosaminyl-proteoglycan 4-beta- Amigo glucuronosyltransferase activity Amigo component|endoplasmic reticulum membrane Amigo process|glycosaminoglycan biosynthesis Amigo component|integral to membrane Amigo process|negative regulation of cell cycle Amigo process|signal transduction Amigo process|skeletal development Amigo function|transferase activity, transferring glycosyl groups KEGG Chondroitin / Heparan Sulfate Biosynthesis PubGene EXT2 Other databases Probes Probe Cancer Cytogenetics (Bari) Probe EXT2 Related clones (RZPD - Berlin) PubMed PubMed 15 Pubmed reference(s) in LocusLink Bibliography Genetic heterogeneity in families with hereditary multiple exostoses. Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G, et al. Am J Hum Genet 1993; 53: 71-79.

Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Wu Y, Heutink P, De Vries BBA, Sandkuijl LA, Van den Ouweland AMW, Niermeijer MF, Galjaard H, Reyniers E, Willems PJ, Halley DJJ. Hum Mol Genet 1994; 3: 167-171.

Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8. Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M. Am J Hum Genet 1995; 56: 1125-1131.

Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Raskind WH, Conrad EU, Chansky H, Matsushita M. Am J Hum Genet 1995; 56: 1132-1139.

Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -412- Wuyts W, Ramlakhan S, Van Hul W, Hecht JT, Van den Ouweland AMW, Raskind WH, Hofstede FC, Reyniers E, Wells DE, De Vries B, et al. Am J Hum Genet 1995; 57: 382-387.

The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA. Nature Genet 1996; 14: 25-32.

Positional cloning of a gene involved in hereditary multiple exostoses. Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul E, De Boulle K, De Vries BBA, Hendrickx J, Herrygers I, et al. Hum Mol Genet 1996; 5: 1547-1557.

The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and caenorhabditis elegans. Clines GA, Ashley JA, Shah S, Lovett M. Genome Res 1997; 7: 359-367.

Isolation and characterization of the murine homolog of the human EXT2 multiple exostoses gene. Stickens D, Evans GA. Biochem Mol Med 1997; 61: 16-21.

Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Cancer 1998; 82: 1657-1663.

The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. J Biol Chem 1998; 273: 26265-26268.

Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Bovee JVMG, Cleton-Jansen AM, Kuipers-Dijkshoorn N, Van den Broek LJCM, Taminiau AHM, Cornelisse CJ, Hogendoorn PCW. Genes Chromosom Cancer 1999; 26: 237-246.

EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Bovee JVMG, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AHM, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PCW. Am J Hum Genet 1999; 65: 689-698.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -413-

The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N- acetylhexosaminyltransferase that transfers N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. Kitagawa H, Shimakawa H, Sugahara K. J Biol Chem 1999; 274: 13933-13937.

New perspectives on the molecular basis of hereditary bone tumours. McCormick C, Duncan G, Tufaro F. Mol Med Today 1999; 5: 481-486.

A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Simmons AD, Musy MM, Lopes CS, Hwang L, Yang Y, Lovett M. Hum Mol Genet 1999; 8: 2155-2164.

The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the golgi apparatus and catalyzes the synthesis of heparan sulfate. McCormick C et al. Proc.Natl.Acad.Sci.USA 2000; 97 (2):668-673.

EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis. Stickens D, Brown D, and Evans GA. Dev.Dyn.2000; 218 (3): 452-464.

Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Wuyts W and Van Hul W. Hum.Mutat.2000; 15 (3): 220-227.

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

BiblioGene - INIST

Contributor(s) Written 01- Judith V.M.G. Bovée 2000 Updated 03- Judith V.M.G. Bovée 2002

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -414- Citation This paper should be referenced as such : Bovée JVMG . EXT2. Atlas Genet Cytogenet Oncol Haematol. January 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/EXT2ID213.html Bovee JVMG . EXT2. Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/EXT2ID213.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -415- Atlas of Genetics and Cytogenetics in Oncology and Haematology

GPHN (Gephyrin)

Identity Other KIAA1385 names GPHRYN Hugo GPHN Location 14q23.3 The markers associated with the gephyrin sequence correspond to the

D14S63-D14S1069 interval. DNA/RNA

Exon-intron organization of the human gephyrin gene: Exons coding for the geghyrin are depicted by large traits and roman numerals with the alternative cassettes C1-C7 and exon VIII represented beneath the constant exons (exon VIII is putatively another cassette because one cDNA lacking this exon has been isolated). C1, C6 and C7 were not localized but their site of insertion is indicated by a ? as described . Exons and introns sizes are not drawn to scale. Exon I is telomeric to exon XXVII.

Description 29 exons (30 exons with the putative C1 exon), spanning over 800 kb Transcription in a telomeric to centromeric direction. The alternative use of different exons, particularly of the exons termed C1 to C7, produces splice variants which are differentially expressed in the central nervous system and other tissues. Protein

Note Gephyrin is a cytoplasmic, peripheral membrane protein that anchors the GlyR as well as a subset of GABAA receptors to the subsynaptic cytoskeleton in neurons Description 736-770 amino acids; sizes varying from 93-105 kDa to smaller

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -416- products 52-60 kDa. The N-terminal domain of gephyrin is homologous to the bacterial protein MogA, and the C-terminal domain is homologous to bacterial MoeA, both proteins being involved in the biosynthesis of Moco. Expression wide if not ubiquitous, especially in brain, spinal cord, lung, liver and kidney. Precise distribution of expression of the different variants is not known. Localisation Gephyrin is a cytoplasmic, peripheral membrane protein. Function anchor inhibitory neuronal receptors (glycine, GABA) to the sub- synaptic cytoskeleton; plays a role in Moco biosynthesis. Homology bacterial MogA et MoeA, drosophila Cinnamon and Arabidopsis thaliana Cnx1. Mutations Note deletion of the exons 2 and 3 resulting into a frameshift after 21codons of the normal coding sequence. No gephyrin detected in the patient's fibroblats. Implicated in Entity Molybdenum cofactor (Moco) hereditary deficiency syndrome. Note Disruption of the gephyrin gene is lethal at birth in the mouse. The mutant phenotype resembles that of humans with hereditary deficiency of molybdenum cofactor and hyperhekplexia, a disease which is associated with defects in glycinergic inhibition in many patients suggesting that gephyrin function may be impaired in patients affected by either of these two diseases. Prognosis lethal in the three cases described.

Entity t(11;14)(q23;q23) in ANLL --> MLL - GPHN Abnormal The fusion protein contains the MLL AT hook motifs and a DNA methyl Protein transferase homology domain fused to the C-terminal part of Gephyrin , including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA.

To be noted High-titer antibodies against gephyrin have been identified in a patient with a mediastinal cancer and clinical features of stiff-man syndrome These findings provided evidence for a link between autoimmunity directed against components of inhibitory synapses and neurologic conditions characterized by chronic rigidity and spams. External links Nomenclature Hugo GPHN GDB GPHN

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -417- Entrez_Gene GPHN 10243 gephyrin Cards Atlas GPHNID317 GeneCards GPHN Ensembl GPHN CancerGene GPHN Genatlas GPHN GeneLynx GPHN eGenome GPHN euGene 10243 Genomic and cartography GPHN - 14q23.3 chr14:66044989-66718268 + 14q23.3 (hg17- GoldenPath May_2004) Ensembl GPHN - 14q23.3 [CytoView]

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

Genbank AB037806 [ SRS ] AB037806 [ ENTREZ ]

Genbank AF272663 [ SRS ] AF272663 [ ENTREZ ]

Genbank AJ272033 [ SRS ] AJ272033 [ ENTREZ ]

Genbank AJ272343 [ SRS ] AJ272343 [ ENTREZ ]

Genbank AK025169 [ SRS ] AK025169 [ ENTREZ ]

RefSeq NM_020806 [ SRS ] NM_020806 [ ENTREZ ]

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

Unigene Hs.208765 [ SRS ] Hs.208765 [ NCBI ] HS208765 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9NQX3 [ SRS] Q9NQX3 [ EXPASY ] Q9NQX3 [ INTERPRO ]

PS01078 MOCF_BIOSYNTHESIS_1 [ SRS ] PS01078 Prosite MOCF_BIOSYNTHESIS_1 [ Expasy ]

PS01079 MOCF_BIOSYNTHESIS_2 [ SRS ] PS01079 Prosite MOCF_BIOSYNTHESIS_2 [ Expasy ]

Interpro IPR008285 MoCF_bios_C [ SRS ] IPR008285 MoCF_bios_C [ EBI ]

Interpro IPR008284 MoCF_bios_N [ SRS ] IPR008284 MoCF_bios_N [ EBI ]

Interpro IPR001453 MoCF_biosynth [ SRS ] IPR001453 MoCF_biosynth [ EBI ]

Interpro IPR005111 MoeA_C [ SRS ] IPR005111 MoeA_C [ EBI ]

Interpro IPR005110 MoeA_N [ SRS ] IPR005110 MoeA_N [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -418- CluSTr Q9NQX3

PF00994 MoCF_biosynth [ SRS ] PF00994 MoCF_biosynth [ Sanger Pfam ] pfam00994 [ NCBI-CDD ] Pfam PF03454 MoeA_C [ SRS ] PF03454 MoeA_C [ Sanger ] pfam03454 [ NCBI-CDD ] Pfam PF03453 MoeA_N [ SRS ] PF03453 MoeA_N [ Sanger ] pfam03453 [ NCBI-CDD ]

Prodom PD002460 MoCF_biosynth[INRA-Toulouse] Prodom Q9NQX3 GEPH_HUMAN [ Domain structure ] Q9NQX3 GEPH_HUMAN [ sequences sharing at least 1 domain ] Blocks Q9NQX3

PDB 1JLJ [ SRS ] 1JLJ [ PdbSum ], 1JLJ [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 603930 [ map ] GENECLINICS 603930

SNP GPHN [dbSNP-NCBI]

SNP NM_020806 [SNP-NCI]

SNP GPHN [GeneSNPs - Utah] GPHN [SNP - CSHL] GPHN] [HGBASE - SRS] General knowledge Family GPHN [UCSC Family Browser] Browser SOURCE NM_020806 SMD Hs.208765 SAGE Hs.208765 Amigo process|Mo-molybdopterin cofactor biosynthesis Amigo function|catalytic activity Amigo component|cytoskeleton BIOCARTA Gamma-aminobutyric Acid Receptor Life Cycle PubGene GPHN Other databases Other KIAA1385 (HUGE) database Probes Probe GPHN Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography Primary structure and alternative splice variants of Gephyrin, a putative glycine receptor-tubulin linker protein. Prior P, Schmitt B, Grenningloh G, Pribilla I., Multhaup G., Beyreuther K, Maulet Y, Langosch D, Kirsch J, Betz H.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -419- Neuron 1992; 8: 1167-1170. Medline 1319186

Dual requirement for Gephyrin in Glycine receptor clustering and Molybdene enzyme activity. Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR. Science 1998; 282: 1321-1324. Medline 9812897

The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells. David-Watine B. Gene 2001; 271(2): 239-245. Medline 11418245

GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24). Eguchi M, Eguchi-Ishimae M, Seto M, Morishita K, Suzuki K, Ueda R, Ueda K, Kamada N, Greaves M. Genes Chromosomes Cancer 2001; 32: 212-221. Medline 11579461

A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency. Reiss J, Gross-Hardt S, Christensen E, Schmidt P, Mendel R R, Schwarz G. Am J Hum Genet 2001; 68: 208-213. Medline 11095995

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Brigitte David-Watine 2002 Citation This paper should be referenced as such : David-Watine B . GPHN (Gephyrin). Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/GPHNID317.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -420- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MLN51

Identity Hugo MLN51 Location 17q11-17q21.3 from centromere to telomere are: TRAF4 (alias MLN62/CART1), Lasp1

(alias MLN50), MLN64, c-erbB2, and MLN51 DNA/RNA Description composed of 14 exons, gene size: approximately 16 kb Transcription cDNA:4.1kb; coding sequence: 2111 bp Protein

Description 703 amino acids; theorical molecular weigth 76kDa, observed molecular weigth 115kDa; contains a functional coiled-coil domain and two functional NLS at its N-terminal part; possesses a proline-rich region with four potential SH3 domain binding sites at its C-terminal part Expression ubiquitous Localisation cytoplasmic with a perinuclear accumulation Function unknown Homology counterparts can be deduced from mouse, zebrafish, worm and drosophila genomes Implicated in Entity breast carcinomas Note overexpression is found in 12 to 30% of primary breast carcinomas

External links Nomenclature Hugo MLN51 GDB CASC3 Entrez_Gene CASC3 22794 cancer susceptibility candidate 3 Cards Atlas MLN51ID241 GeneCards CASC3 Ensembl CASC3

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -421- CancerGene MLN51 Genatlas CASC3 GeneLynx CASC3 eGenome CASC3 euGene 22794 Genomic and cartography CASC3 - chr17:35550102-35581950 + 17q21.1 (hg17- GoldenPath May_2004) Ensembl CASC3 - 17q21.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CASC3 Gene and transcription

Genbank BC030008 [ SRS ] BC030008 [ ENTREZ ]

Genbank BC044656 [ SRS ] BC044656 [ ENTREZ ]

Genbank BC050526 [ SRS ] BC050526 [ ENTREZ ]

Genbank X80199 [ SRS ] X80199 [ ENTREZ ]

RefSeq NM_007359 [ SRS ] NM_007359 [ ENTREZ ]

RefSeq NT_086877 [ SRS ] NT_086877 [ ENTREZ ] AceView CASC3 AceView - NCBI TRASER CASC3 Traser - Stanford

Unigene Hs.350229 [ SRS ] Hs.350229 [ NCBI ] HS350229 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O15234 [ SRS] O15234 [ EXPASY ] O15234 [ INTERPRO ] CluSTr O15234 Blocks O15234 Polymorphism : SNP, mutations, diseases OMIM 606504 [ map ] GENECLINICS 606504

SNP CASC3 [dbSNP-NCBI]

SNP NM_007359 [SNP-NCI]

SNP CASC3 [GeneSNPs - Utah] CASC3 [SNP - CSHL] CASC3] [HGBASE - SRS] General knowledge Family CASC3 [UCSC Family Browser] Browser SOURCE NM_007359 SMD Hs.350229 SAGE Hs.350229

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -422- Amigo process|mRNA processing Amigo process|mRNA-nucleus export Amigo function|molecular_function unknown Amigo component|nucleus Amigo process|transport PubGene CASC3 Other databases Probes Probe MLN51 Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography 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 Bièche I, Tomasetto C, Régnier C, Moog-Lutz C, Rio MC, Lidereau R. Cancer Res 1996; 56: 3886-3890. Medline 8752152

Metastatic Lymph Node 51, a novel nucleo-cytoplasmic protein overexpressed in breast cancer. Degot S, Régnier C, Wendling C, Chenard MP, Rio MC, Tomasetto C. Oncogene in press

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BiblioGene - INIST

Contributor(s) Written 03- Sébastien Degot 2002

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -423- Citation This paper should be referenced as such : Degot S . MLN51. Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MLN51ID241.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -424- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NSD1 (-binding, su(var), enhancer- of-zeste and trithorax domain-containing protein 1

Identity Hugo NSD1 Location 5q35 DNA/RNA Description At least 23 exons. cDNA is 8552 bp, 8088 bp open reading frame Transcription Two transcripts: 9.0 and 10 kb Protein

Description 2696 amino acids. Murine Nsd1 is a nuclear protein containing SET, proline-tryptophan-tryptophan-proline (PWWP) and plant homedomain protein (PHD) finger domains. The protein has two distinct nuclear receptor (NR)-interaction domains (NID-L, NID+L). Human NSD1 shows 86% identity to the murine Nsd1 at the nucleotide level and 83% at the amino acid level, retaining the nuclear interaction domains (NID) as well as the SET/SAC and PHD finger domains. Expression Widely expressed Function Features of a basic transcription factor, also of a bifunctional transcriptional regulator, (similar to murine Nsd1) Homology NSD2: (Wolf-Hirschhorn syndrome critical region on 4p); NSD3: expressed in tumour cell lines Implicated in Entity t(5;11)(q35;p15.5)/ acute non lymphoblastic leukemia (ANLL) Disease De novo childhood ANLL Prognosis Only 5 cases reported. All had poor response to treatment/short survival Cytogenetics Cryptic: associated with del(5q) (sole cytogenetic abnormality) or a normal karyotype Hybrid/Mutated 5' NUP98- 3' NSD1 ; NSD1-NUP98 also present in all cases tested Gene

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -425- Abnormal NH2 NUP98- COOH NSD1: Fuses the FXFG portion of NUP98 to Protein the SET, SAC and PHD finger domains of NSD1. NSD1-NUP98: Fuses the RNA-binding domain of NSD1 to the NID domain NUP98

External links Nomenclature Hugo NSD1 GDB NSD1 Entrez_Gene NSD1 64324 nuclear receptor binding SET domain protein 1 Cards Atlas NSD1ID356 GeneCards NSD1 Ensembl NSD1 CancerGene ARA267 Genatlas NSD1 GeneLynx NSD1 eGenome NSD1 euGene 64324 Genomic and cartography NSD1 - 5q35 chr5:176493532-176655367 + 5q35.2 (hg17- GoldenPath May_2004) Ensembl NSD1 - 5q35.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NSD1 Gene and transcription

Genbank AF085858 [ SRS ] AF085858 [ ENTREZ ]

Genbank AF322907 [ SRS ] AF322907 [ ENTREZ ]

Genbank AF380302 [ SRS ] AF380302 [ ENTREZ ]

Genbank AF395588 [ SRS ] AF395588 [ ENTREZ ]

Genbank AK025916 [ SRS ] AK025916 [ ENTREZ ]

RefSeq NM_022455 [ SRS ] NM_022455 [ ENTREZ ]

RefSeq NM_172349 [ SRS ] NM_172349 [ ENTREZ ]

RefSeq NT_086683 [ SRS ] NT_086683 [ ENTREZ ] AceView NSD1 AceView - NCBI TRASER NSD1 Traser - Stanford

Unigene Hs.208961 [ SRS ] Hs.208961 [ NCBI ] HS208961 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -426- SwissProt Q96L73 [ SRS] Q96L73 [ EXPASY ] Q96L73 [ INTERPRO ]

Prosite PS50868 POST_SET [ SRS ] PS50868 POST_SET [ Expasy ]

Prosite PS50812 PWWP [ SRS ] PS50812 PWWP [ Expasy ]

Prosite PS50280 SET [ SRS ] PS50280 SET [ Expasy ]

Prosite PS01359 ZF_PHD_1 [ SRS ] PS01359 ZF_PHD_1 [ Expasy ]

Prosite PS50016 ZF_PHD_2 [ SRS ] PS50016 ZF_PHD_2 [ Expasy ]

Interpro IPR006560 AWS [ SRS ] IPR006560 AWS [ EBI ]

Interpro IPR003616 PostSET [ SRS ] IPR003616 PostSET [ EBI ]

Interpro IPR000313 PWWP [ SRS ] IPR000313 PWWP [ EBI ]

Interpro IPR001214 SET [ SRS ] IPR001214 SET [ EBI ]

Interpro IPR001965 Znf_PHD [ SRS ] IPR001965 Znf_PHD [ EBI ]

Interpro IPR001841 Znf_ring [ SRS ] IPR001841 Znf_ring [ EBI ] CluSTr Q96L73

Pfam PF00628 PHD [ SRS ] PF00628 PHD [ Sanger ] pfam00628 [ NCBI-CDD ] Pfam PF00855 PWWP [ SRS ] PF00855 PWWP [ Sanger ] pfam00855 [ NCBI- CDD ]

Pfam PF00856 SET [ SRS ] PF00856 SET [ Sanger ] pfam00856 [ NCBI-CDD ]

Smart SM00570 AWS [EMBL]

Smart SM00249 PHD [EMBL]

Smart SM00508 PostSET [EMBL]

Smart SM00293 PWWP [EMBL]

Smart SM00184 RING [EMBL]

Smart SM00317 SET [EMBL] Blocks Q96L73 Polymorphism : SNP, mutations, diseases OMIM 606681 [ map ] GENECLINICS 606681

SNP NSD1 [dbSNP-NCBI]

SNP NM_022455 [SNP-NCI]

SNP NM_172349 [SNP-NCI]

SNP NSD1 [GeneSNPs - Utah] NSD1 [SNP - CSHL] NSD1] [HGBASE - SRS] General knowledge Family NSD1 [UCSC Family Browser] Browser SOURCE NM_022455 SOURCE NM_172349 SMD Hs.208961 SAGE Hs.208961 Amigo function|DNA binding

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -427- Amigo component|nucleus Amigo process|protein ubiquitination Amigo process|regulation of transcription, DNA-dependent Amigo component|ubiquitin ligase complex Amigo function|ubiquitin-protein ligase activity Amigo function|zinc ion binding PubGene NSD1 Other databases Probes Probe HSP2301A4 Probe NSD1 Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. Huang N, vom Baur E, Garnier JM, Lerouge T, Vonesch JL, Lutz Y, Chambon P, Losson R. EMBO J 1998; 17(12): 3398-3412. Medline 9628876

WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf- Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Stec I, Wright TJ, van Ommen GJ, de Boer PA, van Haeringen A, Moorman AF, Altherr MR, den Dunnen JT. Hum Mol Genet 1998; 7(7): 1071-1082. Medline 9618163

A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. Jaju RJ, Haas OA, Neat M, Harbott J, Saha V, Boultwood J, Brown JM, Pirc- Danoewinata H, Krings BW, Muller U, Morris, SW, Wainscoat JS, Kearney L. Blood 1999; 94(2): 773-780. Medline 10397745

NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines. Angrand PO, Apiou F, Stewart AF, Dutrillaux B, Losson R, Chambon P. Genomics 2001; 74(1): 79-88. Medline 11374904

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -428- A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Jaju RJ, Fidler C, Haas OA, Strickson AJ, Watkins F, Clark K, Cross NC, Cheng JF, Aplan PD, Kearney L, Boultwood J, Wainscoat JS. Blood 2001; 98(4): 1264-1267 Medline 11493482

Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene. Kurotaki N, Harada N, Yoshiura K, Sugano S, Niikawa N, Matsumoto N. Gene 2001; 279(2): 197-204 Medline 11733144

NUP98 gene fusions in hematologic malignancies. Lam DH, Aplan PD. Leukemia 2001; 15(11): 1689-1695.(REVIEW) Medline 11681408

A cryptic t(5;11)(q35;p15.5) in two AML children with apparently normal karyotypes, identified by a multiplex FISH telomere assay. Brown M, Jawad M, Eils R, Twigg SFR, Saracoglu K, Sauerbrey A, Thomas AE, Harbott J, Kearney L. Blood (2002) (in press)

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Lyndal Kearney 2002 Citation This paper should be referenced as such : Kearney L . NSD1 (Nuclear receptor-binding, su(var), enhancer-of-zeste and trithorax domain-containing protein 1. Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NSD1ID356.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -429- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NUP98 (nucleoporin 98 kDa)

Identity Hugo NUP98 Location 11p15 DNA/RNA Transcription 3.6, 6.5 , 7.0 kb mRNA Protein

NUP98 protein - Lyndal Kearney

Description 920 amino acids; 97 kDa; contains repeated motifs (GLFG and FG) in N-term and a RNA binding motif in C-term Expression wide Localisation nuclear membrane localisation Function nucleoporin: associated with the nuclear pore complex; role in nucleocytoplasmic transport processes Homology member of the GLFG nucleoporins Implicated in Entity inv (11)(p15q22)/ myelodysplasic syndrome (MDS) or acute non lymphocytic leukemia (ANLL) --> NUP98-DDX10 Disease therapy related MDS (t-MDS) and ANLL; de novo ANLL Hybrid/Mutated 5' NUP98 - 3' DDX10 Gene Abnormal fuses the GLFG repeat domains of NUP98 to the acidic domain of Protein DDX10

Entity t(1;11)(q23;p15.5) / t-MDS orANLL --> NUP98-PMX1 Disease One case of t-ANLL Hybrid/Mutated 5' NUP98 - 3' PMX1 Gene

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -430- Abnormal fuses the GLFG repeat domains of NUP98 to the homeodomain of Protein PMX1

Entity t(2;11)(q31;p15)/treatment related leukaemia --> NUP98-HOXD13 Disease so far, only 1 case of treatment related myelodysplasia evolving towards M6 acute non lymphocytic leukaemia Hybrid/Mutated 5' NUP98 - 3' HOXD13 Gene Abnormal fuses the GLFG repeat domains of NUP98 to the HOXD13 Protein homeodomain

Entity t(4;11)(q21;p15.5)/ T- acute lymphoblastic leukemia (ALL) --> NUP98-RAP1GDS1 Disease 3 cases of adult T-ALL Hybrid/Mutated 5' NUP98 - 3' RAP1GDS1 Gene Abnormal fuses the GLFG repeat domains of NUP98 to the entire coding Protein region of RAP1GDS1. The product, rap1gds, has guanine nucleotide exchange factor activity.

Entity t(5;11)(q35;p15.5)/ ANLL--> NUP98-NSD1 Disease ANLL. 5 cases reported to date. All were children or young adults (age range 3-18 years). Note that the t(5;11)(q35;p15.5) is not detectable by G-banding. Three cases were reported as cryptic t(5;11) associated with del(5q); a further two cases were identified in apparently normal karyotypes. Hybrid/Mutated 5' NUP98 - 3' NSD1 Gene Abnormal fuses the GLFG repeat domains of NUP98 to the conserved SET, Protein SAC and PHD finger domains of the NSD1 gene.

Entity t(7;11)(p15;p15) /ANLL --> NUP98-HOXA9 Disease M2-M4 ANLL mostly; occasionally: CML-like cases Prognosis mean survival: 15 mths Cytogenetics sole anomaly most often Hybrid/Mutated 5' NUP98 - 3' HOXA9 Gene Abnormal fuses the GLFG repeat domains of NUP98 to the HOXA9 homeobox Protein

Entity t(9;11)(p22;p15.5)/ANLL--> NUP98-LEDGF Disease One case of de novo ANLL

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -431- Hybrid/Mutated 5' NUP98 - 3' LEDGF Gene Abnormal fuses the GLFG repeat domains of NUP98 to the COOH terminal of Protein the LEDGF gene (encoding transcriptional activators p52 and p75)

Entity t(11;12)(p15;q13)/treatment related leukemia (t-ANLL/MDS) Disease 1patient with t-MDS/ANLL Hybrid/Mutated 5'; NUP98 - 3'; unknown Gene

Entity t(11;17)(p15.5;q21) t-MDS/ANLL Disease 1 patient with t-MDS/ANLL Hybrid/Mutated 5' NUP98 - 3' unknown Gene

Entity t(11;20)(p15.5;q11)/ANLL, t-MDS/ANLL--> NUP98-TOP1 Disease ANLL, t-MDS/ANLL Hybrid/Mutated 5' NUP98 - 3' TOP1 Gene Abnormal fuses the GLFG repeat domains of NUP98 to the catalytic domain of Protein TOP1

Breakpoints

External links

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -432- Nomenclature Hugo NUP98 GDB NUP98 Entrez_Gene NUP98 4928 nucleoporin 98kDa Cards Atlas NUP98 GeneCards NUP98 Ensembl NUP98 CancerGene NUP98 Genatlas NUP98 GeneLynx NUP98 eGenome NUP98 euGene 4928 Genomic and cartography NUP98 - 11p15 chr11:3689635-3775468 - 11p15.4 (hg17- GoldenPath May_2004) Ensembl NUP98 - 11p15.4 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NUP98 Gene and transcription

Genbank AB038344 [ SRS ] AB038344 [ ENTREZ ]

Genbank AB040538 [ SRS ] AB040538 [ ENTREZ ]

Genbank AF071076 [ SRS ] AF071076 [ ENTREZ ]

Genbank AF071077 [ SRS ] AF071077 [ ENTREZ ]

Genbank AF116074 [ SRS ] AF116074 [ ENTREZ ]

RefSeq NM_005387 [ SRS ] NM_005387 [ ENTREZ ]

RefSeq NM_016320 [ SRS ] NM_016320 [ ENTREZ ]

RefSeq NM_139131 [ SRS ] NM_139131 [ ENTREZ ]

RefSeq NM_139132 [ SRS ] NM_139132 [ ENTREZ ]

RefSeq NT_086779 [ SRS ] NT_086779 [ ENTREZ ] AceView NUP98 AceView - NCBI TRASER NUP98 Traser - Stanford

Unigene Hs.524750 [ SRS ] Hs.524750 [ NCBI ] HS524750 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P52948 [ SRS] P52948 [ EXPASY ] P52948 [ INTERPRO ] CluSTr P52948 Blocks P52948

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -433- Polymorphism : SNP, mutations, diseases OMIM 601021 [ map ] GENECLINICS 601021

SNP NUP98 [dbSNP-NCBI]

SNP NM_005387 [SNP-NCI]

SNP NM_016320 [SNP-NCI]

SNP NM_139131 [SNP-NCI]

SNP NM_139132 [SNP-NCI]

SNP NUP98 [GeneSNPs - Utah] NUP98 [SNP - CSHL] NUP98] [HGBASE - SRS] General knowledge Family NUP98 [UCSC Family Browser] Browser SOURCE NM_005387 SOURCE NM_016320 SOURCE NM_139131 SOURCE NM_139132 SMD Hs.524750 SAGE Hs.524750 Amigo process|DNA replication Amigo component|nuclear pore Amigo process|nuclear pore organization and biogenesis Amigo process|nucleocytoplasmic transport Amigo component|nucleoplasm Amigo function|protein binding Amigo process|protein transport Amigo process|protein-nucleus import, docking Amigo function|structural constituent of nuclear pore Amigo function|transporter activity PubGene NUP98 Other databases Probes Probe NUP98 Related clones (RZPD - Berlin) PubMed PubMed 29 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -434- Bibliography Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP, Jenkins NA, Copeland NG, Shaughnessy JD Jr. Nat Genet 1996 Feb;12(2):154-158 Medline 96154187

The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N, Kaneko Y, Ohki M. Blood 1997 Jun 1;89(11):3936-44 Medline 97309415

The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways. Powers MA, Forbes DJ, Dahlberg JE, Lund E J Cell Biol 1997 Jan 27;136(2):241-50 Medline 97167679

NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD Cancer Res 1998; 58(19): 4269-4273 Medline 98438040

The t(11;20)(p15;q11) chromosomal translocation associated with therapy- related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Ahuja HG, Felix CA, Aplan PD Blood 1999; 94(9): 3258-3261 Medline 10556215

The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A. Blood 1999; 94(6): 2072-2079. Medline 10477737

A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. Jaju RJ, Haas OA, Neat M, Harbott J, Saha V, Boultwood J, Brown JM, Pirc- Danoewinata H, Krings BW, Muller U, Morris, SW, Wainscoat JS, Kearney L. Blood 1999; 94(2): 773-780. Medline 10397745

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -435- NUP98 gene rearrangements in leukemia detected by fluorescence in situ hybridization (FISH). Kobzev YN, Rowley JD. Blood 1999; 94 Suppl 1: Abst 2221.

NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Nakamura T, Yamazaki Y, Hatano Y, Miura I. Blood 1999 ;94(2): 741-747 Medline 10397741

Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Ahuja HG, Felix CA, Aplan PD Genes Chromosomes Cancer 2000; 29(2): 96-105 Medline 10959088 t(9;11)(p22;p15) in acute myeloid leukemia results in a fusion between NUP98 and the gene encoding transcriptional coactivators p52 and p75-lens epithelium-derived growth factor (LEDGF). Ahuja HG, Hong J, Aplan PD, Tcheurekdjian L, Forman SJ, Slovak ML. Cancer Res 2000; 60(22): 6227-6229 Medline 11103774

A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Jaju RJ, Fidler C, Haas OA, Strickson AJ, Watkins F, Clark K, Cross NC, Cheng JF, Aplan PD, Kearney L, Boultwood J, Wainscoat JS. Blood 2001; 98(4): 1264-1247 Medline UI

NUP98 gene fusions in hematologic malignancies. Lam DH, Aplan PD. Leukemia 2001; 15(11): 1689-1695 (REVIEW) Medline 11681408

A cryptic t(5;11)(q35;p15.5) in two AML children with apparently normal karyotypes, identified by a multiplex FISH telomere assay Brown M, Jawad M, Eils R, Twigg SFR, Saracoglu K, Sauerbrey A, Thomas AE, Harbott J, Kearney L. Blood (2002) (in press)

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

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -436- Contributor(s) Written 01- Jean-Loup Huret 1998 Updated 11- Jean-Loup Huret 1998 Updated 02- Jean-Loup Huret 2000 Updated 03- Lyndal Kearney 2002 Citation This paper should be referenced as such : Huret JL . NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol. January 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NUP98.html Huret JL . NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol. November 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NUP98.html Huret JL . NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol. February 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NUP98.html Kearney L . NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NUP98.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -437- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TPR (Translocated promoter region)

Identity Other Tumor potentiating region names Hugo TPR Location 1q25 The 3' coding end of Tpr overlaps with the 3' no-coding region of the PRG4 (Proteoglycan 4) gene (or MGCSF for megacaryocyte stimulating

factor) which is involved in the Camptodactyly-arthropathy-coxa vara- pericarditis syndrom DNA/RNA Description 51-52 exons spanning about 63 kb Transcription in a telomeric to centromeric direction. 10kb mRNA. Protein

Description 2349 amino acids, 267 kDa. The protein contains extensive coilecoiled domains and an acidic globular C-terminus, and is phosphorylated. Expression widespread, if not ubiquitous; highest in testis, thymus, spleen and brain, lower levels in heart, liver and kidney. Localisation nucleoplasmic side of the nucleopore and discrete foci in the nuclear interior, binds to the nucleoporin Nup98. Function still controversial, part of a filamentous intranuclear network, role in nuclear protein and/or polyA+RNA export. Homology yeast Mlp1 and Mlp2, drosophila Bx34 , xenopus Tpr. Mutations Note Tpr was first described as a fusion partner with the MET oncogene (7q) in a cell line rendered tumorigenic with the direct acting carcinogen N- methyl-N-prime-nitrosoguanidine (MNNG). Then, this Tpr-MET rearrangement was also described in gastric cancers and a TRK-Tpr fusion was found in thyroid cancers. Fusions with at least one other proto-oncogene have since been described. Implicated in Entity gastric cancers with TPR- MET hybrid gene Disease the TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -438- Hybrid/Mutated 5' TPR- 3'MET 5 kb mRNA Gene Abnormal 65 kDa, The fusion protein contains the constitutive promoter and Protein first 424 coding nucleotides (142 amino acids) of Tpr, and the the tyrosine kinase domain of the c-met protooncogene. Oncogenesis transgenic expression of TPR-MET oncogene leads to development of mammary hyperplasia and tumors.

Entity humanpapillary thyroid carcinomas with TPR- NTRK1 hybrid gene Hybrid/Mutated TRK-T1 (TPR-NTRK1): 598 nucleotides of the TPR gene 5' end are Gene fused to 1148 bp of the TRK proto-oncogene which contain the TRK tyrosine kinase domain. TRK-T2 : 3073 nucleotides of Tpr 5' end fused to 1412 nucleotides of TRK . There is another hybrid gene between TPR and NTRK1 named TRK-T4. Arise by paracentric inversions on . Abnormal 55 kDa for the TRK-T1 fusion protein. Protein Oncogenesis TRK-T1 induces neoplastic transformation of thyroid epithelium in transgenic mice expressing the hybrid gene.

Entity rat induced tumors (adenocarcinomas and fibroblastomas). with Tpr- raf

Breakpoints Note All TRK breakpoints fall within a 2,9 kb genomic region of NTRK1. In the Tpr locus, the TRK-T1 and TRK-T2 break points are at least 11 kb apart, indicating the absence of a region prone to rearrangements. External links Nomenclature Hugo TPR GDB TPR TPR 7175 translocated promoter region (to activated MET Entrez_Gene oncogene) Cards Atlas TPRID282 GeneCards TPR Ensembl TPR CancerGene TPR Genatlas TPR GeneLynx TPR eGenome TPR

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -439- euGene 7175 Genomic and cartography TPR - 1q25 chr1:183014616-183076114 - 1q31.1 (hg17- GoldenPath May_2004) Ensembl TPR - 1q31.1 [CytoView]

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

Genbank AL133553 [ SRS ] AL133553 [ ENTREZ ]

Genbank AL596220 [ SRS ] AL596220 [ ENTREZ ]

Genbank X94208 [ SRS ] X94208 [ ENTREZ ]

Genbank U69668 [ SRS ] U69668 [ ENTREZ ]

Genbank X63105 [ SRS ] X63105 [ ENTREZ ]

RefSeq NM_003292 [ SRS ] NM_003292 [ ENTREZ ]

RefSeq NT_086598 [ SRS ] NT_086598 [ ENTREZ ] AceView TPR AceView - NCBI TRASER TPR Traser - Stanford

Unigene Hs.279640 [ SRS ] Hs.279640 [ NCBI ] HS279640 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P12270 [ SRS] P12270 [ EXPASY ] P12270 [ INTERPRO ] CluSTr P12270 Blocks P12270 Polymorphism : SNP, mutations, diseases OMIM 189940 [ map ] GENECLINICS 189940

SNP TPR [dbSNP-NCBI]

SNP NM_003292 [SNP-NCI]

SNP TPR [GeneSNPs - Utah] TPR [SNP - CSHL] TPR] [HGBASE - SRS] General knowledge Family TPR [UCSC Family Browser] Browser SOURCE NM_003292 SMD Hs.279640 SAGE Hs.279640 Amigo component|cytoplasm Amigo component|nuclear pore Amigo component|nucleus

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -440- Amigo process|protein-nucleus import Amigo process|transport PubGene TPR Other databases Probes Probe TPR Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography Rat c-raf oncogene activation by a rearrangement that produces a fused protein. Ishikawa F, Takaku F, Nagao M, Sugimura T. Mol Cell Biol 1987; 7(3): 1226-1232. Medline 3550433

Characterization of the TPR-MET oncogene p65 and the MET protooncogene p140 protein-tyrosine kinases. Gonzatti-Haces M, Seth A, Park M, Copeland T, Oroszlan S, Vande Woude GF. Proc Natl Acad Sci U S A 1988; 85: 21-25. Medline 3277171

The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Soman NR, Correa P, Ruiz BA, Wogan GN. Proc Natl Acad Sci U S A 1991; 88: 4892-4896. Medline 2052572

Chromosome 1 rearrangements involving the genes TPR and NTRK1 produce structurally different thyroid-specific TRK oncogenes. Greco A, Miranda C, Pagliardini S, Fusetti L, Bongarzone I, Pierotti MA. Genes Chromosomes Cancer 1997; 19(2): 112-123. Medline 9172002

Functional analysis of Tpr: identification of nuclear pore complex association and nuclear localization domains and a role in mRNA export. Bangs P, Burke B, Powers C, Craig R, Purohit A, Doxsey S. J Cell Biol 1998; 143: 1801-1812. Medline 9864356

Frequency of TPR-MET rearrangement in patients with gastric carcinoma and in first-degree relatives. Yu J, Miehlke S, Ebert MP, Hoffmann J, Breidert M, Alpen B, Starzynska T, Stolte Prof M, Malfertheiner P, Bayerdorffer E. Cancer 2000; 88: 1801-1806.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -441- Medline 10760755

Tpr is localized within the nuclear basket of the pore complex and has a role in nuclear protein export. Frosst P, Guan T, Subauste C, Hahn K, Gerace L. J Cell Biol 2002; 156: 617-630. Medline 11839768

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Brigitte David-Watine 2002 Citation This paper should be referenced as such : David-Watine B . TPR (Translocated promoter region). Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TPRID282.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -442- Atlas of Genetics and Cytogenetics in Oncology and Haematology

BCL11A (B-cell lymphoma/leukemia 11A)

Identity Hugo BCL11A Location 2p13-15

BCL11A (2p15) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA

Description 5 exons, with a CpG island in 5' of the gene Transcription the major transcript is the longest transcript: (5941 bp); other transcripts of 3.8 kb and 1.5 kb; alternate splices in exon 4 Protein

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -443-

Description 835 amino acids, predicted molecular weight of 91.3 kDa for the longest isoform, called BCL11AXL, with 6 Kruppel C2H2 zinc fingers, a prolin rich domain, and an acidic domain; 773 and 243 amino acids for the BCL11AL and the BCL11AS respectively Expression expressed in the fetal brain; low level or undetectable expression in most adult tissues, apart from lymph nodes, thymus, and bone marrow. Function contains DNA binding motifs (Zn fingers) Homology Evi9 (mouse); human BCL11B (14q32.1) Implicated in Entity t(2;14)(p13;q32) in B-cell malignancies Disease chronic lymphocytic leukemia / immunocytoma aggressive disease; possibly also other t(2;14)(p13;q32) in other B-ell diseases (acute lymphocytic leukemia, myeloma, ...) involve the same genes, but probably not Hodgkin disease cases with 2p amplification Cytogenetics most often the sole anomaly Hybrid/Mutated head to head translocation of BCL11A with IGH switch sequences on Gene the der(2) Oncogenesis BCL11A is overexpressed

External links Nomenclature Hugo BCL11A GDB BCL11A Entrez_Gene BCL11A 53335 B-cell CLL/lymphoma 11A (zinc finger protein) Cards Atlas BCL11AID391 GeneCards BCL11A Ensembl BCL11A CancerGene BCL11A Genatlas BCL11A GeneLynx BCL11A eGenome BCL11A euGene 53335 Genomic and cartography GoldenPath BCL11A - chr2:60589953-60692284 - 2p16.1 (hg17-

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -444- May_2004) Ensembl BCL11A - 2p16.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BCL11A Gene and transcription

Genbank AB058712 [ SRS ] AB058712 [ ENTREZ ]

Genbank AF080216 [ SRS ] AF080216 [ ENTREZ ]

Genbank AJ404611 [ SRS ] AJ404611 [ ENTREZ ]

Genbank AJ404612 [ SRS ] AJ404612 [ ENTREZ ]

Genbank AJ404613 [ SRS ] AJ404613 [ ENTREZ ]

RefSeq NM_018014 [ SRS ] NM_018014 [ ENTREZ ]

RefSeq NM_022893 [ SRS ] NM_022893 [ ENTREZ ]

RefSeq NM_138553 [ SRS ] NM_138553 [ ENTREZ ]

RefSeq NM_138559 [ SRS ] NM_138559 [ ENTREZ ]

RefSeq NT_086611 [ SRS ] NT_086611 [ ENTREZ ] AceView BCL11A AceView - NCBI TRASER BCL11A Traser - Stanford

Unigene Hs.370549 [ SRS ] Hs.370549 [ NCBI ] HS370549 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9H165 [ SRS] Q9H165 [ EXPASY ] Q9H165 [ INTERPRO ]

PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 Prosite ZINC_FINGER_C2H2_1 [ Expasy ]

PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 Prosite ZINC_FINGER_C2H2_2 [ Expasy ]

Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr Q9H165 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ]

Smart SM00355 ZnF_C2H2 [EMBL]

Prodom PD000003 Znf_C2H2[INRA-Toulouse] Prodom Q9H165 BC1A_HUMAN [ Domain structure ] Q9H165 BC1A_HUMAN [ sequences sharing at least 1 domain ] Blocks Q9H165 Polymorphism : SNP, mutations, diseases OMIM 606557 [ map ] GENECLINICS 606557

SNP BCL11A [dbSNP-NCBI]

SNP NM_018014 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -445- SNP NM_022893 [SNP-NCI]

SNP NM_138553 [SNP-NCI]

SNP NM_138559 [SNP-NCI]

SNP BCL11A [GeneSNPs - Utah] BCL11A [SNP - CSHL] BCL11A] [HGBASE - SRS] General knowledge Family BCL11A [UCSC Family Browser] Browser SOURCE NM_018014 SOURCE NM_022893 SOURCE NM_138553 SOURCE NM_138559 SMD Hs.370549 SAGE Hs.370549 Amigo component|cytoplasm Amigo process|hemopoiesis Amigo function|nucleic acid binding Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|zinc ion binding PubGene BCL11A Other databases Probes Probe Cancer Cytogenetics (Bari) Probe BCL11A Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in LocusLink Bibliography Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells. Saiki Y, Yamazaki Y, Yoshida M, Katoh O, Nakamura T. Genomics 2000; 70: 387-391.

The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Sattenwhite E, Sonoki T, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Orcier DG, Siebert R, Tucker PW, Dyer MJS. Blood 2001; 98: 3413-3420.

Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -446- Martin-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B, Grote W, Novo FJ, Calasanz MJ, Hansmann ML, Dyer MJS, Siebert R Blood 2002; 99: 1474-1477.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Jean-Loup Huret 2002 Citation This paper should be referenced as such : Huret JL . BCL11A (B-cell lymphoma/leukemia 11A). Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/BCL11AID391.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -447- Atlas of Genetics and Cytogenetics in Oncology and Haematology

RECQL5

Identity Hugo RECQL5 Location 17q25.2-25.3 DNA/RNA Transcription Three different transcripts : 3715 bases (RecQ5a), 3703 bases (RecQ5b), 1749 bases (RecQ5g). Protein

Description 410 amino acids (RecQ5a), 991 amino acids (RecQ5b), 435 amino acids (RecQ5g). The predicted protein structures of all three polypeptides share seven motifs conserved for DNA helicases. RecQ5b contains a large C-terminal region that includes a domain homologous to the non-helicase domain of the E. coli RecQ DNA helicase. Localisation RecQ5a and RecQ5g are localized in the cytoplasm, whereas RecQ5b is localized in the nucleus. Function Unknown Homology Homologous to RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. In particular, similarities with the four known human members in the RecQ subfamily, human RecQL, human RecQL4, human BLM, the product of the Bloom syndrome gene and human WRN, the product of the Werner syndrome gene. Mutations Note Not described yet, and correlation with genetic disorder, if any, is unknown. External links Nomenclature Hugo RECQL5 GDB RECQL5 Entrez_Gene RECQL5 9400 RecQ protein-like 5 Cards Atlas RECQL5ID286 GeneCards RECQL5 Ensembl RECQL5

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -448- Genatlas RECQL5 GeneLynx RECQL5 eGenome RECQL5 euGene 9400 Genomic and cartography RECQL5 - chr17:71156540-71174864 - 17q25.1 (hg17- GoldenPath May_2004) Ensembl RECQL5 - 17q25.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RECQL5 Gene and transcription

Genbank AF135183 [ SRS ] AF135183 [ ENTREZ ]

Genbank AB006533 [ SRS ] AB006533 [ ENTREZ ]

Genbank AB042823 [ SRS ] AB042823 [ ENTREZ ]

Genbank AB042824 [ SRS ] AB042824 [ ENTREZ ]

Genbank AB042825 [ SRS ] AB042825 [ ENTREZ ]

RefSeq NM_001003715 [ SRS ] NM_001003715 [ ENTREZ ]

RefSeq NM_001003716 [ SRS ] NM_001003716 [ ENTREZ ]

RefSeq NM_004259 [ SRS ] NM_004259 [ ENTREZ ]

RefSeq NT_086886 [ SRS ] NT_086886 [ ENTREZ ] AceView RECQL5 AceView - NCBI TRASER RECQL5 Traser - Stanford

Unigene Hs.514480 [ SRS ] Hs.514480 [ NCBI ] HS514480 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O94762 [ SRS] O94762 [ EXPASY ] O94762 [ INTERPRO ]

PS00690 DEAH_ATP_HELICASE [ SRS ] PS00690 Prosite DEAH_ATP_HELICASE [ Expasy ]

Interpro IPR001410 DEAD [ SRS ] IPR001410 DEAD [ EBI ]

Interpro IPR002464 DEAH_box [ SRS ] IPR002464 DEAH_box [ EBI ]

Interpro IPR001650 Helicase_C [ SRS ] IPR001650 Helicase_C [ EBI ]

Interpro IPR004589 RecQ [ SRS ] IPR004589 RecQ [ EBI ]

Interpro IPR010716 RecQ5 [ SRS ] IPR010716 RecQ5 [ EBI ] CluSTr O94762 Pfam PF00270 DEAD [ SRS ] PF00270 DEAD [ Sanger ] pfam00270 [ NCBI-CDD ]

PF00271 Helicase_C [ SRS ] PF00271 Helicase_C [ Sanger Pfam ] pfam00271 [ NCBI-CDD ] Pfam PF06959 RecQ5 [ SRS ] PF06959 RecQ5 [ Sanger ] pfam06959 [ NCBI- CDD ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -449- Smart SM00487 DEXDc [EMBL]

Smart SM00490 HELICc [EMBL] Blocks O94762 Polymorphism : SNP, mutations, diseases OMIM 603781 [ map ] GENECLINICS 603781

SNP RECQL5 [dbSNP-NCBI]

SNP NM_001003715 [SNP-NCI]

SNP NM_001003716 [SNP-NCI]

SNP NM_004259 [SNP-NCI]

SNP RECQL5 [GeneSNPs - Utah] RECQL5 [SNP - CSHL] RECQL5] [HGBASE - SRS] General knowledge Family RECQL5 [UCSC Family Browser] Browser SOURCE NM_001003715 SOURCE NM_001003716 SOURCE NM_004259 SMD Hs.514480 SAGE Hs.514480 Amigo function|ATP binding Amigo function|ATP-dependent helicase activity Amigo function|DNA helicase activity Amigo process|DNA repair Amigo function|hydrolase activity Amigo function|nucleic acid binding Amigo component|nucleus PubGene RECQL5 Other databases Probes Probe RECQL5 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -450- Bibliography Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Kitao, S.; Ohsugi, I.; Ichikawa, K.; Goto, M.; Furuichi, Y.; Shimamoto, A. Genomics. 1998, 54: 443-452. Medline 9878247

Differential regulation of human RecQ family helicases in cell transformation and cell cycle. Kawabe, T. ; Tsuyama, N. ; Kitao, S. ; Nishikawa, K. ; Shimamoto, A. ; Shiratori, M. ; Matsumoto, T. ; Anno, K. ; Sato, T. ; Mitsui, Y. ; Seki, M. ; Enomoto, T. ; Goto, M. ; Ellis, NA. ; Ide, T. ; Furuichi, Y. ; Sugimoto, M. Oncogene. 2000, 19: 4764-4772. Medline 11032027

Human RecQ5beta, a large isomer of RecQ5 DNA helicase, localizes in the nucleoplasm and interacts with topoisomerases 3alpha and 3beta. Shimamoto, A.; Nishikawa, K.; Kitao, S.; Furuichi, Y. Nucleic Acids Res. 2000, 28: 1647-1655. Medline 0710432

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Mounira Amor-Guéret 2002 Citation This paper should be referenced as such : Amor-Guéret M . RECQL5. Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/RECQL5ID286.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -451- Atlas of Genetics and Cytogenetics in Oncology and Haematology

SDHB (succinate dehydrogenase complex II, subunit B, iron-sulfur protein or IP)

Identity Other SDH1 (succinate dehydrogenase 1) names Hugo SDHB Location 1p36.1-p35 DNA/RNA Description 1123 bp, 8 exons Protein

Description 280 amino acids and 31 kDa Expression widely expressed Localisation mitochondrial inner membrane Function The complex II (succinate-ubiquinone oxidoreductase) is un key component of the mitochondrial respiratory chain and the tricarboxylic acid cycle. It is involved in the oxidation of succinate (succinate + ubiquinone = fumarate + ubiquinol) and carries electrons from FADH to CoQ. It is composed of four nuclear-encoded subunits. The subunit B protein or iron-sulfur protein, which binds three different iron-sulfur clusters, is directly involved in the catalytic activity of succinate dehydrogenase. Homology The complex II includes SDHD (cybS) and SDHC (cybL) which are also implicated in paragangliomas and pheochromocytomas.END_PROTEIN_DESCRIPTION Mutations Germinal Germline mutations cause hereditary paraganglioma, non-familial paraganglioma, familial and sporadic pheochromocytomas. Different germline mutations have been reported: i) a nonsense mutation (R90X) in a family with cervical paraganglioma and ectopic pheochromocytoma, ii) a missense mutation (P197R) in a family with extraadrenal pheochromocytoma and a 1bp deletion in a sporadic pheochromocytoma, iii) a missense (P131R) mutation and 1 bp insertion (M71fsX80) in familial paraganglioma and a nonsense mutation (Q59X) in sporadic paraganglioma. Somatic Loss of wild type allele in tumor DNA is usually observed.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -452- Implicated in Entity Hereditary paraganglioma type 4 Note Alias: Familial non chromaffin paragangliomas 4; Familial glomus tumor; Familial and sporadic pheochromocytoma Disease Hereditary paraganglioma type 4 (PGL4) is a rare autosomal dominant disorder non maternally imprinted. Paragangliomas are slow growing highly vascular tumor, usually benigns, derived from crest-neural cells. They are preferentially located in the neck (carotid body and glomus vagal) and head (glomus jugulare and tympanicum). They may be associated with adrenal or extraadrenal pheochromocytomas which produce catecholamines. Prognosis It depends on extent of the disease at the time of diagnosis.

External links Nomenclature Hugo SDHB GDB SDHB SDHB 6390 succinate dehydrogenase complex, subunit B, iron Entrez_Gene sulfur (Ip) Cards Atlas SDHBID388 GeneCards SDHB Ensembl SDHB CancerGene SDHB Genatlas SDHB GeneLynx SDHB eGenome SDHB euGene 6390 Genomic and cartography GoldenPath SDHB - chr1:17090559-17125952 - 1p36.13 (hg17-May_2004) Ensembl SDHB - 1p36.13 [CytoView]

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

Genbank AJ549502 [ SRS ] AJ549502 [ ENTREZ ]

Genbank U17886 [ SRS ] U17886 [ ENTREZ ]

Genbank BC007840 [ SRS ] BC007840 [ ENTREZ ]

Genbank D10245 [ SRS ] D10245 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -453- Genbank M32246 [ SRS ] M32246 [ ENTREZ ]

RefSeq NM_003000 [ SRS ] NM_003000 [ ENTREZ ]

RefSeq NT_086575 [ SRS ] NT_086575 [ ENTREZ ] AceView SDHB AceView - NCBI TRASER SDHB Traser - Stanford

Unigene Hs.465924 [ SRS ] Hs.465924 [ NCBI ] HS465924 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P21912 [ SRS] P21912 [ EXPASY ] P21912 [ INTERPRO ]

PS00197 2FE2S_FERREDOXIN [ SRS ] PS00197 Prosite 2FE2S_FERREDOXIN [ Expasy ]

PS00198 4FE4S_FERREDOXIN [ SRS ] PS00198 Prosite 4FE4S_FERREDOXIN [ Expasy ]

Interpro IPR006058 2Fe2S_fd_BS [ SRS ] IPR006058 2Fe2S_fd_BS [ EBI ] Interpro IPR001450 4Fe4S_ferredoxin [ SRS ] IPR001450 4Fe4S_ferredoxin [ EBI ]

Interpro IPR004489 DhsB [ SRS ] IPR004489 DhsB [ EBI ]

Interpro IPR001041 Ferredoxin [ SRS ] IPR001041 Ferredoxin [ EBI ]

Interpro IPR009051 Helical_ferredxn [ SRS ] IPR009051 Helical_ferredxn [ EBI ] CluSTr P21912

Pfam PF00111 Fer2 [ SRS ] PF00111 Fer2 [ Sanger ] pfam00111 [ NCBI-CDD ] Blocks P21912 Polymorphism : SNP, mutations, diseases OMIM 185470 [ map ] GENECLINICS 185470

SNP SDHB [dbSNP-NCBI]

SNP NM_003000 [SNP-NCI]

SNP SDHB [GeneSNPs - Utah] SDHB [SNP - CSHL] SDHB] [HGBASE - SRS] General knowledge Family SDHB [UCSC Family Browser] Browser SOURCE NM_003000 SMD Hs.465924 SAGE Hs.465924

Enzyme 1.3.5.1 [ Enzyme-SRS ] 1.3.5.1 [ Brenda-SRS ] 1.3.5.1 [ KEGG ] 1.3.5.1 [ WIT ] Amigo process|electron transport Amigo function|electron transporter activity Amigo function|iron ion binding Amigo component|mitochondrion Amigo function|oxidoreductase activity

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -454- Amigo function|succinate dehydrogenase (ubiquinone) activity Amigo process|tricarboxylic acid cycle KEGG Citrate Cycle (TCA Cycle) KEGG Oxidative Phosphorylation PubGene SDHB Other databases Probes Probe SDHB Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of iron sulphur (Ip) subunit of liver mitochondria. Kita K, Oya H, Gennis RB, Ackrell BAC, Kasahara M. Biochem. Biophys. Res. Commun. 1990; 166: 101-108. Medline 90147684

The gene for the iron sulfur protein of succinate dehydrogenase (SDH-IP) maps to human chromosome 1p35-36.1. Leckschat S, Ream-Robinson D, Scheffler IE. Somat. Cell Molec. Genet. 1993; 19: 505-511. Medline 94120484

Structural organization of the gene encoding the human iron-sulfur subunit of succinate dehydrogenase. Au HC, Ream-Robinson D, Bellew LA, Broomfield PLE, Saghbini M, Scheffler IE. Gene. 1995; 159: 249-253. Medline 95347607

Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Astuti D, Latif F, Dallol A, Dahia PLM, Douglas F, George E, Skšldberg F, Husebye ES, Eng C, Maher ER. Am J Hum Genet. 2001; 69: 49-54. Medline 21303033

Prevalence of SDHB, SDHC and SDHD germline mutations in clinic patients with head and neck paragangliomas. Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH, Myers EN, Ferrell RE, Rubinstein WS. J Med Genet. 2002; 39: 178-183 Medline 21895997

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -455- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Anne-Paule Gimenez-Roqueplo 2002 Citation This paper should be referenced as such : Gimenez-Roqueplo AP . SDHB (succinate dehydrogenase complex II, subunit B, iron-sulfur protein or IP). Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SDHBID388.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -456- Atlas of Genetics and Cytogenetics in Oncology and Haematology

SDHC (succinate dehydrogenase complex II, subunit C, integral membrane protein)

Identity Other SDH3 (succinate dehydrogenase 3) names Hugo SDHC Location 1q21 DNA/RNA Description 1180 bp, 6 exons Protein

Description 169 amino acids and 15.5 kDa Expression widely expressed Localisation mitochondrial inner membrane Function Complex II (succinate-ubiquinone oxidoreductase) of the respiratory chain is involved in the oxidation of succinate, carries electrons from FADH to CoQ. It is composed of four nuclear-encoded subunits. The subunit C protein or large subunit (cybL) is one of two integral membrane proteins anchoring the complex to membrane. Homology The complex II includes SDHD (cybS) and SDHB (iron-sulfur protein) which are also implicated in paragangliomas and pheochromocytomas. Mutations Germinal Germline mutations cause hereditary paraganglioma. At this time, an unique mutation which destroyed the initial site of traduction (ATG, start codon) of SDHC gene has been reported in a family with a hereditary paraganglioma. Somatic Loss of wild type allele in tumor DNA is usually observed. Implicated in Entity Hereditary paraganglioma type 3 Note Alias: Familial non chromaffin paragangliomas 3; Familial glomus tumor Disease Hereditary paraganglioma type 3 (PGL3) is a rare autosomal dominant disorder non maternally imprinted. Paragangliomas are slow growing highly vascular tumor, usually benign, derived from crest-neural cells. They are preferentially located in the neck (carotid body and glomus vagal) and head (glomus jugulare and tympanicum).

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -457- Prognosis It depends on extent of the disease at the time of diagnosis.

External links Nomenclature Hugo SDHC GDB SDHC SDHC 6391 succinate dehydrogenase complex, subunit C, integral Entrez_Gene membrane protein, 15kDa Cards Atlas SDHCID389 GeneCards SDHC Ensembl SDHC CancerGene SDHC Genatlas SDHC GeneLynx SDHC eGenome SDHC euGene 6391 Genomic and cartography SDHC - 1q21 chr1:158097243-158146049 + 1q23.3 (hg17- GoldenPath May_2004) Ensembl SDHC - 1q23.3 [CytoView]

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

Genbank AF039594 [ SRS ] AF039594 [ ENTREZ ]

Genbank AL592295 [ SRS ] AL592295 [ ENTREZ ]

Genbank AK131051 [ SRS ] AK131051 [ ENTREZ ]

Genbank BC012735 [ SRS ] BC012735 [ ENTREZ ]

Genbank BC020808 [ SRS ] BC020808 [ ENTREZ ]

RefSeq NM_003001 [ SRS ] NM_003001 [ ENTREZ ]

RefSeq NT_086596 [ SRS ] NT_086596 [ ENTREZ ] AceView SDHC AceView - NCBI TRASER SDHC Traser - Stanford

Unigene Hs.444472 [ SRS ] Hs.444472 [ NCBI ] HS444472 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q99643 [ SRS] Q99643 [ EXPASY ] Q99643 [ INTERPRO ]

Prosite PS01000 SDH_CYT_1 [ SRS ] PS01000 SDH_CYT_1 [ Expasy ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -458- Prosite PS01001 SDH_CYT_2 [ SRS ] PS01001 SDH_CYT_2 [ Expasy ]

Interpro IPR000701 Sdh_cyt [ SRS ] IPR000701 Sdh_cyt [ EBI ] CluSTr Q99643 Pfam PF01127 Sdh_cyt [ SRS ] PF01127 Sdh_cyt [ Sanger ] pfam01127 [ NCBI-CDD ] Blocks Q99643 Polymorphism : SNP, mutations, diseases OMIM 602413 [ map ] GENECLINICS 602413

SNP SDHC [dbSNP-NCBI]

SNP NM_003001 [SNP-NCI]

SNP SDHC [GeneSNPs - Utah] SDHC [SNP - CSHL] SDHC] [HGBASE - SRS] General knowledge Family SDHC [UCSC Family Browser] Browser SOURCE NM_003001 SMD Hs.444472 SAGE Hs.444472 Amigo process|electron transport Amigo function|electron transporter activity Amigo component|integral to membrane Amigo component|mitochondrial membrane Amigo function|succinate dehydrogenase activity Amigo process|tricarboxylic acid cycle KEGG Citrate Cycle (TCA Cycle) KEGG Oxidative Phosphorylation PubGene SDHC Other databases Probes Probe SDHC Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in LocusLink Bibliography Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignement of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23 Hirawake H, Taniwaki M, Tamura A, Kojima S, Kita K. Cytogenet Cell Genet. 1997; 79: 132-138. Medline 98194224

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -459- Characterization of the human SDHC gene encoding one of the integral membrane proteins of succinate-quinone oxidoreductase in mitochondria. Elbehti-Green A, Au HC, Mascarello JT, Ream-Robinson D, Scheffler IE. Gene. 1998; 213: 133-140. Medline 98372071

Mutations in SDHC cause autosomal dominant paraganglioma, type 3 Niemann S, MŸller U. Nature Genet 2000; 26: 268-270. Medline 20517329

Assignement of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma. Niemann S, Becker-Follmann J, NŸnberg G, RŸschendord F, Sieweke N, HŸgens- Penzel M, Traupe H, Wienker TF, Reis A, MŸller U. Am J Med Genet. 2001; 98: 32-36. Medline 21319742

Prevalence of SDHB, SDHC and SDHD germline mutations in clinic patients with head and neck paragangliomas. Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH, Myers EN, Ferrell RE, Rubinstein WS. J Med Genet. 2002; 39: 178-183. Medline 21895997

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Anne-Paule Gimenez-Roqueplo 2002 Citation This paper should be referenced as such : Gimenez-Roqueplo AP . SDHC (succinate dehydrogenase complex II, subunit C, integral membrane protein). Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SDHCID389.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -460- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Glypican-3 (GPC3)

Identity Other names MXR7 OCI-5

GTR2-2 Hugo GPC3 Location Xq26.1 DNA/RNA Description The gene spans more than 500 kb of DNA consisting of 8 exons. Transcription 2.2kb mRNA; 1740 bp open reading frame. Protein

Description 580 amino acids; 65 kDa protein. GPC3 is a heparan sulfate proteoglycan (HSPG) that is attached to the cell surface via a glycosyl-phosphatidylinositol (GPI) anchor. Expression GPC3 is highly expressed in embryonal tissues such as the developing intestine and the mesoderm-derived tissues, and its expression is downregulated in most adult tissue. Localisation Attached to the membrane by a GPI anchor. Function The biochemical function of GPC3 has yet to be established. HSPG may be involved in the suppression/modulation of growth in the predominantly mesodermal tissues and organs; may play a role in the modulation of IGF-II interactions with its receptor and thereby modulate its function; can have a potential role as a regulator of growth and tumor predisposition. Therefore it is likely that GPC3 is able not only to bind more than one growth factor, but also to functionally affect the signalling of different growth factors. A role for GPC3 in the regulation of insulin-like growth (IGF) factors has been proposed. IGF-II is a growth factor that can act as a survival factor in the early stages of tumourigenesis. The co-expression of GPC3 and IGF-II has been observed in embryonal tumors as well as in mouse foetal tissues; GPC3 expression is able to induce apoptosis in a cell-specific manner, but this effect could be reversed by the addition of IGF peptides; IGFs could be needed to prevent GPC3- induced apoptosis in any cell, allowing cellular responses to other factors to take place and be mediated, enhanced or inhibited by GPC3; GPC3 mutations lead to SGBS (see below), a syndrome that shares significant similarities with

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -461- the Beckwith-Wiedemann syndrome that is an overgrowth syndrome that is thought to be associated with increased expression of IGF2. Homology Belongs to the glypican family; six members, glypican-1 to 6, have been identified in mammalians; the protein core of are 20-50% identical; The glypican family is represented by at least two known members in Drosophila, dally and dally-like. Mutations Germinal Most known mutations are deletions involving different exons of GPC3; missense, nonsense as well as splicing site mutations. Somatic The expression of GPC3 is altered in cancer cells. GPC3 is upregulated in hepatocellular carcinoma, in WilmÕs tumor and in metastatics colorectal malignancie. With regard to tumours with neuronal phenotype, GPC3 was detected at variable levels in a neurofibrosarcoma and in most neuroblastomas, but was absent from medulloblastomas. These findings suggest that GPC3 expression is differentially regulated in the various cell lineages giving rise to pediatric tumours of the peripheral and central nervous systems. On the other hand, GPC3 is frequently silenced in mesotheliomas, in ovarian cancer cell lines and in breast cancer, often due to hypermethylation of the GPC3 promoter. Implicated in Entity Simpson-Golabi-Behmel Syndrome (SGBS) Disease X-linked disease characterized by a wide variety of clinical manifestations, including pre- and post-natal overgrowth, tissue dysplasia, in particular of the kidneys, and cardiac anomalies; associated with a greater risk of developing embryonal cancers; caused by loss-of-function mutation in the GPC3 gene ; the abnormalities found in SGBS patients suggest that GPC3 might be involved in the regulation of growth and/or apoptosis during development.

To be noted

The ability of GPC3 to bind various growth factors or morphogens, including IGF-II, Fibroblast Growth Factor 2 as well as the tissue factor pathway inhibitor, is supported by evidence from other members of the glypican family and HSPGs in general. HSPGs of the cell surface are highly interactive macromolecules playing various roles in cell migration, proliferation, differentiation and adhesion, and participating in many developmental and pathological processes. HSPGs consist of two major families: syndecans and glypicans. Syndecans are attached to the cell membrane by a transmembrane domain while glypicans are attached through a GPI anchor. To date six members of the glypican family, glypican-1 to 6, have been identified in mammalians ; the glypican family is represented by at least two known members in Drosophila, dally and dally-like. Dally is now known to act as a co-receptor that controls signalling by morphogens and growth factors such as decapentaplegic (dpp) and wingless. Although GPC3 cannot as yet be thought of as the strict orthologue of dally, this information strengthens the notion that it may have growth factor binding and regulatory properties.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -462- External links

Nomenclature Hugo GPC3 GDB GPC3 Entrez_Gene GPC3 2719 glypican 3 Cards Atlas GPC3ID156 GeneCards GPC3 Ensembl GPC3 CancerGene GPC3 Genatlas GPC3 GeneLynx GPC3 eGenome GPC3 euGene 2719 Genomic and cartography GPC3 - Xq26.1 chrX:132395298-132845186 - Xq26.2 (hg17- GoldenPath May_2004) Ensembl GPC3 - Xq26.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene GPC3 Gene and transcription

Genbank AF003529 [ SRS ] AF003529 [ ENTREZ ]

Genbank L47124 [ SRS ] L47124 [ ENTREZ ]

Genbank BC035972 [ SRS ] BC035972 [ ENTREZ ]

Genbank L47125 [ SRS ] L47125 [ ENTREZ ]

Genbank L47176 [ SRS ] L47176 [ ENTREZ ]

RefSeq NM_004484 [ SRS ] NM_004484 [ ENTREZ ]

RefSeq NT_086975 [ SRS ] NT_086975 [ ENTREZ ] AceView GPC3 AceView - NCBI TRASER GPC3 Traser - Stanford

Unigene Hs.435036 [ SRS ] Hs.435036 [ NCBI ] HS435036 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P51654 [ SRS] P51654 [ EXPASY ] P51654 [ INTERPRO ]

Prosite PS01207 GLYPICAN [ SRS ] PS01207 GLYPICAN [ Expasy ]

Interpro IPR001863 Glypican [ SRS ] IPR001863 Glypican [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -463- CluSTr P51654

Pfam PF01153 Glypican [ SRS ] PF01153 Glypican [ Sanger ] pfam01153 [ NCBI-CDD ] Blocks P51654 Polymorphism : SNP, mutations, diseases OMIM 300037 [ map ] GENECLINICS 300037

SNP GPC3 [dbSNP-NCBI]

SNP NM_004484 [SNP-NCI]

SNP GPC3 [GeneSNPs - Utah] GPC3 [SNP - CSHL] GPC3] [HGBASE - SRS] General knowledge

Family Browser GPC3 [UCSC Family Browser] SOURCE NM_004484 SMD Hs.435036 SAGE Hs.435036 Amigo component|extracellular matrix (sensu Metazoa) Amigo component|integral to plasma membrane Amigo process|morphogenesis PubGene GPC3 Other databases

Probes Probe GPC3 Related clones (RZPD - Berlin) PubMed PubMed 15 Pubmed reference(s) in LocusLink Bibliography Isolation of a cDNA corresponding to a developmentally regulated transcript in rat intestine. Filmus J, Church JG, Buick RN. Mol Cell Biol. 1988; 8: 4243-4149. Medline 3185547

Simpson-Golabi-Behmel Syndrome associated with renal dysplasia and embryonal tumor: Localization of the gene to Xqcen-q21. Hughes-Benzie RM, Hunter AGW, Allanson JE, Mackenzie AE. Am. J. Med. Genet 1992; 43: 428-435 Medline 1605222

The division abnormally delayed (dally) gene : a putative integral membrane proteoglycan required for patterning during postembryonic development of

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -464- the nervous system in Drosophila. Nakato H, Futch TA, Selleck SB. Development 1995; 121: 3687-3702. Medline 8582281

Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan P, Chen EY, Huber R, Neri G, Cao A, Forabosco A, Schlessinger D. Nat Genet. 1996; 12: 241-247. Medline 8589713

Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution Hsu HC, Cheng W, Lai PL. Cancer Res. 1997; 57: 5179-5184. Medline 9371521

Dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp Jackson SM, Nakato H, Sugiura M, Jannuzi A, Oakes R, Kaluza V, Golden C, Selleck SB. Development 1997; 124: 4113-4120. Medline 9374407

Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor. Mast AE, Higuchi DA, Huang ZF, Warshawsky I, Schwartz AL, Broze GJ Jr. Biochem J. 1997; 327: 577-583. Medline 9359432

OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2. Song HH, Shi W, Filmus J. J Biol Chem. 1997; 272: 7574-7577. Medline 9065409

Expression of the novel mitoxantrone resistance associated gene MXR7 in colorectal malignancies. Lage H, Dietel M, Froschle G, Reymann A. Int J Clin Pharmacol Ther 1998; 36: 58-60. Medline 9476151

Overgrowth syndromes and genomic imprinting: from mouse to man. Li M, Squire JA, Weksberg R. Clin Genet. 1998; 53: 165-170. Medline 9630066

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -465- Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome. Neri G, Gurrieri F, Zanni G, Lin A. Am J Med Genet. 1998; 79: 279-283. Medline 9781908

Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome Pellegrini M, Pilia G, Pantano S, Lucchini F, Uda M, Fumi M, Cao A, Schlessinger D, Forabosco A. Dev Dyn. 1998; 213: 431-439. Medline 9853964

Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling Lin X, Perrimon N. Nature 1999; 400: 281-284. Medline 1042137

Frequent silencing of the GPC3 gene in ovarian cancer cell lines. Lin H, Huber R, Schlessinger D, Morin PJ. Cancer Res. 1999; 59: 807-810. Medline 10029067

The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila. Tsuda M, Kamimura K, Nakato H, Archer M, Staatz W, Fox B, Humphrey M, Olson S, Futch T, Kaluza V, Siegfried E, Stam L, Selleck SB. Nature. 1999; 400: 276-280. Medline 10421371

Dally-like protein, a new Drosophila glypican with expression overlapping with wingless. Khare N, Baumgartner S. Mech Dev. 2000; 99: 199-202. Medline 11091094

Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma. Murthy SS, Shen T, De Rienzo A, Lee WC, Ferriola PC, Jhanwar SC, Mossman BT, Filmus J, Testa JR. Oncogene 2000; 19: 410-416. Medline 10656689

Expression of glypican 3 (GPC3) in embryonal tumors Saikali Z, Sinnett D. Int J Cancer. 2000; 89: 418-422. Medline 11008203 Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions. Tumova S, Woods A, Couchman JR.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -466- Int J Biochem Cell Biol. 2000; 32: 269-288. Medline 10716625

Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene. Veugelers M, Cat BD, Muydermans SY, Reekmans G, Delande N, Frints S, Legius E, Fryns JP, Schrander-Stumpel C, Weidle B, Magdalena N, David G. Hum Mol Genet. 2000; 9: 1321-1328. Medline 10814714

Glypicans in growth control and cancer. Filmus J. Glycobiology 2001; 11: 19R-23R Medline 11320054

Glypican-3 expression is silenced in human breast cancer. Xiang YY, Ladeda V, Filmus J. Oncogene 2001; 20: 7408-7412 Medline 11704870

Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition. DeBaun MR, Ess J, Saunders S. Mol Genet. Metab 2001; 72: 279-286 Medline 11286501

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05-2002 Daniel Sinnett Citation This paper should be referenced as such : Sinnett D . Glypican-3 (GPC3). Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/GPC3ID156.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -467- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(5;11)(q35;p15.5)

Clinics and Pathology Disease de novo acute non lymphocytic leukemia (ANLL) Phenotype / No specific subtype. Only 5 cases reported to date (1 ANLL-M1, 2 cell stem ANLL-M2, 2 ANLL-M4) origin Epidemiology all 5 reported cases were children or young adults (age range 3-18 years). Male: female ratio 1.5:1 Cytogenetics Cytogenetics The t(5;11)(q35;p15.5) is not detectable by G-banding. Three cases Morphological were reported as cryptic t(5;11) associated with del(5q); a further two cases were identified in apparently normal karyotypes. Cytogenetics In one FISH study using whole chromosome paints, three out of four Molecular cases of childhood ANLL with del(5q) as the sole cytogenetic abnormality were found to have a cryptic t(5;11). In a second study using chromosome-specific subtelomeric probes, two out of 31 children and young adults (19 years) with a normal G-banded karyotype were found to have a cryptic t(5;11). Note: While the der(11) is detectable by single colour painting using whole chromosome paint (WCP), the der(5) is not detectable using chromosome 11 WCP. Neither M-FISH or SKY can reliably detect the t(5;11).

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -468- Fig 1. Identification of a cryptic t(5;11) using the M-TEL assay. Bone marrow metaphase from a normal karyotype ANLL child hybridized with the M-TEL1 probe set. Chromosomes 1, 3, 7, 9, 13, 15, 17, 19, 21 and X and Y probes were all correctly hybridized. However, one homologue of chromosome 5 has chromosome 11 material on the q arm (yellow), and the corresponding chromosome 11 homologue has chromosome 5 material on the p arm (green). This corresponds to a balanced translocation, t(5q;11p). The der(5) and der(11) are indicated by arrows.

Probes Subtelomeric probes: PAC GS-240-G13 (5q), PAC GS-908-H22 (11p), both from Incyte Genomics NSD1 BAC: CTC HSP 2301A4 (available from Incyte Genomics); NUP98: PAC1173 K1, p9R1 (exons 10-12 of NUP98 gene), p6G2 (exons 13-14 of NUP98 gene) Genes involved and Proteins Gene NUP98 Name Location 11p15.5 Note at least 8 different fusion partners for NUP98 in leukaemia Two major transcripts: 4.0 and 7.0 kb. The 4.0 kb transcript consists of Dna / Rna 20 exons. Protein 98 kD protein. Component of the nuclear pore complex, which regulates nucleocytoplasmic transport of protein and RNA. Contains multiple phenylalanine-glycine (FG) repeats which act as Œdocking' sites for transport receptors. Gene NSD1 (nuclear receptor-binding, SET domain-containing protein 1) Name Location 5q35 Dna / Rna at least 21 exons, cDNA is 8552 bp, open reading frame of 8088 bp Protein predicted protein of 2696 amino acids. Contains at least 6 functional domains: su(var)3-9, enhancer-of-zeste, trithorax (SET), proline- tryptophan-tryptophan-proline (PWWP-I, PWWP-II), plant homeodomain proteinfinger domains (PHD-I, PHD-II, PHD-III) and ten putative nuclear localization signals. Result of the chromosomal anomaly Hybrid reciprocal NSD1-NUP98 fusion also present in all cases tested gene Note Description The NUP98 and NSD1 mRNA are fused in-frame joining nucleotides 1552 of NUP98 to nucleotide 3506 of NSD1. The reciprocal transcript fuses NSD1 and NUP98 mRNA in-frame joining nucleotide 3505 of NSD1 to nucleotide 1553 of NUP98. Detection RT-PCR with sense NUP98-5 (5'-TCTTGGTACAGGAGCCTTTG-3', and antisense NSD1-1 (5'TCCAAAAGCCACTTGCTTGGC-3') primers

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -469-

Fusion Protein

Fig 2. Schematic representation of the NUP98-NSD1 fusion protein. The wild type NUP98 and NSD1 proteins are also shown. The putative NUP98-NSD1 fusion protein would retain the NH2 terminal region of NUP98 containing the phenylalanine-glycine (FG) repeat domains and the COOH terminal region of NSD1 containing the SET, SET domain associated cysteine-rich (SAC) and PHD finger domains.

External links Other t(5;11)(q35;p15.5) Mitelman database (CGAP - NCBI) database Other t(5;11)(q35;p15.5) 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 Two distinct nuclear receptor interaction domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivators. Huang N, vom Baur E, Garnier JM, Lerouge T, Vonesch JL, Lutz Y, Chambon P, Losson R. EMBO J 1998; 17(12): 3398-3412. Medline 9628876

An optimized set of human telomere clones for studying telomere integrity and architecture. Knight SJ, Lese CM, Precht KS, Kuc J, Ning Y, Lucas S, Regan R, Brenan M, Nicod A, Lawrie NM, Cardy DL, Nguyen, H, Hudson TJ, Riethman HC, Ledbetter DH, Flint

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -470- J. Am J Hum Genet 2000; 67(2): 320-332.

A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. Jaju RJ, Haas OA, Neat M, Harbott J, Saha V, Boultwood J, Brown JM, Pirc- Danoewinata H, Krings BW, Muller U, Morris, SW, Wainscoat JS, Kearney L. Blood 1999; 94(2): 773-780. Medline 10397745

Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Ahuja HG, Felix CA, Aplan PD. Genes Chromosomes Cancer 2000; 29(2): 96-105. Medline 10959088

A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Jaju RJ, Fidler C, Haas OA, Strickson AJ, Watkins F, Clark K, Cross NC, Cheng JF, Aplan PD, Kearney L, Boultwood J, Wainscoat JS. Blood 2001; 98(4): 1264-1247. Medline 11493482

Subtelomeric chromosome rearrangements are detected using an innovative 12-color FISH assay (M-TEL). Brown J, Saracoglu K, Uhrig S, Speicher MR, Eils R, Kearney L. Nat Med 2001; 7(4): 497-501. Medline 11283680

Molecular characterization of NSD1, a human homologue of the mouse Nsd1 gene. Kurotaki N, Harada N, Yoshiura K, Sugano S, Niikawa N, Matsumoto N. Gene 2001; 279(2): 197-204. Medline 11733144

NUP98 gene fusions in hematologic malignancies. Lam DH, Aplan PD. Leukemia 2001; 15(11): 1689-1695 (REVIEW) Medline 11681408

A cryptic t(5;11)(q35;p15.5) in two AML children with apparently normal karyotypes, identified by a multiplex FISH telomere assay. Brown M, Jawad M, Eils R, Twigg SFR, Saracoglu K, Sauerbrey A, Thomas AE, Harbott J, Kearney L. Blood 2002 (in press)

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Contributor(s) Written 03- Lyndal Kearney 2002

Citation This paper should be referenced as such : Kearney L . t(5;11)(q35;p15.5). Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0511q35p15ID1209.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -472- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(1;19)(p13;p13.1)

Clinics and Pathology Disease myeloid malignancies Epidemiology only 2 cases to date Clinics a 1 yr old infant with M5a acute non lymphocytic leukemia (ANLL), and a 21 yr old female patient with refractory anemia with ringed sideroblasts (RARS) and a suspicion of Fanconi anemia11 yrs before diagnosis of RARS Prognosis death occurred 8 mths after diagnosis in the case with ANLL Cytogenetics Cytogenetics the translocation presents as + der(1) t(1;19)(p13;p13) in both known Morphological cases Additional sole anomaly in one of the two cases anomalies Genes involved and Proteins Note genes involved are unknown

External links Other t(1;19)(p13;p13.1) Mitelman database (CGAP - NCBI) database Other t(1;19)(p13;p13.1) 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 Novel der(1)t(1;19) in two patients with myeloid neoplasias. Tchinda J, Volpert S, Neumann T, Kennerknecht I, Ritter J, Buchner T, Berdel WE, Horst J. Cancer Genet Cytogenet 2002; 133: 61-65.

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Contributor(s) Written 04- Jean-Loup Huret 2002 Citation This paper should be referenced as such : Huret JL . t(1;19)(p13;p13.1). Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0119p13p13ID1230.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -474- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(11;14)(q23;q24)

Identity

t(11;14)(q23;q24), G-banding

Clinics and Pathology Disease ANLL and therapy related AL Phenotype / cell stem monoblastic, unclassified origin Epidemiology Rare. Three cases reported so far. Prognosis Very poor. Less than 2 months survival in two cases. Cytogenetics Additional Not found in mainline in reported cases. anomalies Genes involved and Proteins Gene MLL Name Location 11q23 Dna / Rna 36 exons, spans over 100kb, ORF 12kb. Protein 3969 amino acids; 431 kDa; contains two DNA binding motifs (a AT hook and a DNA methyltransferase homology motif), trithorax homology domains, zinc finger domains with features of PHD fingers and the C- terminal SET domain. Gene Gephyrin (GPHN) Name

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -475- Location 14q24 Dna / Rna 29 exons, spans approximately 800kb, ORF 2.3kb Protein 736 to 770 amino acids; 93-105 kDa; submembraneous scaffold protein that anchors glycine receptor to postsynaptic cytoskeletal elements through a putative microtubule binding motif. GPHN is also involved in molybdenum cofactor biosynthesis (MoaB, MogA and MoeA homology domain), and interacts with RAFT-1. Result of the chromosomal anomaly Hybrid gene 5' MLL-3' GPHN on der (11) Description Transcript no GPHN-MLL reciprocal transcript

Fusion MLL-GPHN protein Protein

Description C-terminal half of GPHN, including the suspected putative microtubule binding motif and MoeA homology domain, is fused to the N-terminal portion of MLL.

External links Other t(11;14)(q23;q24) Mitelman database (CGAP - NCBI) database Other t(11;14)(q23;q24) 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 Leukemic evolution in three patients with myelodysplastic syndrome and unusual chromosome changes. Palka G, Calabrese G, Stuppia L, Guanciali Franchi P, Antonucci A, Spadano A, Di Lorenzo R, Torlontano G. Cancer Genet Cytogenet 1992; 61: 162-164. Medline 92346545

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Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein. Prior P, Schmitt B, Grenningloh G, Pribilla I, Multhaup G, Beyreuther K, Maulet Y, Werner P, Langosch D, Kirsch J, et al. Neuron 1992; 8:1161-1170 Medline 92304583

Receptors, gephyrin and gephyrin-associated proteins: novel insights into the assembly of inhibitory postsynaptic membrane specializations. Kneussel M, Betz H. J Physiol 2000; 525: 1-9. Medline 20272043

Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Ayton PM, Cleary ML. Oncogene 2001; 20: 5695-5707. Medline 21519130

The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells. David-Watine B. Gene 2001; 271: 239-245. Medline 21311639

GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24). Eguchi M, Eguchi-Ishimae M, Seto M, Morishita K, Suzuki K, Ueda R, Ueda K, Kamada N, Greaves M. Genes Chromosomes Cancer 2001; 32: 212-221. Medline 11579461 t(11;14)(q23;q24) Generates an MLL-Human Gephyrin Fusion Gene along with a de facto Truncated MLL in Acute Monoblastic Leukemia. Kuwada N, Kimura F, Matsumura T, Yamashita T, Nakamura Y, Wakimoto N, Ikeda T, Sato K, Motoyoshi K. Cancer Res 2001; 61: 2665-2669. Medline 11289145

Contributor(s) Written 04- Mariko Eguchi 2002

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -477- Citation This paper should be referenced as such : Eguchi M . t(11;14)(q23;q24). Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1114q23q24ID1198.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Classification of acute myeloid leukemias

Identity Note Basis of classification in conformity with WHO recommandations.

The classification of acute myeloid leukemia (AML) and myelodysplasic syndromes (MDS) includes clinical data (previous history, age) and biologic characteristics (morphology, cytochemistry, immunophenotype, cytogenetic and molecular biology). The separation of homogeneous classes allows us to distinguish pronostic parameters and to identify groups of patients sensitive to drugs or to specific treatment. Recurrent cytogenetic abnormalities are strong prognostic indicators in AML and MDS. Molecular studies of structural chromosomal changes have enabled the cloning of genes located at chromosomal breakpoints and have helped to characterize the proteins involved in leukemogenesis. Morphologic studies remain important because of a strong correlation with cytogenetic and molecular abnormalities.

The clinico-biological classification of acute myeloid leukemia (AML) should include morphological, cytochemical, immunophenotypic, cytogenetic and molecular characterization of the leukemia blasts. The identification of homogeneous categories would allow the development and refinement of treatment strategies. - Recurrent cytogenetic abnormalities are important as prognostic indicators in AML. The identification of specific abnormalities is used increasingly to decide treatment. Cytogenetic findings have contributed to the understanding of morphological and clinical heterogeneity of AML. Molecular genetic analysis of recurrent translocations and inversions has led to clone genes adjacent to chromosome breakpoint and to characterize their protein products involved in the leukemogenesis process. - Over the years, leukemia classifications have been mainly descriptive, which was open to regular criticism, revision and reassessment. During the last 20 years, classification according to morphological features of leukemia has been proposed (F.A.B. defined classification). This classification is based on cell morphology on May-Grunwald-Giemsa (MGG) staining of peripheral blood and bone marrow smears with the addition of simple cytochemical techniques

Rationale for a new classification approach - The age-incidence of AML is subtly bimodal. Between early childhood and age 45, the annual incidence of acute myeloid leukemia (AML) remains constant at 0.8 cases/105population. The incidence rises

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -479- exponentially after the age of 45, exceeding 15 cases/105 population by age 75. AML has been extensively characterized using cytogenetic since the mid-1970s. - Available data have suggested an alternative classification in four main groups; a first one for patients identified with specific balanced translocations, the second group for patients with "multilineage" deregulation, a third one for "secondary" AML (after exposure to mutagenic agent or chemo/radiotherapy). Although this is a more rational model of AML classification, some patients cannot be classified into the three first groups and defined a fourth group. At least for the moment, the diagnosis of this last group of patients must rely on the classical cytologic approach (FAB) defining "morphological"-based category.

The first group is characterized by recurring chromosomal abnormalities, mainly balanced reciprocal translocations and affects children and young adults. In this group, it is assumed that there is involvement of committed precursor. This may explain the cellular involvement of a specific subset of myeloid cells for example pure granulocytic cells in t(15;17) AML, granulocytic and eosinophilic cells in t(8;21) AML, and monocytes and eosinophils in inv(16). These patients often have a high rate of complete remission with cytotoxic chemotherapy.

The second group has similar abnormalities to those which are associated with myelodysplastic syndromes, occur mainly in the elderly population and are rare in childhood. They are characterized by multilineage involvement of bone marrow cells suggesting an early commitment precursor (stem cell). Cytogenetic studies usually show complex chromosome aberrations, mainly loss of genetic material. These diseases are associated with a poor prognosis and a lesser incidence of complete remission after chemotherapy.

The third group concerns "secondary" AML (mainly after treatment for malignant diseases) usually morphologically and cytogenetically related with the second group, or more rarely with the first one, depending of the type of triggering drug used. Clinics and Pathology Disease First group WHO: AML with "recurrent cytogenetic translocations" Note Although the term "de novo" is not fully appropriate (see below "secondary AML"), this category of patients is usually referred as such in the literature since MDS or chemo/radiotherapy does not usually precede them either. The most commonly identified abnormalities are reciprocal translocations: t(8;21), inv(16) or t(16;16), t(15;17), t(11;17), t(9;11), t(6;9), t(1;22) and t(8;16). Molecular studies have shown that these structural chromosome rearrangements create a fusion gene encoding a chimeric protein. Most can be detected by RT-PCR

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -480- including complex and cryptic cytogenetic variants. The altered expression and/or structure of cellular gene products leads to functional activation that may contribute to the initiation or progression of leukemogenesis. The most frequent anomalies are : t(8;21)(q22;q22) - inv/del16( p13q22)/del(16)(q22)/t(16;16)(p13q22) - t(15;17)(q22;q21) - t(11;17)(q23;q21) - 11q23 Cytogenetics t(8;21)(q22;q22)

DEFINITION: The translocation t(8;21)(q22;q22) is one of the most common structural aberration in acute myeloid leukemia and is found in 5-12% of AML and in one-third of karyotypically abnormal M2 cases according to the French-American-British (FAB) classification. MORPHOLOGY AND CYTOCHEMISTRY: Among the non-random chromosomal aberrations observed in AML, t(8;21)(q22;q22) is one of the best known and usually correlates with AML M2, with well defined and specific morphological features. AML M2 FAB is the morphological type predominating in correlation with t(8;21), but some AML M1 or AML M4 cases have been also reported. Rare cases with a low bone marrow blast cell count (<20%) may be distinguished to RAEB and should be include in the AML group with low blast cell count category (see below). AML M2 with t(8;21) are more common in children than adults. IMMUNOLOGICAL MARKERS: M2 AML with t(8;21) show frequent co- expression of the B lymphoid marker CD19 with CD33 and CD34 and less often CD56. CLINICAL FEATURES: t(8;21) is usually associated with a good response to chemotherapy and a high remission rate with long-term disease-free survival. A large number of patients demonstrate additional chromosome abnormalities: loss of sex chromosome and del(9)(q22); no adverse outcome have been noted for either additional abnormality.Tumoral manifestation such as bony chloromas, may be seen at presentation; in such cases the initial bone marrow aspiration may show a limited and misleadingly low number of blast cells. These should not be confused with MDS. In these particular cases, AML M2 can still be diagnosed even if the morphological features described above are present, although the blasts are below 20% (see below). MOLECULAR ANALYSIS: Both heterodimeric components of the core binding factor complex (CBF), CBFalpha (also known as AML1) and CBFbeta are known to be involved in translocations associated with leukemia. The translocation t(8;21)(q22;q22) involves the AML1 (21q22) and ETO (8q22) genes. The AML/ETO - fusion transcript is consistently detected in patients with t(8;21) AML. Disruption of the AML1 gene is clustered within a single intron. AML1 has similarities to the drosophilia segmentation gene RUNT. Some AML M2 patients with the cytological profile described above, demonstrate rearrangement of AML1 and ETO despite being cytogenetically negative for the 8;21 translocation.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -481- inv/del(16)(p13q22)/del(16)(q22)/t(16;16)(p13;q22)

DEFINITION: Patients with inv(16)(p13q22) usually correspond to the subclass of AML M4, with a specific abnormal eosinophil component and is considered as a distinct entity in correlation with these specific chromosomal abnormalities. These cases of AML M4 are referred as AML M4EO. MORPHOLOGY AND CYTOCHEMISTRY: In addition to the morphological features of AML M4, the bone marrow shows a variable number of eosinophils at all stages of maturation without significant maturation arrest. The most strinking abnormalities involve the immature eosinophilic granules. Whilst the majority of inv(16)(p13q22) have been identified as AML M4EO, this abnormality may occasionally been seen in other myeloid malignancies, including AML M2, M4 without eosinophilia, M5 and MDS. IMMUNOPHENOTYPE: Although no specific markers for the monocytic cell line have been identified, some positive markers such as CD14, CD15, CD4, CD11b and CD11c in addition to CD13 and CD33 may be a good indication for monocytic differentiation. In M4 AML with inv(16), co-expression of CD2 with myeloid markers have been demonstrated. CLINICAL FEATURES: Convergent studies has revealed that patients with M4 AML with inv(16) and t(16;16) achieved higher complete remission (CR) rates. Conversely del(16q) is different and do not have a better outcome than other M4 AML or MDS. It remains to be defined whether CBFbeta is involved in these deletions. MOLECULAR ANALYSIS: Inv(16) and t(16;16) both result in the fusion of the CBFbeta gene at 18q22 to the smooth muscle myosin heavy chain ( MYH11) at 16p13. CBFbeta codes for Core Binding Factor (CBFbeta) sub-unit, a heterodimeric transcription factor known to bind the enhancers of various murine leukemia viruses and similar motifs in the regulatory regions of T cell (TCR), myeloperoxidase, neutrophil elastase and several growth factor receptor gene. The CBFbeta sub- unit is identical to AML1, one of the gene involved in the t(8;21) translocation usually associated with AML M2. Occasionally cytological features of AML M4EO may be present without karyotypic evidence of abnormality of chromosome 16. The CBFbeta/MYH11 is usually demonstrated by molecular studies. Thus, at diagnosis, the use of FISH and RT-PCR methods are important when evaluating inv(16).

t(15;17)(q22;q21)

DEFINITION: t(15;17)(q22;q21) is associated consistently with M3 AML. This chromosomal abnormality first appeared to be confined to the characteristic or morphologically typical M3 AML or "hypergranular promyelocytic leukemia", defined by bone marrow replacement with highly granulated blast cells, with occasional pseudo Pelger-Huet cells MORPHOLOGY AND CYTOCHEMISTRY. The nuclear size and shape is irregular and highly variable; they are often kidney-shaped or bilobed.The cytoplasm is completely occupied by densely packed or even coalescent granules, staining bright pink, red or purple by MGG.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -482- In some cells the cytoplasm is filled with fine dust-like granules. Characteristic cells contain bundle of Auer rods ("faggot cells"). In M3 AML, MPO is always strongly positive in all blast cells. Cases with a similar t(15;17) but with different morphological features, have been subsequently reported and have been called alternatively "M3-variant" AML, or "microgranular" variant. Distinct morphological features such as paucity or absence of granules, and a prominently bilobed nuclear shape characterize them. IMMUNOLOGICAL MARKERS: M3 AML with t(15;17) is usually characterized by the association of the lymphoid marker, CD2 and CD19, with myeloid markers and the negativity of HLA-DR and CD34. CLINICAL FEATURES: M3/M3-variant AML is frequently associated with disseminated intra-vascular coagulation (DIC). A particular sensitivity to treatment with all-trans retinoic acid (ATRA) has been demonstrated. ATRA act as a differentiation therapy for acute promyelocytic leukemia. The prognostic value of M3 AML/t(15;17) is inferior to t(8;21) and inv(16) and superior to the poor prognostic group (AML with abnormalities of the chromosomes 5 and 7). AML M3 patients are however increasingly treated in independent protocols, rendering such comparison difficult. MOLECULAR ANALYSIS: The sensitivity of M3 cells to all-trans retinoic acid led to the discovery that the retinoic acid receptor alpha ( RARalpha) gene on 17q21 fuses with a zinc finger binding transcription factor on 15q22 (promyelocytic leukemia or PML) gene, thus giving rise to a PML-RARalpha fusion gene product. Chromosomal variant of t(15;17). Rare cases lacking the classical t(15;17) have been described either having complex variant translocations involving both chromosomes 15 and 17 with additional chromosome(s), expressing in all studied cases, the PML/RARalpha transcript, or cases where neither chromosome 15 nor chromosome 17 are apparently involved, but with submicroscopic insertion of RARalpha into PML leading to expression of the PML/RARalpha transcript; these latter cases are considered as cryptic or masked t(15;17). Morphological analysis showed no major difference between the t(15;17) positive control group and the PML/RARalpha positive patients without t(15;17).

t(11;17)(q23;q21)

DEFINITION: Several AML cases with translocation t(11;17)(q23;q21), in which the promyelocytic leukemia zinc finger ( PLZF) gene is translocated to RARalphagene on 17q21 have been reported. This finding that the RARalpha gene is involved in both t(15;17) and t(11;17) suggests the importance of the modified RARalpha in AML. MORPHOLOGY AND CYTOCHEMISTRY: Patients were initially reported as having M3 morphology. Interestingly, the t(11;17)(q23;q21) PLZF/RARalpha subgroup showed clearly morphological differences with predominance of cells with regular nuclei, many granules, usually no Auer rods, increased number of pseudo Pelger-Huet cells and a strong MPO activity. These particular characteristics could allow the definition of a separate morphological entity among APL.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -483- CLINICAL FEATURES: M3-like patients with t(11;17)(q23;q21) are resistant to ATRA, both in vivo and in vitro. MOLECULAR ANALYSIS: In patients with t(11;17)(q23;q21), where RARalpha is fused to the PLZF (promyelocytic leukemia zinc finger) gene, chromosome 17 and RARalpha but not PML are involved.

11q23

DEFINITION: Molecular studies have identified a human homologue of the drosophila trithorax gene (designed HRX or MLL). MLL is a developmental regulator and is structurally altered in leukemia associated translocations that show an abnormality at band 11q23. MORPHOLOGY AND CYTOCHEMISTRY: There is a strong association between AML M5/M4 and deletion and translocations involving 11q23. Sometimes cases of 11q23 M5B and M4, and occasionally M2 or M1 also show MLL rearrangement. Two clinical subgroups of patients have a high frequency of 11q23 aberration and M5 subtypes: one is AML in infants with MLL rearrangement in about 50% of cases; the other group is "secondary leukemia" (sAML) potentially after treatment with DNA topoisomerase II inhibitors. In general the translocations in these leukemia are the same as those occurring in "de novo" leukemia i.e.t(9;11), t(11;19). MOLECULAR ANALYSIS: The MLL gene on 11q23 is involved in a number of translocations with different partner chromosomes. The most common translocations observed in childhood AML are the t(9;11)(p21;q23) and the t(11;19)(q23;p13.1); other translocations of 11q23 involve at least 50 different partners chromosomes. A partial tandem duplication of MLL gene has also been reported in the majority of adult patients whose leukemic blast cells have a +11 and in some with normal karyotype. Molecular studies have shown that MLL is rearranged more frequently than is revealed by conventional cytognetic studies.

Disease Second group WHO: mAML : Multilineage AML Note DEFINITION: This category is defined by the presence of multilineage dysplasia on cytological analysis. In contrast to the patients with "recurrent translocation", "multilineage AML" by definition involve all myeloid cell lineages. This category of AML occurs mainly in elderly patients and is rare in children. Translocations typical of "de novo AML" in young patients are not found in "multilineage AML". Dysplasia may be analyzed according to standard criteria (presence in >50% of each cell category). Granulocytic dysplasia (DysG) may be defined as polymorphonuclear neutrophils (PMN) with agranular or with hyposegmented nuclei (pseudo Pelger-Huet anomaly). Dysplastic features of erythroblastic precursors define Erythroid dysplasia (DysE): (megaloblastic or macroblastic aspects, karyorexis, nuclear fragments or multinuclearity). Megakaryocytic dysplasia (DysM) may be diagnosed when micromegakaryocytes, large megakaryocytes with monolobed or with multiple separated nuclei are found. A special

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -484- mention has to be made of the high frequency of dysmegakaryopoiesis and the utmost importance of clearly separating abnormal megakaryocytic cells with normal ploidy and non lobed ("monolobed") nuclei from hypoploid ("micromegakaryocytes") megakaryocytes and from megakaryocytes with multiple separated nuclei. Cytogenetics KARYOTYPIC/MOLECULAR ANALYSIS: In this group of patients chromosomes abnormalities include gain or loss of major segments of chromosomes: -5, -7/del(7q), +8, +9, +11, del(11q), del(12p), del(17p), -18, +19, del(20q), +21 and less often specific translocations t(2;11), t(1;7)(q10;p10) and translocations involving 3q21 and 3q26.

Disease Third group WHO: "Secondary AML" Note DEFINITION The term "secondary" AML has been utilized to encompass several different situations. A first class of secondary AML include those patients with a longstanding exposure to environmental toxins, including smoking, occupational chemicals such as benzene and related petrochemicals. The importance of detailed occupational history of all patients cannot be overstated. The second category corresponds to patients who received prolonged administration of chemotherapy and/or radiotherapy for non- MDS/MPS malignancies (epithelial cancer, malignant lymphomas, myelomas, Hodgkin's disease). These AML occur after a latent period of a few years. They may present with myelodysplastic features evolving rapidly to AML. Until recently these were assumed to be exclusively the result of administration of alkylating agents. These AML are frequently associated with acquired chromosomal abnormalities involving 5q, - 7/del(7q) and other complex rearrangements, and more rarely with translocations. The morphological presentation and cytogenetic features of these two first types of "secondary" AML (sAML) are somewhat similar to "multilineage AML" (mAML). Another situation that has been described more recently is AML developing after the administration of agents that bind to DNA- topoisomerase II. In contrast to the loss of chromosomal material after alkyliting agent exposure, balanced translocations ("de novo" type AML): 11q23, usually t(9;11), or 21q22, t(8;21) or even t(15;17) have been noted in these leukemias. This category has a morphologic presentation similar to the corresponding "de novo" AML and a much more favorable outcome with chemotherapy.

Disease Fourth group WHO: Morpholocical and Immunophenotyping classification Note DEFINITION: A morphological and immunophenotypic classification remains necessary for the other situations which do not fit with the two preceding main categories, respectively: "recurrent translocations AML" (so-called "de novo") and "multilineage AML". Morphologically, the diagnosis of AML is based on the cytological aspect of the blast cells and the maturation of the different cell lineages

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -485- in bone marrow aspirate, in addition to quantitative parameters obtained from the peripheral blood. Blood films, although essential, are not considered sufficient for diagnosis. The major criteria required for sub- classification are based on bone marrow aspirates. This explains the care required in difficult cases, in which the bone marrow aspirate is hypocellular. In these cases, as well as those with myelofibrosis, precise diagnosis needs the additional information of histological examination of a bone marrow biopsy. When the bone marrow is hypercellular or normocellular and easy to aspirate, bone marrow biopsy is usually not essential and cytological examination of smears is sufficient. With some reservations the sub-classification criteria can also be used for the material from patients with relapsing acute leukemia. MORPHOLOGICAL CATEGORIES. The categories of this fourth group reflect the previous FAB classification with eight main types of AML (from M0 to M7 AML) and one additonal category for the so-called "biphenotypic AL". AML M1 and M2 show predominantly granulocytic (neutrophil) differentiation. Very specific hypergranular cells characterize M3 AML. AML M4 and M5 both show monocytic differentiation, predominantly monocytic for M5, and mixed monocytic- granulocytic for M4. Predominantly erythroblastic and megakaryoblastic differentiation are characteristic of AML M6 and M7 AML respectively; the myeloid nature of M0 is defined only on immunological markers (myeloid and no lymphoid markers) in patients lacking morphological or cytochemical criteria for AML. Biphenotypic acute leukemias are defined for patients having both lymphoid and myeloid immunological markers. Bibliography Proposals for the classification of the acute leukaemias. French-American- British (FAB) co-operative group. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Brit J Haematol 1976; 33: 451-458.

Morphologic, Immunologic and Cytogenetic (MIC) working classification of the acute myeloid leukaemias. MIC second MIC cooperative study group. Brit J Haematol 1988; 68: 487-494.

World Health Organization Classification of Neoplastic Disease ot the Hematopoietic and Lymphoid Tissues : Report of the Clinical Advisory Committee Meeting Airlie House, Virginia, November 1997. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink, Vardiman J, Lister T, Bloomfield C. J Clin Oncol 1999; 17: 3835-3849.

Contributor(s) Written 05- Georges Flandrin 2002

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -486- Citation This paper should be referenced as such : Flandrin G . Classification of acute myeloid leukemias. Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/ClassifAMLID1238.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -487- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Classification of myelodysplasic syndromes

Identity Note Basis of classification in conformity with WHO recommandations.

The classification of acute myeloid leukemia (AML) and myelodysplasic syndromes (MDS) includes clinical data (previous history, age) and biologic characteristics (morphology, cytochemistry, immunophenotype, cytogenetic and molecular biology). The separation of homogeneous classes allows us to distinguish pronostic parameters and to identify groups of patients sensitive to drugs or to specific treatment. Recurrent cytogenetic abnormalities are strong prognostic indicators in AML and MDS. Molecular studies of structural chromosomal changes have enabled the cloning of genes located at chromosomal breakpoints and have helped to characterize the proteins involved in leukemogenesis. Morphologic studies remain important because of a strong correlation with cytogenetic and molecular abnormalities. Clinics and Pathology Note The myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenia and bone marrow dysplasia. This is resulting from proliferation, differentiation and apoptotic processes of hematopoietic precursors with frequent evolution to acute myeloid leukemia (AML). Anemia, neutropenia or thrombocytopenia, separated or in combination, despite a hyper or normo-cellular bone marrow, define MDS. The concept of myelodysplastic syndromes has evolved gradually from the description of a group of anemias previously described as "refractory anemias".

MDS is a somewhat heterogeneous group of patients with regard to clinical presentation, laboratory findings and prognosis. Methods for evaluating the potential clinical outcome have been developed by taking into account the hematological presentation (degree of cytopenia, classification in subgroup based on the percentage of bone marrow blast cells), bone marrow karyotype and some clinical parameters, mainly age.

Primary and secondary MDS are defined by taking into account the prior patients history: previous treatments with chemotherapy, radiotherapy or professional exposure to toxic substances are defining secondary MDS (sMDS) or "primary" MDS. Cytogenetically, a difference between the two groups is the complexity of abnormal karyotypes since single

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -488- chromosome aberrations are typical for primary MDS, while multiple changes are more frequently seen in secondary disorders. Some drugs may have specific targets such as: hydroxurea for 17p, topoisomerases inhibitors for 11q23 and 21q22. The genetic changes in the malignant cells of MDS result mainly in the loss of genetic material, including probable tumor suppressor genes.

Primary MDS

MDS IN ELDERLY PATIENTS: MDS is primarily a disease of the elderly. The median age of patients varies from about 60 years to 75 years. Patients below the age of 50 years are less frequent and their number varies greatly among different series in the literature. MDS sub- types, as defined by the FAB-working group, have prognostic significance in the elderly, in whom survival and incidence of AML progression are more favorable in lower stages of the disease (lower blast cell count). MDS characteristically responds poorly to AML chemotherapy, with prolonged cytopenias and poor remission rates. Less than 50% of MDS cases have cytogenetic abnormalities at presentation; this frequency increases with progression and includes gain or loss of major segments of chromosomes ( -5/del(5q), -7/del(7q), +8, +9, +11, del(11q), del(12p), del(17p), -18, +19, del(20q), +21). CHILDHOOD MDS: MDS appears to be uncommon in children but it is characterized by a higher rate of progression to overt acute leukemia. Their classification has been the subject of controversy. If some cases of childhood MDS are similar to adult MDS, others have a more "myeloproliferative" presentation with prominent hepato-splenomegaly, leucocytosis, monocytosis, frequent skin involvement, and presence of immature cells in the peripheral blood. These cases have been referred to chronic myelomonocytic leukemia (CMML) or juvenile chronic myelogenous leukemia ( JCML). This feature is primarily observed in infancy and early childhood. THE CRITERIA FOR DIAGNOSIS: The diagnosis of MDS is mainly morphological and based on the presence of dysplastic features in the peripheral blood and bone marrow. The French-American-British (FAB) Cooperative Group has proposed (1982) a classification based on easily obtainable laboratory information; despite its effectiveness for classifying MDS, omission of biological parameters such as marrow cytogenetics and the degree of cytopenia makes necessary a reappraisal of certain novel aspects of the diagnosis and prognosis.

Secondary MDS (sMDS) Cases of MDS related to chemotherapy and radiotherapy (sMDS) are increasingly being recognized as long-term complications of cancer therapy. This entity is not clearly different from sAML (sAML frequently evolves from a preceeding myelodysplastic phase. The bone marrow blast cell cut-off of 20% that distinguishes sAML from sMDS, often depends on the hematological follow-up of at-risk groups of patients who have received chemotherapy and/or radiotherapy. If early bone marrow examination is performed, MDS may be diagnosed but AML

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -489- could be diagnosed too if bone marrow examination is delayed until the blast cells appeared in the peripheral blood. sMDS/AML after chemotherapy is diagnosed after lymphoma therapy with a percentage of relative risk ranging from 2.2 to 3.3 at 15 years. For both sMDS and sAML the most frequently involved drugs include alkykating agents, epipodophyllotoxins and anthracyclins. The majority of sMDS/AML are morphologically characterized by multilineage myeloid dysplasia; the great majority have chromosome abnormalities, the most common being the loss of genetic material of either part or all of chromosome 7 and/or 5 (7q/-7, /5q-, -5). sMDS has a rapid course and a short survival.

Morphological classification Historical background and basis for the practical classification The diagnosis of MDS is often made unexpectedly after a routine blood count. There are no specific symptoms other than those related to progressive bone marrow failure. PERIPHERAL BLOOD: Patients are commonly anemic with normal or low reticulocyte counts. Anemia is usually normocytic or macrocytic. In cases with severe dyserythropoiesis in the bone marrow, the peripheral blood may show poikilocytosis and anisocytosis. The neutrophil count is variable and may be low. Neutrophil granulations may be reduced or not visible on MGG stained smears. Thrombocytopenia is common in MDS but the platelet count may be normal. BONE MARROW: In the bone marrow, different degrees of morphological and functional abnormalities of erythroid (DysE), megakaryocytic (DysM) and granulocytic (DysG) lineages are a hallmark of the disease. In the granulocytic lineage, hypogranular cells may be associated with other abnormalities such as persistent cytoplasmic basophilia and vacuolisation; abnormal nuclear feature are common, such as hyposegmented forms (pseudo Pelegre-Huet) or binucleated cells. Abnormal eosinophils, basophils and mast cells are rarely seen. Cytochemical abnormalities include reduced myeloperoxidase or inappropriately increase in alpha-napthtyl esterase activity. Megacaryocytic dysplastic features are particularly frequent in MDS and include megakaryocyte hypoploidy (micromegakaryocytes) and multinucleated megakaryocytes or large monolobed cells.

WHO Reassessment of MDS morphological classification The FAB cooperative group initially proposed (1982) morphological criteria to distinguish between MDS and AML on the basis of the arbitrary bone marrow blast count and divided MDS into five subtypes: Refractory anemia (RA), RA with excess of blasts (RAEB), RA with excess of blasts in Transformation (RAEBT), RA with ringed sideroblasts (RARS), Chronic myelomonocytic leukemia (CMML). This subdivision is mainly based on the percentage of blasts in the peripheral blood and bone marrow (RA to RAEBT) but, also, on the absolute peripheral blood monocyte count (CMML) and the percentage of ring sideroblasts (RARS). Readjustment of this FAB classification has recently been undertaken in order to resolve some ambiguities (WHO Classification). RAEB T is

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -490- suppressed as category and is included with AML M2. Disease Refractory anemia (RA) Clinics Refractory anemia demonstrates less than 5% bone marrow blast cells. RA should be included in a more general group of myelodysplastic syndromes without excess blasts. The typical presentation is anemia but the first hematological manifestation could be thrombocytopenia alone, or more rarely neutropenia alone (refractory cytopenia). Since refractory cytopenias (RC) are heterogeneous with regard to their morphology, clinical features and survival, it has been proposed to separate RC patients in two categories: RC with multilineage dyspalsia (mRC), a distinct subset with an unfavorable clinical outcome and RC with minimal dysplasia (RC).

Disease Refractory anemia with excess of blasts (RAEB) Clinics The RAEB category remain unchanged and as previously described include MDS patient having more than 5 and less than 20% bone marrow blasts. Suppressing the RAEB-T category. This subclass was identical to RAEB except for a higher percentage blasts: between 20 and 30% in the bone marrow and/or more than 5% in the peripheral blood. Most of these patients have been recognized to have an AML M2 outcome. For that reason, it has been suggested that patients with more than 20% of blast cells in the peripheral blood or bone marrow may be considered as acute myeloid leukemia M2. Presence of Auer rods that was an indication for RAEBT is no more taken into consideration for the classification. Splitting RAEB into two classes: RAEB I and RAEB II. It has been recommended to separate RAEB patients in two groups: RAEB I with < 10 % blasts in the bone marrow and/or 1 to 5% blast cells in the peripheral blood. RAEB II with 10-20 % in the bone marrow and/or 5% to 20% blast cells in the peripheral blood.

Disease Refractory anemia with ringed sideroblasts (RARS). Clinics Restricting the definition of RARS. Ineffective erythropoiesis, dysplastic erythroid precursors and progressive anemia characterize RARS. The FAB has defined RARS as <15% sideroblasts. Some confusion has arisen in using this point. It has been shown that patients with increased sideroblasts and other myelodysplastic features have a more severe course than those without additional dysplasia. The "pure" RARS (without dysplasia) is characterized by a very low risk of progression to leukemia and has usually a high percentage of bone marrow erythroblasts and ringed sideroblasts. An increase in ring sideroblasts in other MDS/MPS with dysplasia should be mentioned as an additional factor but is not crucial for classification.

Disease Chronic myelomonocytic leukemia (CMML) Clinics The arbitrary definition of the FAB CMML subtype has led to some controversy. The minimal monocyte count for CMML was set at 1 x 109/l. Many subsequent studies have recognized the heterogeneity that

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -491- exists within the subgroup of CMML. Some patients present with a modest monocytosis and leukocytosis (MDS/CMML) and others have an extreme leukocytosis and extramedullary hematopoiesis characterized by splenomegaly, serous effusions or skin infiltration (MPS/CMML). Whether dysplastic and proliferative CMML represent different phases of a single disease or are distinct entities remains unclear. Disparate results have been obtained concerning median survival between these two subtypes. The WHO classification recommends putting CMML into a new category between Myelodysplastic and Myelproliferative syndromes (MDS/MPS). The WHO classification recommends keeping only the CMML patients with myeloproliferative features defined as having > 1x109/l monocytes in the peripheral blood. The WHO classification recommand to classify CMML in a separate group (SMD/SMP) having both criteria of MDS and MPS.

Disease Atypical Chronic Myeloid Leukemia (a-CML) Clinics This new definition,(SMD/SMP), simplifies the distinction between CMML and another MPS category, atypical chronic myeloid leukemia which may have an increased monocytic count in addition to significant increase in circulating immature granulocytes; a-CML is usually characterized by more obvious myelodysplastic changes. Whether CMML and a-CML are separate disorders or part of a spectrum of MPS with various dysplastic features remains unclear. The WHO classification recommand to classify a-CML into the SMD/SMP group. Amongst patients that are presenting as MDS or MPS (depending on their WBC count), a peculiar morphological syndrome is the " abnormal chromatin clumping syndrome" (ACCS). This subtype is only based on morphologic features and is characterized by abnormal chromatin clumping of the granulocytic lineage. No precise correlation has been yet demonstrated with chromosomal changes in the few cases described in the literature the clinical outcome is poor.

Disease "Unclassified" MDS Clinics Other distinct MDS subgroups, such as hypocellular MDS and MDS with myelofibrosis have been recognized. Some cases of MDS with abnormal eosinophilia and MDS associated with abnormal mast cell have been described. Genetics Cytogenetic classification.

CHROMOSOMAL ABNORMALITIES IN PRIMARY MDS: Myelodysplastic syndromes are typical cytogenetic models of the leukemogenesis process: the clonal population progresses through a chronic phase that can last for years, to frank leukemia. Chromosome abnormalities should be taken in consideration in addition to specific hematological abnormalities in order to define new MDS syndromes. Most investigators working on MDS integrate morphology and

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -492- cytogenetics in diagnosis and classification. In (primary) MDS, non- random chromosomal aberrations contribute to characterized distinct clinico-pathological entities in which cytogenetic findings correlate with morphological features or with the clinical course of the disease. In primary MDS, around 50% of karyotypes are abnormal, depending on the patient series and on the techniques used. Cytogenetic studies have focused on chromosomal deletions as the most typical changes in MDS. Molecular genetics allow narrowing of the loss of genomic regions and are useful to discover cryptic deletions. It is obvious that some cases of MDS will need multi-color FISH to identify complex chromosomal rearrangements.

PATTERNS OF CHROMOSOMAL ABNORMALITIES IN SECONDARY MDS (sMDS): The incidence of chromosomal abnormalities is higher in sMDS (more than 85%) than in the corresponding de novo diseases (about 50%). The ploidy is different in secondary MDS and primary MDS: hypoploidy is clearly more frequent in secondary MDS. Several numerical and/or structural chromosomal abnormalities are frequently associated with sMDS: among the most common, there is the association of abnormalities of chromosomes 5 and 7 (-5 or 5q- and -7 or 7q-).

KARYOTYPIC/MORPHOLOGIC CORRELATION IN MDS: Attempts to correlate cytogenetic changes with the morphological subtypes of MDS as defined by the initial FAB criteria have not been successful. However, some molecular changes and karyotypic aberrations are more or less correlated with a specific cytological presentation, mainly in primary MDS. The major chromosomal anomalies are the following: del(5)q, monosomy 7, del(20)(q), trisomy 8 and less frequently +6, +13, +21, t(5;12)(q33;p13), other 12p changes, t(3;5)(q25;q34), inv(3)(q21q26), rearrangements involving 1q, 11q23, 17p-/-17 and X. Cytogenetics Cytogenetics del(5q), the "5q- syndrome" Morphological An interstitial deletion of the long arm of chromosome 5, del(5q), has been identified as a non-random aberration in a specific group of refractory anemia (RA). This "5q-" syndrome is characterized by a distinct clinico-morphological presentation: high prevalence of elderly females with a relatively good prognosis. This syndrome is characterized by a macrocytic anemia, a normal or high platelet count, a modest leukopenia, no excess blasts in the bone marrow and, as hallmark of the disease, the presence of monomorphous large normoploid megakaryocytes with hypolobulated nuclei and without other megakaryocytic abnormalities. Karyotypic clonal evolution and transformation into acute leukemia are rare. Cytogenetically, the 5q- appears polymorphic since the breakpoints as well as the size of deletion are variable with a critical region of deletion between bands q31 and q33. This genomic region is extremely rich in genes encoding growth factors.del(5q) has also been observed in other MDS/AML. In secondary (sMDS/AML) cases, del(5q) is frequently associated with

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -493- other chromosomal abnormalities, particularly chromosome 7. In that case, the dysmegakaryopoiesis is more polymorphic with the association of monolobed megakaryocytes and other types (mainly micromegakaryocytes). When re-examined by FISH some cases of del(5q) are found to be more complex than expected (with cryptic t(5;7) for example). These abnormalities are often impossible to detect using conventional cytogenetics. Monosomy 7 as well as partial deletion of the long arm of chromosome 7, - 7/del(7q), is among the most typical changes of sMDS with loss of a narrow genomic segment at 7q22.1. Chromosome 7 deletions are associated with bad prognosis. Monosomy 7 in primary MDS is often found in children 'childhood monosomy 7' with juvenile chronic myelomonocytic leukemia (JCML) and in familial -7 MDS. RAS gene mutations or loss of the NF1 gene are thought to be critical events in the pathogenesis of MDS with -7. Monosomy 7 and del(7q) are frequent in sMDS and quite rare in primary MDS; these deletions are variable in size and are always interstitial with two main zones at 7q22 and 7q32-34. Monosomy 7 is often associated with other chromosome changes. Chromosome 7 anomalies are more frequent in RAEB and CMML (20%) than in RA with abnormal karyotypes. Monosomy 7 is frequently associated with circulating and bone marrow micromegakaryocytes. In sMDS, 40 to 60% of cases have simultaneous del(7q) / -7 and del(5q) / -5. Patients with del(7)q and -7 have a severe outcome with sensitivity to infections and therapy resistance. Although non-specific, monosomy 7 is the most common cytogenetic abnormality in childhood MDS. MDS and AML in childhood may be associated with Fanconi's anemia, Kostmann's syndrome, Schwachman-Diamond syndrome, Down's syndrome and other inherited diseases characterized by chromosome breakage. del(20q) A chromosome 20q deletion is associated with about 5% of primary MDS. Erythrocytic and meagakaryocytic lineages appear to be involved preferentially. The majority of cases have an interstitial deletion between 20q11.2 and q13.3. del(20q) can be associated with both all subtypes of MDS (AR to AREB and CMML) and myeloproliferative syndromes (MPS). del(20q) is frequently associated with del (7q) /-7 and/or 3 del(13q). As a single anomaly, the del(20)(q) has a favorable prognosis. del (13q) Loss of interstitial material of the long arm of chromosome 13, del(13q), may occur in different types of AL and MDS or more frequently in MPS. del(13q) can be an isolated anomaly or associated with other karyotypic aberrations. del(13q) is an interstitial deletion; q14 and q21 are consistently deleted and this region contains a number of candidate tumor suppresser genes. No precise morphological correlation has been identified to date. del (11q) Interstitial deletions of the long arm of chromosome 11, del(11q), with breakpoints at q14 and q23 are typically associated with MDS and

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -494- bone marrow sideroblastosis. Trisomy 8 +8 is, like monosomy 7, one of the most frequent numerical aberration in MDS. Its prognostic significance is controversial. t(5;12)(q33;p13) t(5;12)(q33;p13) has been described in MDS and borderline cases between MDS and MPS. Bone marrow eosinophilia and/or monocytosis are predominant features. Cloning of the breakpoints have shown the involvement of an ETS-related gene TEL/ETV6 at 12p13 and the gene for receptor of PDGFb (platelet derived growth factor beta) at 5q33, generating a new transcript from the fusion gene. Variant translocation involving TEL/ETV6 and chromosomes 3, 6 or 10 have been identified and can define a molecular subgroup of MDS with ETV6 rearrangement. Other 12p changes MDS presenting with deletion of the short arm of chromosome 12, del(12p) are heterogeneous. Association with multiple karyotypic changes in sMDS is more common than de novo disorders with an 12p- chromosome as a sole aberration. Deletions are usually interstitial, with loss of material between band p11 and p13. FISH method has been used to show that both ETV6 and the gene for an inhibitor of a G1 cyclin-dependant protein kinase ( CDKN1B) are deleted in all myeloid malignancies with a del(12p) including MDS. t(3;5)(q25.1;q34) Translocation t(3;5)(q25;q34) is considered as the hallmark of a hematological syndrome presenting as MDS or AML with myelodysplasia. The breakpoints have been characterized at the molecular level and have shown the involvement of NPM on 5q34 and MLF1 gene on 3q25.1. inv(3)(q21q26) or t(3;3)(q21;q26) An inversion of the long arm of chromosome 3: inv(3)(q21q26), or a translocation between both homologous chromosome 3: t(3;3)(q21;q26) can be associated with AML or MDS with disturbances of thrombopoiesis expressed by elevated platelet count, dysmegakaryopoiesis (clumps of micromegakaryocytes) and poor prognosis. Transcriptional activation of the EVI1 gene on 3q26 is a consequence at molecular level. Chromosomal changes in addition to the 3q anomalies are frequently demonstrated predominantly aberrations of chromosome 5 or 7. Rearrangements involving 1q At least three recurrent unbalanced translocations have been found in primary MDS with a partial trisomy for the long arm of chromosome 1. Such rearrangements are described as t(1;15)(q11;p11); t(Y;1)(q12;q12); der(16) t(1;16)(q11;q11). 11q23/MLL-ALL1-HRX gene in MDS Chromosomal translocations involving 11q23 are common in acute monocytic leukemia. A small proportion of hematological neoplasms with 11q23 abnormalities has an initial presentation as MDS, some presenting as sMDS. It can be assumed that some of these translocations are involving MLL, if not all of them. t(11;16)(q23;p13.3)

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -495- involve MLL and CREBBP and is associated with therapy-related AML or MDS. 17p- / -17 and p53 mutations There is an association between vacuolated pseudo-Pelger-Huet granulocytes and chromosome 17p deletion with consistent involvement of p53 gene located at 17p13. It occurs in MDS and AML with poor prognosis. The 17p anomaly is found mainly in sMDS/AML after chemotherapy and/or radiotherapy, usually in association with other complex chromosomal anomalies. X mutations changes Pure monosomy X as an acquired abnormality has been sporadically found in female patients with MDS. A typical rearrangement such as an isodicentric chromosome X with breakpoint at q13 has been proposed as typical for acquired sideroblastic anemia with ring sideroblasts. Xq13 may also be involved in translocations in MDS without ring sideroblasts. del(Y) The IPSS (International Prognostic Scoring System) considers the del(Y) as a group with a favorable outcome. To be noted IPSS (International Prognostic Scoring System) for MDS

RISK FACTORS AND PROGNOSTIC CRITERIA IN MDS: In spite of the longstanding usefulness of the MDS FAB criteria, additional risk classifications including multiple scoring systems, have been used. In order to identify prognosis in MDS and to evaluate their AML transformation, these classifications have included, in addition to the bone marrow blast cell percentage, the bone marrow biopsy features, the degree of specific cytopenias, the age and cytogenetic pattern. Recently an International Prognostic Scoring System (IPSS) has been proposed which takes into account all these parameters. This international MDS risk classification defined four risk sub-groups: low, INT-1, INT-2 and high. The patients are separated for both survival and AML evolution into three prognostic subgroups related to their cytogenetic pattern:

good (normal, isolated del(5q) alone, isolated del(20q) and -Y ; poor (complex abnormalities i.e >3 anomalies) or chromosome 7 anomalies ; and intermediate (the remaining cases). Multivariate analysis combined these cytogenetics subgroups with the percentage of bone marrow blasts and the degree of cytopenia to generate a prognostic model. Stratification for age further improved analysis of survival Bibliography Proposals for the classification of the myelodysplastic syndromes. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. The French American British (FAB) co-operative Group.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -496- Brit J Haematol 1982; 51: 189-199.

Recommendations for a morphologic, Immunologic and Cytogenetic (MIC) working classification of the primary and therapy-related myelodysplastic disorders. MIC third mic cooperative study group. Canc Genet Cytogenet 1988; 32: 1-10.

The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C., Cox C. (The French-American-British (FAB) cooperative group). Brit J Haematol 1994; 87: 746-754.

World Health Organization Classification of Neoplastic Disease ot the Hematopoietic and Lymphoid Tissues : Report of the Clinical Advisory Committee Meeting Airlie House, Virginia, November 1997. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink, Vardiman J, Lister T, Bloomfield C. J Clin Oncol 1999; 17: 3835-3849.

Contributor(s) Written 05- Georges Flandrin 2002 Citation This paper should be referenced as such : Flandrin G . Classification of myelodysplasic syndromes. Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/ClassifMDSID1239.html

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M0 acute non lymphocytic leukemia (M0-ANLL)

Identity Note Stasi's criteria 30% blast cells in the bone marrow with <50% erythroblasts Cytochemical staining MPO/SSB <3% of blasts Cytochemical staining for PAS, AcP and NSE negative or weak At least one of these three immunologic markers positive : MPO, CD13, CD33, in flow cytometry or ultrastructurally Absence of cCD3, cCD22 and cCD79a Other Minimally differentiated acute leukemia names Clinics and Pathology Epidemiology rare: 3 - 5 % of ANLL; med age 45 yrs; 20% are children; unbalanced sex ratio in the adults: 1.6 M/1F, p< 0.01 Clinics High WBC mostly in children; frequently low Hb and platelets; organomegaly in children Cytology Undifferentiated blasts, cytochemistry: negative for myeloperoxydase. Positivity of at least one myeloid marker (CD13, CD33, CD65, CD117- c-KIT). Frequent expression of early progenitor markers CD34, DR; TdT in 30-40% of the cases; CD7 expression frequent in children. MPO antigen identified in about 50% of the cases. Prognosis Poor: CR in 50% of cases, med survival: 8 mths Poor prognosis factors: older age, high WBC, low platelets, CD10, CD14, CD15. Cytogenetics Cytogenetics high percentage of complex (20%) and unbalanced karyotypes; partial Morphological or complete monosomy (5/del(5q, -7/del(7q), or rearrangements of chromosome 5 and/or 7 in 15-20%; chromosome 11 rearrangements (11q23 in particular), and involvement (+8) in 10-15%; chromosome 13 involvement ( +13) in 9% ;t(9;22)(q34;q11) in 5%; near-tetraploidy in 6%; normal karyotype in 25% Bibliography The immunophenotype of minimally differentiated acute myeloid leukemia (AML-M0): reduced immunogenicity and high frequency of CD34+/CD38- leukemic progenitors. Costello R, Mallet F, Chambost H, Sainty D, Arnoulet C, Gastaut JA, Olive D. Leukemia 1999; 13: 1513-1518.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -498- Medline 99448220

AML-M0: a review of laboratory features and proposal of new diagnostic criteria. Stasi R, Amadori S. Blood Cells Mol Dis 1999; 25: 120-129. Medline 99317825

Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients. Bene MC, Bernier M, Casasnovas RO, Castoldi G, Doekharan D, van der Holt B, Knapp W, Lemez P, Ludwig WD, Matures E, Orfao A, Schoch C, Sperling C, van 't Veer MB, on behalf of the European Group for the Immunological Characterization of Leukemias (EGIL). Br J Haematol. 2001; 113: 737-745. Review. Medline 11380465

Contributor(s) Written 12- Jean-Loup Huret 1999 Updated 05- Marie Christine Bene 2002 Citation This paper should be referenced as such : Huret JL . M0 acute non lymphocytic leukemia (M0-ANLL). Atlas Genet Cytogenet Oncol Haematol. December 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/M0ANLLID1057.html Bene MC . M0 acute non lymphocytic leukemia (M0-ANLL). Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/M0ANLLID1057.html

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t(1;3)(p36;q21)

Identity

t(1;3)(p36;q21) G-banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, Cytogenetics at the Waisman Center; R-banding (right) Courtesy Pascale Cornillet-Lefebvre and StŽphanie Struski (above) and Christiane Charrin (below)

Clinics and Pathology Disease Myeloid lineage (MDS, ANLL, therapy related ANLL, CML, MPD); features similar to those of the 3q21q26 syndrome including normal or elevated platelet count at diagnosis, megakaryocytic hyperplasia and dysplasia. Very rarely in lymphoid lineage Phenotype / of 39 cases, there were: 22 myelodysplastic syndromes (MDS) (17/22 cell stem transformed into refractory acute non lymphoblastic leukemia (ANLL) origin of -M1 or -M4 type), 8 de novo ANLL, 3 therapy-related MDS, 2 polycythemia vera, 1 essential thrombocythemia, 1 chronic myelogenous leukemia (CML), 1 multiple myeloma, 1 waldenstrom's macroglobulinemia Epidemiology patients are aged: 30-80 yrs Clinics Roughly 50% of patients present with MDS, another 10% with therapy associated MDS, 25% with de novo AML, and the remainder with a range of other myeloproliferative disorders. The majority of MDS patients transform into AML with a short preleukemic phase. Blood data: frequent thrombocytosis or normal platelet count

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -500- Cytology frequently characterized by dysmegakaryocytopoiesis Pathology The pathology is typical of MDS, often with a prominent monocytic component. Trilineage dysplasia. Acute leukemias that evolve usually show the morphology of M4 AML. Treatment Patients are treated with conventional chemotherapy for AML. Prognosis Very poor so far: from 16 cases, median survival was 6 mths in ANLL, 20 mths in MDS Cytogenetics Note Other rearrangements showing similar clinical features include inv(3)(q21q26), t(3;3)(q21;q26), t(3;5)(q21;q31), t(3;8)(q21;q24), and t(3;21)(q26;q22). The breakpoints in 3q21 cluster in a 50 kb region centromeric to the breakpoint in inv(3)(q21;q26) and the ribophorin gene (RPN1). The breakpoints at 1p36 are clustered in a 90 kb region at 1p36.3. Additional del (5q) in 5 of 20 cases (1/4) anomalies Genes involved and Proteins Note Mechanisms of Oncogenesis : The available data suggest that transcription of MEL1 (MDS1/EVI1 -like gene) is activated as a result of translocation bringing the gene just 3Õ to RPN1 gene at 3q21. MEL1 is a 1257 amino acid protein that is homologous (63% similar in amino acid sequence) to EVI. The mechanism of activation of MEL1 is similar to EVI1 that is activated by juxtaposition 3Õ to RPN1 in the t(3;3)(q21;q26) and 5Õ to RPN1 in the inv(3)(q2126). It appears that MEL1 is normally expressed in uterus and kidney and not in normal hematopoietic cells or in leukemias that lack the t(1;3)(p36;q31 The MEL1 protein contains 2 DNA binding domains (7 C2H2 zinc finger repeats at the amino terminus and 3 zinc finger repeats at the carboxyl terminus). The amino terminal domain of MEL1 contains a PRD domain, a motif also found in the same location in the MDS1/EV1 protein but not in MDS1). This is of interest because this domain is also found in RIZ, PRDI-BF1, and egl-43 and is homologous to the SET (Suvar3-9, Enhancer of zeste, Trithorax) domain that present in MLL. Inclusion of this domain in EVI1 appears to convert EVI1 from a transcriptional repressor to an activator. Therefore MEL1 may be a transcriptional activator. The target genes of MEL1 have not been identified.

External links Other t(1;3)(p36;q21) Mitelman database (CGAP - NCBI) database Other t(1;3)(p36;q21) CancerChromosomes (NCBI) database

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -501- Bibliography A new translocation , t(1;3)(p36;q21), in myelodysplastic disorders. Moir DJ, Jones PA, Pearson J, Duncan JR, Cook P, Buckle VJ. Blood 1984; 64: 553-555. Medline 6743828

Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute non-lymphocytic leukemia. Bittner MA, Neilly ME, Le Beau MM, Pearson MG, Rowley JD. Blood 1985; 66: 1362-1370. Medline 4063525 t(1;3)(p36;q21) in acute nonlymphocytic leukemia: a new cytogenetic- clinicopathologic association. Bloomfield CD, Garson OM, Volin L, Knuutilia S, de la Chapelle A. Blood 1985; 66: 1409-1413. Medline 4063527

Diagnostic and prognostic significance of t(1;3)(p36;q21) in the disorders of hematopoiesis. Welborn JL, Lewis JP, Jenks H, Walling P Cancer Genet Cytogenet. 1987; 28: 277-285. Medline 87301329

Acute leukemia with t(1;3)(p36;q21), evolution to t(1;3)(p36;q21) , t(14;17)(q32;q21) and loss of red cell A and Le(b) antigens. Marsden KA, Pearse AM, Collins GG, Ford DS, Heard S, Kimber RI. Cancer Genetics Cytogenetics 1992; 64: 80-85. Medline 1458454

Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3. Grigg AP, Gascoyne RD, Phillips GL, Horsman DE Br J Haematol. 1993; 83: 158-165. Medline 93168610

Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom cancer cytogenetic group study. Secker-Walker LM, Mehta A, Brain B. Br J Haematol. 1995; 91: 490-501. Medline 96027684

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -502- The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin mediated . Huang S, Shao G, Limin L. J Biological Chem 1998; 273: 15933-15939. Medline 9632640

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

Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21). Shimizu S, Suzukawa K, Kodera T, Nagasawa T, Abe T, Taniwaki M, Yagasaki F, Tanaka H, Fujisawa S, Johansson B, Ahlgren T, Yokota J, Morishita K. Genes Chromosom Cancer 2000; 27: 229-238. Medline 20146274

Contributor(s) Written 08- Jean-Loup Huret 1997 Updated 11- Pascale Cornillet-Lefebvre, Sylvie Daliphard, Stéphanie Struski 2000 Updated 05- Jay L Hess 2002 Citation This paper should be referenced as such : Huret JL . t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol. August 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0103.html Cornillet-Lefebvre P, Daliphard S, Struski S . t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0103.html Hess JL . t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0103.html

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t(1;3)(p36;p21)

Clinics and Pathology Disease found in various hematological malignancies: 2 chronic myelogenous leukemia (CML), i of which in accelerated phase, 1 myelodysplastic syndrome (MDS) of RAEB type, 2 treatment related MDS, 2 M3- ANLL (acute non lymphocytic leukemia), 2 acute lymphocytic leukemias (ALL), and 1 treatment related ALL, 3 non Hodgkin lymphoma (NHL), (2 follicular and 1 diffuse large cell NHL) . Five patients had a history of a previous treatment for malignancy (alkylating agent in 3 cases). Epidemiology only 13 cases to date; 7 to 87 yr old patients, most patients being in the fifties; sex ratio: 7M/6F Prognosis very variable survival, from 25 days to 16 yrs+ Genetics according to the variability in the above data, the t(1;3)(p36;p21) is likely to be heterogeneous also at the molecular level. Cytogenetics Cytogenetics t(1;3)(p36;p21) is part of a complex karyotype in 12 of the 13 cases, Morphological and it appears to be a secondary anomaly: accompanying t(9;22)(q34;q11) in CML, t(15;17)(q22;q21) in M3 ANLL, -7 in t-MDS, t(14;18)(q32;q21) in follicular NHL, and also del(6q) in 3 cases and various non recurrent anomalies. In 2 cases, the der(1) appears the crucial event: a complex t(1;2;3) in M3 ANLL, where 3p21->pter is translocated onto der(1), and a der(1) without der(3) t(1;3) in NHL External links Other t(1;3)(p36;p21) Mitelman database (CGAP - NCBI) database Other t(1;3)(p36;p21) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity, especially so, since it looks quite heterogeneous: you are welcome to submit a paper to our new Case Report section. Bibliography Cytogenetic analysis of chimerism and leukemia relapse in chronic

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -504- myelogenous leukemia patients after T cell-depleted bone marrow transplantation. Offit K, Burns JP, Cunningham I, Jhanwar SC, Black P, Kernan NA, O'Reilly RJ, Chaganti RSK et al. Blood 1990; 75:1346-1355 Medline 2310831

Sequential analysis of 43 patients with non-Hodkin's lymphoma: clinical correlations with cytogenetic, histologic, immunophenotyping, and molecular studies. Whang-Peng J, Knutsen T, Jaffe ES, Steinberg SM, Raffeld M, Zhao WP, Duffey P, Condron K, Yano T, Longo DL. Blood 1995; 85:203-216. Medline 7803794

3p21 is a recurrent treatment-related breakpoint in myelodysplastic syndrome and acute myeloid leukemia. Shi G, Weh HJ, Martensen S, Seeger D, Hossfeld DK. Cytogenet Cell Genet 1996;74: 295-299. Medline 8976389

Analysis of secondary chromosomal alterations in 165 cases of follicular lymphoma with t(14;18). Horsman DE, Connors JM, Pantzar T, Gascoyne RD. Genes Chromosomes Cancer 2001; 30: 375-382. Medline 11241790

Cytogenetic characterization of diffuse large cell lymphoma using multi-color fluorescence in situ hybridization. Dave BJ, Nelson M, Pickering DL, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Sanger WG. Cancer Genet Cytogenet 2002; 132:125-132 Medline 11850073 t(1;3)(p36;p21) is a recurring therapy-related translocation. Sato Y, Izumi T, Kanamori H, Davis EM, Miura Y, Larson RA, Le Beau MM, Ozawa K, Rowley JD. Genes Chromosomes Cancer 2002; 34: 186-192 Medline 11979552

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -505- Contributor(s) Written 05- Jean-Loup Huret 2002

Citation This paper should be referenced as such : Huret JL . t(1;3)(p36;p21). Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0103p36p21ID1237.html

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t(1;16)(q11;q11)

Clinics and Pathology Disease only 3 cases of myelodysplastic syndrome (MDS) and 1 case of non Hodgkin lymphoma (NHL). The 3 MDS cases were: 2 refractory anemia with excess of blasts (RAEB), evolving towards M2 acute non lymphocytic leukemia (ANLL), and 1 refractory anemia with ringed sideroblasts (RARS) evolving towards M6-ANLL; the NHL case was a VIH-associated large cell NHL. Epidemiology the MDS cases were aged 59-74 yrs, the NHL patient was 29 yr old; sex ratio: 4M/0F. Prognosis survival in MDS: 13 mths, 15 mths+, 54 mths+; death of an unrelated cause in the NHL. Cytogenetics Cytogenetics presents as a der(16) t(1;16) in the 3 MDS Morphological Additional sole anomaly in 1 MDS, accompanied with +8 in the 2 other MDS anomalies cases; the NHL case exhibited a t(8;14)(q24;q11) and a complex caryotype; i.e. probable primary anomaly in MDS, secondary anomaly in the NHL case Genes involved and Proteins Note genes involved are unknown.

External links Other t(1;16)(q11;q11) Mitelman database (CGAP - NCBI) database Other t(1;16)(q11;q11) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -507- Bibliography Centromeric instability of chromosome 1 resulting in multibranced chromosomes, telomeric fusions, and "jumping translocations" of 1q in a human immunodeficiency virus-related non-Hodgkin's lymphoma. Sawyer JR, Swanson CM, Koller MA, NOrth PE, Ross SW. Cancer 1995; 76: 1238-1244. Medline 8630904

Der(16)t(1;16)(q11;q11) in myelodysplastic syndromes: a new non-random abnormality characterized by cytogenetic and fluorescence in situ hybridization studies. Mugneret F, Dastugue N, Favre B, Sidaner I, Salles B, Huguet-Rigal F, Solary E. Brit J Haematol 1995; 90: 119-124. Medline 7786773

Contributor(s) Written 05- Jean-Loup Huret 2002 Citation This paper should be referenced as such : Huret JL . t(1;16)(q11;q11). Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0116q11q11ID1247.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -508- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Trisomy 5

Clinics and Pathology Disease Trisomy 5 is found in both acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), but very rarely as the sole karyotypic abnormality. Clinics In childhood ALL, an extra chromosome 5 is commonly encountered in cases with hyperdiploidy > 50 chromosomes. The presence of trisomy 5 in high hyperdiploid childhood ALL is associated with a less favourable clinical outcome. Trisomy 5 as a sole abnormality in ALL is exceedingly rare and described in only 3 cases, including 2 adult ALL and 1 paediatrics case occurring in a 12-year old girl. Trisomy 5 has been described in 19 cases of AML. Gain of chromosome 5 usually occurs in association with other cytogenetics aberrations, although very rarely it may exist as the sole abnormality. A case of AML-M2 with normal karyotype at diagnosis showed trisomy 5 as the sole abnormality at relapse, and a case of AML-M5 showed trisomy 5 as the only chromosome aberration in 3% of 59 metaphases at presentation. A further case of AML-M4 showed a clone with trisomy 5 as the sole abnormality together with a second clone with trisomy 5 and evolutionary change. In the other 16 cases, trisomy 5 was found in association with numerical (n = 4), structural changes (n = 4), or both numerical and structural changes (n = 8). A number of interesting observations with respect to AML and trisomy 5 should be noted. First, an association between trisomy 5 and t(8;21) (n = 3) and trisomy 8 (n = 6) is observed. Second, five out of 6 cases with concurrent trisomies 5 and 8 show monocytic differentiation and are diagnosed as either AML-M4 or M5. Finally, trisomy 5 has been described in all FAB subtypes of AML except acute promyelocytic leukaemia.Given the rarity of trisomy 5 in AML, it is possible that the associated cytogenetic aberrations such as t(8;21) or trisomy 8 and not trisomy 5 per se that predicts for the myeloid phenotype. Prognosis Trisomy 5 in childhood ALL with hyperdiploidy > 50 chromosomes is associated with a poorer clinical outcome. Among the 3 cases of ALL with trisomy 5 as the sole karyotypic abnormality, 2 (one case each of adult and paediatric ALL) showed short survival whilst one adult ALL case showed event free survival of 4 years off chemotherapy. Among 19 AML patients with trisomy 5, complete remission was achieved in 8 and the median overall survival was 15 months. For the remaining 11 patients, 2 achieved partial remission and died, 4 did not attain remission at all, 1 was not treated, and the status of 4 patients

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -509- was unknown. Bibliography Multiple leukemic clones in acute leukemia of childhood. Morse HG, Ducore JM, Hays T, Peakman D, Robinson A. Hum Genet 1978; 40: 269-278. Medline 273006

Evolution of karyotypes in acute nonlymphocytic leukemia. Testa JR, Mintz U, Rowley JD, Vardiman JW, Golomb HM. Cancer Res 1979; 39: 3619-3627. Medline 476688

Nonrandom cytogenetic changes in New Zealand patients with acute myeloid leukemia. Fitzgerald PH, Morris CM, Fraser GJ, Giles LM, Hamer JW, Heaton DC, Beard ME. Cancer Genet Cytogenet 1983; 8: 51-66. Medline 6572548

High-resolution chromosomes as an independent prognostic indicator in adult acute nonlymphocytic leukemia. Yunis JJ, Brunning RD, Howe RB, Lobell M. N Engl J Med 1984; 311: 812-818. Medline 6472383

Chromosomal alterations in acute leukemia patients studied with improved culture methods. Testa JR, Misawa S, Oguma N, Van Sloten K, Wiernik PH. Cancer Res 1985; 45: 430-434. Medline 3855285

Myeloblastoma with an 8;21 chromosome translocation in acute myeloblastic leukemia. Abe R, Umezu H, Uchida T, Kariyone S, Maseki N, Kaneko Y, Sakurai M. Cancer 1986; 58: 1260-1264. Medline 3461872

Acute myelogenous leukemia with translocation t(8;21): a cytogenetic study of seven cases. Sessarego M, Mareni C, Panarello C, Garre L, Frassoni F, Boccaccio P, Ajmar F. Cancer Genet Cytogenet 1986; 20: 363-368. Medline 3455871

Cytogenetics and acute non lymphocytic leukemia. Palka G, Fioritoni G, Geraci L, Calabrese G, Mosca L, Peca S, Guanciali Franchi P, Spadano A, Arduini A, Torlontano G.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -510- Ann Genet 1987; 30: 39-46. Medline 3498428

Detection of karyotypic abnormalities in most patients with acute nonlymphocytic leukemia by adding ethidium bromide to short-term cultures. Misawa S, Yashige H, Horiike S, Taniwaki M, Nishigaki H, Okuda T, Yokota S, Tsuda S, Edagawa J, Imanishi H. Leuk Res 1988; 12: 719-729. Medline 3193811

Specific chromosome changes and nonoccupational exposure to potentially carcinogenic agents in acute leukemia in China. Li YS, Zhao YL, Jiang QP, Yang CL. Leuk Res 1989; 13: 367-376. Medline 2747268

Cytogenetic study of a case of childhood erythroleukemia. Duarte MH, Tone LG, Soares LR, dos Santos SA. Cancer Genet Cytogenet 1990;49: 25-30. Medline 2397470

Clinical and cytogenetic correlations of abnormal megakaryocytopoiesis in patients with acute leukemia and chronic myelogenous leukemia in blast crisis. Lee EJ, Schiffer CA, Tomiyasu T, Testa JR. Leukemia 1990; 4: 350-353. Medline 2388480

Unusual translocations and other changes in acute leukemia. Ferro MT, del Potro E, Krsnik I, Villegas A, Fernandez-Ranada JM, Resino M, Garcia-Sagredo JM, San-Roman C. Cancer Genet Cytogenet 1991; 54: 163-171. Medline 1884348

Abnormalities of chromosome 16q in myeloid malignancy: 14 new cases and a review of the literature. Betts DR, Rohatiner AZ, Evans ML, Rassam SM, Lister TA, Gibbons B. Leukemia 1992; 6: 1250-1256. Medline 1453770

A case of trisomy 5 in a Philadelphia positive leukemia. Smadja N, Varette C, Louvet C, Gramont A, Krulik M. Cancer Genet Cytogenet 1992 ;61: 216-217. Medline 1638509

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -511- A new case of trisomy 5 as sole cytogenetic anomaly in acute myeloid leukemia. Rios R, Sole F, Montes C, Vicente A, Perez MM, Valle M, Gascon F. Cancer Genet Cytogenet 1995; 84: 120-122. Medline 8536225

Trisomy 5 in two cases of acute monocytic leukemia with hyperdiploid clones. Ma SK, Wan TS, Au WY, Chan LC. Leuk Res 1998; 22: 961-964. Medline 9766757

Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes). Heerema NA, Sather HN, Sensel MG, Zhang T, Hutchinson RJ, Nachman JB, Lange BJ, Steinherz PG, Bostrom BC, Reaman GH, Gaynon PS, Uckun FM. J Clin Oncol 2000; 18: 1876-1887. Medline 10784628

Trisomy 5 as a sole cytogenetic abnormality in pediatric acute lymphoblastic leukemia. Sandoval C, Mayer SP, Ozkaynak MF, Tugal O, Jayabose S. Cancer Genet Cytogenet 2000; 118: 69-71. Medline 10731595

Contributor(s) Written 05- Edmond Ma, Thomas Wan. 2002 Citation This paper should be referenced as such : Ma E, Wan T. . Trisomy 5. Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/tri5ID1255.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -512- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(Y;1)(q12;q12)

Identity

der(Y)t(Y;1)(q12;q12) G-banding

Clinics and Pathology Disease 10 cases of hematological malignancy with der(Y)t(Y;1) had been reported to date. There were 8 cases of myelodysplastic syndrome, 1 case of polycythemia vera and 1 case of myelofibrosis. Phenotype / Suggested involvement of a pluripotent stem cell or a myeloid cell stem progenitor cell origin Etiology Presence of der(Y)t(Y;1)(q12;q12) abnormality is relatively restricted to myelodysplastic syndrome. Prognosis Owing to the small number of cases reported, the prognostic implication of der(Y)t(Y;1) remains to be defined. It is however known to be compatible with long survival of up to 13 Ð 15 years. This aberration occurs as a transient abnormality in one case. Cytogenetics Cytogenetics found it the unbalanced form + der(Y)t(Y;1)(q12;q12) Morphological Genes involved and

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -513- Proteins Note Genes involved are unknown. Whether an increased dosage of gene products located at 1q12-qter or the breakpoint at chromosomal location of Yq12 is important in the pathogenesis of MDS remains to be elucidated. Furthermore, since juxtaposition of heterochromatin and euchromatin has been shown to affect gene function, this may contribute to the pathogenic mechanism underlying der(Y)t(Y;1) as the heterochromatin at Yq12 is involved in the translocation.

External links Other t(Y;1)(q12;q12) Mitelman database (CGAP - NCBI) database Other t(Y;1)(q12;q12) 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 Karyotypic patterns and their clinical significance in polycythemia vera. Testa JR, Kanofsky JR, Rowley JD, Baron JM, Vardiman JW. Am J Hematol 1981; 11(1): 29-45. Medline 6943932

An identical t(Y;1)(q12;q21) in two patients with myelodysplastic syndromes. Hollings PE, Giles LM, Rosman I, Fitzgerald PH. Cancer Genet Cytogenet 1988; 34(2): 285-293. Medline 3165704

Transient t(Y;1)(q12;q21) in a patient with Fanconi anemia and myelodysplastic syndrome. Thompson PW, Standen GR, Geddes AD. Cancer Genet Cytogenet 1991; 52(2): 201-202. Medline 2021922

Translocation (Y;1)(q12;q21) in acute leukemia. Singh S, Wass J, Devaraj J, Young G, Vincent P. Cancer Genet Cytogenet 1993; 70(2): 136-139 Medline 8242595 der(Y)t(Y;1) is a nonrandom abnormality in myelodysplastic syndrome. Wei DCC, Wan TSK, Ma SK, Chan LC, Cheng PNM.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -514- Cancer Genet Cytogenet 1993; 70(2): 155-156. Medline 8242602

A rosy future for heterochromatin. Cook KR, Karpen GH. Proc Natl Acad Sci USA 1994; 91: 5219-521. Medline 8031404

Translocation (Y;1)(q12;q21) in hematologic malignancies. Report on two new cases, FISH characterization, and review of the literature. Michaux L, Wlodarska I, Vellosa ER, Verhoef G, Van Orshoven A, Michaux JL, Scheiff JM, Mecucci C, Van den Berghe H. Cancer Genet Cytogenet 1996; 86(1): 35-38. Medline 8616783

Derivative (Y)t(Y;1)(q12;q12),+9 in a patient with polycythemia vera during transition into myelodysplasia. Raymakers R, Stellink F, Geurts van Kessel A. Cancer Genet Cytogenet 1996; 88(1): 83-85. Medline 8630987

Association between der(Y)t(Y;1)(q12;q12) and myelodysplastic syndrome. Wan TSK, Ma SK, Chan LC, Au WY. Cancer Genet Cytogenet 2001; 124: 84-85. Medline S0165-4608(00)00331-9

Contributor(s) Written 05- Thomas SK Wan and Edmond SK Ma 2002 Citation This paper should be referenced as such : Wan TSK, Ma ESK . t(Y;1)(q12;q12). Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/tY1q12q12ID1160.html

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Bone: Chondrosarcoma

Identity

Figure 1: En bloc resection specimen of the proximal fibula of a 43 year old female, containing a lobulated bluish white, translucent tumour (4.5 x 2 x 1.9 cm) located centrally within the medullary cavity, consistent with central chondrosarcoma Figure 2: Corresponding macro-slice showing a lobular architecture, and endosteal cortical thinning. Cytonucle ar appearance can be more readily appreciated in figure 3 Classification Note approximately 90% of chondrosarcomas are histologically of the conventional type; in addition to conventional chondrosarcoma, some rare variants with distinctive microscopic and clinical features are discerned: clear cell chondrosarcoma (1%), mesenchymal chondrosarcoma (2%), juxtacortical chondrosarcoma (2%) and extra- skeletal myxoid chondrosarcoma (5%). Furthermore, dedifferentiated chondrosarcoma is a relatively rare high grade sarcoma next to a low- grade conventional malignant cartilage-forming tumor, comprising 6- 10% of all chondrosarcomas. Conventional chondrosarcomas can be categorized according to their location in bone. The majority of chondrosarcomas (75%) are located centrally within the medullary cavity (central chondrosarcoma), a small percentage of which arise within a preexisting benign precursor (enchondroma). While most

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -516- enchondromas are solitary, patients with Ollier's disease and Maffucci's syndrome demonstrate multiple enchondromas.A minority (15%) of chondrosarcomas develops from the surface of bone (peripheral chondrosarcoma) as a result of malignant transformation within the cartilaginous cap of a solitary or hereditary pre-existent osteochondroma. Clinics and Pathology Epidemiology primary malignant bone tumours occur 1/100,000, of which 17-24% consists of chondrosarcoma; the majority of patients are between 35 and 60 years old with equal sex distribution Clinics compared to benign cartilaginous tumours, chondrosarcomas more frequently present with pain and tenderness; they usually develop in the trunk, pelvis and long bones.

Figure 3: Micrograph displaying low cellularity with limited cytonuclear atypia, and a high amount of chondroid matrix surrounding tumor cells consistent with a grade I chondrosarcoma. Note the presence of a binucleated cell

Pathology There are no apparent cytonuclear differences between central and peripheral conventional chondrosarcomas and both are histologically classified into three grades using the criteria of Evans et al. Grade I chondrosarcomas demonstrate low cellularity, limited cytonuclear atypia, few multinucleated cells, a mainly chondroid matrix and the absence of mitoses; Grade II chondrosarcomas demonstrate increased cellularity, and increased muco-myxoid degeneration of the matrix. There is moderate cytonuclear atypia and occasional mitoses are found. Grade III chondrosarcomas are highly cellular, with nuclear polymorphism, mitoses and a mostly myxoid matrix; Increasing histological grade is correlated with higher metastatic potential; it is considered difficult to assess the histological grade of

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -517- cartilaginous tumours and to reliably distinguish between benign tumours and those of low-grade malignancy. Treatment because chondrosarcoma is highly resistant to chemotherapy and radiotherapy, surgical treatment is the only option for curative treatment Evolution the majority of central chondrosarcomas are considered to arise de novo and malignant transformation of solitary enchondroma is extremely rare (<1%); in patients demonstrating multiple enchondromas, such as Ollier's disease, the incidence of secondary central chondrosarcoma is much higher (30-35%). Peripheral chondrosarcomas usually originate from the cartilaginous cap of an osteochondroma; malignant transformation is low in solitary osteochondromas (<1%) but is estimated to occur in 1-5% of cases of hereditary multiple exostoses. Furthermore, an occasional recurrent chondrosarcoma may exhibit a higher grade of malignancy than the original neoplasm, suggesting that tumours may additionally progress from low to high grade Prognosis metastasis in chondrosarcoma highly depends on the histological grade of malignancy; grade I chondrosarcomas demonstrate local recurrence, but seldom metastasize; grade II chondrosarcomas demonstrate metastases in 10-30% of the cases, whereas grade III chondrosarcomas demonstrate metasases in the majority of cases. In contrast to chondrosarcomas located elsewhere in the skeleton, those located in the phalanx behave as a locally aggressive lesion with minimal metastatic potential Cytogenetics Cytogenetics extra-skeletal myxoid chondrosarcoma, is characterized by a Morphological reciprocal translocation t(9;22)(q22;q12), fusing the EWS to the CHN gene. cytogenetic analysis on a heterogeneous group of chondrosarcomas revealed that structural aberrations of chromosomes 1, 6, 9, 12 and 15 and numerical aberrations of chromosomes 5, 7, 8 and 18 were most frequent; abnormalities of chromosome 1 and 7 (especially trisomy 7) were confined to malignant cartilaginous tumours; like in other mesenchymal neoplasms, band 12q13-15 is prominently involved in the aberrations; Aberrations of chromosome 9, especially the 9p12-22 region are more common in central chondrosarcomas. the presence of chromosome aberrations was found to strongly correlate with increasing histological grade; complex aberrations were mainly seen in the high-grade chondrosarcomas. Loss of 13q was found to be an independent factor for metastasis, regardless of tumor grade or size. Cytogenetics in a comparative study of central and peripheral chondrosarcomas, Molecular 19 of 20 peripheral chondrosarcomas showed LOH at all loci (EXT, EXTL, 13q14, 17p13, 9p21 and chromosome 10) tested while only 3 of 12 central chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14 and 17p13. DNA-flow-cytometry demonstrated a wide variation

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -518- in the ploidy status in peripheral chondrosarcomas (DNA-indices 0.56 - 2.01), whereas central chondrosarcomas were predominantly peridiploid; these results indicate that peripheral chondrosarcomas, arising secondarily to an exostosis, may obtain genetic alterations during malignant transformation, with subsequent genetic instability as demonstrated by a high percentage of LOH and a wide variation in ploidy status. In contrast, peridiploidy and a low percentage of LOH in central tumors suggest that a different oncogenic molecular mechanism may be operative; no somatic mutations in the EXT1and EXT2 genes were found in secondary peripheral chondrosarcoma. A mutation (R150C) in the PTH/PTHrP type I receptor was demonstrated in 2 patients with Ollier's disease (one germline and one somatic), while this mutation was absent in 50 sporadic chondrosarcoma specimens. unfortunately, most other genetic analyses on chondrosarcoma were performed on a heterogeneous group including all different subtypes of chondrosarcoma; ploidy-analysis of chondrosarcomas has been described and aneuploidy is more frequently found in high-grade chondrosarcomas; two series of chondrosarcomas (n=23 and n=50) studied by CGH revealed extensive genetic aberrations; the majority of these changes were gains of whole chromosomes or whole chromosome arms, most frequent at 20q (32-38%), 20p (24-31%), and 14q23-qter (24-28%). A correlation between gain at 8q24.1 and shorter overall survival was reported; amplification of the c-myc proto- oncogene, located at 8q24, was found in four of 12 chondrosarcomas, and was not associated with any clinicopathological features. The only recurrent high-level amplification, seen in two tumours (7%), affected the minimal common region 12cen-q15; although both cytogenetic analysis and CGH point at 12cen-q15, CDK4, MDM2 and SAS were not frequently amplified in chondrosarcoma. Partial allelotypings of a heterogeneous group of chondrosarcoma revealed that in addition to LOH at the EXT-loci on chromosomes 8 (4/17) and 11 (7/17), LOH was found at 10q11 (12/18), the Rb- (9/25) and p53-locus (7/28). Overexpression of the p53 protein, 17p1 alterations and TP53 mutations have been observed mainly in high- grade chondrosarcomas, suggesting that the p53 gene could play a role in the progression of chondrosarcoma. Dedifferentiated chondrosarcoma: investigating both the cartilaginous as well as the high-grade malignant component of dedifferentiated chondrosarcoma, an identical somatic 6 bp deletion in exon 7 of p53 and loss of the same copy of chromosome 13 provided compelling evidence for a common origin instead of the “collision tumor_ theory; in addition, many different genetic alterations were found, indicating that the separation of the two clones is a relatively early event in the histogenesis of dedifferentiated chondrosarcoma. External links OMIM 215300 Bibliography

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -519- Cytophotometric studies of the nuclear DNA content in cartilaginous tumors. Cuvelier C, Roels HJ. Cancer 1979; 44: 1363-1374.

Prognostic factors in chondrosarcoma: a comparative study of cellular DNA content and clinicopathologic features. Kreicbergs A, Boquist L, Borssen B, Larsson SE. Cancer 1982; 50: 577-583.

Flow DNA analysis of primary bone tumors. Relationship between cellular DNA content and histopathologic classification. Kreicbergs A, Silfversw”rd C, Tribukait B. Cancer 1984; 53: 129-136.

Flow cytometric analysis of DNA in bone and soft-tissue tumors using nuclear suspensions. Xiang JH, Spanier SS, Benson NA, Braylan RC. Cancer 1987; 59: 1951-1958.

Amplification of the c-myc proto-oncogene in human chondrosarcoma. Castresana JS, Barrios C, Gomez L, Kreicbergs A. Diagn Mol Pathol 1992; 1: 235-238.

Amplification of c-myc oncogene and absence of c-Ha-ras point mutation in human bone sarcoma. Barrios C, Castresana JS, Ruiz J, Kreicbergs A. J Orthop Res 1993; 11: 556-563.

Biologic and clinical significance of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions. Bridge JA, Bhatia PS, Anderson JR, Neff JR. Cancer Genet Cytogenet 1993; 69: 79-90. p53 Expression and its relationship to DNA alterations in bone and soft tissue sarcomas. Wadayama B, Toguchida J, Yamaguchi T, Sasaki MS, Kotoura Y, Yamamuro T. Br J Cancer 1993; 68: 1134-1139.

The cytogenetics of bone and soft tissue tumors. Sandberg AA, Bridge JA. Austin: R.G. Landes Company; 1994. p53 Expression and DNA ploidy of cartilage lesions. Coughlan B, Feliz A, Ishida T, Czerniak B, Dorfman HD. Hum Pathol 1995; 26: 620-624.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -520- Differentiation and proliferative activity in benign and malignant cartilage tumors of bone. Hasegawa T, Seki K, Yang P, Hirose T, Hizawa K, Wada T, Wakabayashi J-I. Hum Pathol 1995; 26: 838-845.

Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8. Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M. Am J Hum Genet 1995; 56: 1125-1131.

Chondrosarcoma of bone. A clinical and DNA flow cytometric study. Heli H, Karaharju E, Bohling T, Kivioja A, Nordling S. Eur J Surg Oncol 1995; 21: 408-413.

Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Raskind WH, Conrad EU, Chansky H, Matsushita M. Am J Hum Genet 1995; 56: 1132-1139. p53 expression in dedifferentiated chondrosarcoma. Simms WW, OrdÛÒez NG, Johnston D, Ayala AG, Czerniak B. Cancer 1995; 76: 223-227.

Frequent loss of heterozygosity for markers on chromosome arm 10q in chondrosarcomas. Raskind WH, Conrad EU, Matsushita M. Genes Chromosom Cancer 1996; 16: 138-143.

Loss of heterozygosity and tumor suppressor gene mutations in chondrosarcomas. Yamaguchi T, Toguchida J, Wadayama B, Kanoe H, Nakayama T, Ishizaki K, Ikenaga M, Kotoura Y, Sasaki M. Anticancer Res 1996; 16: 2009-2016.

Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma. Brody RI, Ueda T, Hamelin A, Jhanwar SC, Bridge JA, Healey JH, Huvos AG, Gerald WL, Ladanyi M. Am J Pathol 1997; 150: 1049-1058.

Gains, losses, and amplifications of DNA sequences evaluated by comparative genomic hybridization in chondrosarcomas. Larramendy ML, Tarkkanen M, Valle J, Kivioja AH, Ervasti H, Karaharju E, Salmivalli T, Elomaa I, Knuutila S. Am J Pathol 1997; 150: 685-691.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -521- Altered p53 is associated with aggressive behavior in chondrosarcoma; a long term follow-up study. Oshiro Y, Chaturvedi V, Hayden D, Nazeer T, Johnson M, Johnston DA, Ordonez NG, Ayala AG, Czerniak B. Cancer 1998; 83: 2324-2334.

Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Bovee JVMG, Cleton-Jansen AM, Kuipers-Dijkshoorn N, Van den Broek LJCM, Taminiau AHM, Cornelisse CJ, Hogendoorn PCW. Genes Chromosom Cancer 1999; 26: 237-246.

Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis. Bovee JVMG, Cleton-Jansen AM, Rosenberg C, Taminiau AHM, Cornelisse CJ, Hogendoorn PCW. J Pathol 1999; 189: 454-462.

EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Bovee JVMG, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AHM, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PCW. Am J Hum Genet 1999; 65: 689-698.

Chondrosarcoma of the Phalanx: a locally aggressive lesion with minimal metastatic potential. A report of 35 cases and a review of the literature. Bovee JVMG, Van der Heul RO, Taminiau AHM, Hogendoorn PCW. Cancer 1999; 86: 1724-1732.

Clinical significance of genetic imbalances revealed by comparative genomic hybridization in chondrosarcomas. Larramendy ML, Mandahl N, Mertens F, Blomqvist C. Kivioja AH, Karaharju E, Valle J. Bohling T, Tarkkanen M, Rydholm A, Akerman M, Bauer HCF, Anttila J, Elomaa I, and Knuutila S. Hum Pathol 1999; 30:1247-1253.

Cartilage forming tumors of bone and soft tissue and their differential diagnosis. Bovee JVMG, Hogendoorn PCW. Curr Diagn Pathol 2001; 7: 223-234.

Chromosome 9 alterations and trisomy 22 in central chondrosarcoma: a cytogenetic and DNA flow cytometric analysis of chondrosarcoma subtypes. Bovee JVMG, Sciot R, Dal Cin P, Debiec-Rychter M, Van Zelderen-Bhola SL, Cornelisse CJ, Hogendoorn PCW. Diagn.Mol.Pathol.2001; 10 (4): 228-236.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -522- A mutant PTH/PTHrP type I receptor in enchondromatosis. Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG, Bell RS, Juppner H, Andrulis IL, Wunder JS, Alman BA. Nature Genet Advance online publication 2002; feb 19.

Cytogenetic aberrations and their prognostic impact in chondrosarcoma. Mandahl N, Gustafson P, Mertens F, Akerman M, Baldetorp B, GisselssonD, Knuutila S, Bauer HCF, Larsson O. Genes Chromosomes Cancer 2002; 188-200.

Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumors. A report from the chromosomes and morphology (CHAMP) collaborative study group. Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CDM, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Sciot R, Van den Berghe H, Vanni R, Willen H. J Pathol 2002; 196: 194-203.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Judith V.M.G. Bovee 2000 Updated 03- Judith V.M.G. Bovee 2002 Citation This paper should be referenced as such : Bovee JVMG . Bone: Chondrosarcoma. Atlas Genet Cytogenet Oncol Haematol. January 2000 . URL : http://AtlasGeneticsOncology.org/Tumors/chondrosarcID5063.html Bovee JVMG . Bone: Chondrosarcoma. Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://AtlasGeneticsOncology.org/Tumors/chondrosarcID5063.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -523- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Hereditary multiple exostoses (HME) Identity Other EXT names diaphyseal aclasis Inheritance autosomal dominant disorder, genetically heterogeneous; males are more often affected, possibly partly due to an incomplete penetrance in females; approximately 62% of the patients have a positive family history Clinics Phenotype presence of multiple osteochondromas (osteocartilaginous exostosis), and clinics bony protrusions covered by a cartilaginous cap on the outer surface of bone, resulting in a variety of orthopaedic deformities such as disproportionate short stature and bowing of the forearm; osteochondromas are the most common benign bone tumours, representing approximately 50% of all primary benign tumours of bone; they gradually develop and increase in size in the first decade of life; the stratified zones of chondrocytes that are normally found in the growth plate can still be recognised on the interface of cartilage and bone in osteochondroma; consequently, osteochondromas cease growing as the growth plates close during puberty; the majority of osteochondromas is asymptomatic and is located in bones that developed from cartilage, especially the long bones in the extremities

Figure 1: X-ray of the upper arm of a patient coming from a family with hereditary multiple exostoses (HME), demonstrating multiple osteochondromas (exostoses)

Neoplastic malignant transformation is low in solitary osteochondromas (<1%) but is risk estimated to occur in 1-3% of cases of hereditary multiple exostoses

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -524- Treatment osteochondromas can be surgically removed for cosmetic or functional reasons Cytogenetics Cytogenetics clonal karyotypic abnormalities in the cartilaginous cap of of cancer osteochondroma involving 8q22-24.1 were found in ten out of 30 sporadic and in 1 out of 13 hereditary osteochondromas, supporting a neoplastic origin; this was confirmed since aneuploidy was found in 4 out of 10 osteochondromas and LOH was almost exclusively found at the EXT1 locus in 5 out of 14 osteochondromas; no somatic EXT1 cDNA alterations were found in sporadic osteochondromas Genes involved and Proteins Note HME is a genetically heterogeneous disorder for which at present, two genes, EXT1 and EXT2 located respectively on 8q24 and 11p11- p12, have been isolated; the EXT1 gene was reported to show linkage in 44%-66% of the HME families, whereas EXT2 would be involved in 27%; additional linkage to chromosome 19p has been found, suggesting the existence of an EXT3 -gene, although loss of heterozygosity studies could not confirm this; two patients with multiple osteochondromas demonstrated a germline mutation in EXT1 combined with loss of the remaining wild type allele in three osteochondromas, confirming the tumour suppressor function of the EXT genes and indicating that in cartilaginous cells of the growth plate inactivation of both copies of the EXT1-gene is required for osteochondroma formation in hereditary cases

Gene EXT1 Name Location 8q24 Protein Function a tumour suppressor function is suggested for the EXT genes, which was confirmed by the combination of EXT1 germline mutations with loss of the remaining wildtype allele in osteochondroma; Both EXT1 and EXT2 mRNA is ubiquitously expressed. A high level of expression of Ext1 and Ext2 mRNA has been found in developing limb buds of mouse embryos and expression was demonstrated to be confined to the proliferating and prehypertrophic chondrocytes of the growth plate.The gene products, exostosin-1 (EXT1) and exostosin-2 (EXT2), are endoplasmic reticulum localized type II transmembrane glycoproteins which form a Golgi-localized hetero-oligomeric complex that catalyzes heparan sulphate (HS) polymerization. Heparan sulphate proteoglycans (HSPG) are large macromolecules composed of heparan sulphate glycosaminoglycan chains linked to a protein core. Four HSPG families have been identified: syndecan, glypican, perlecan and isoforms of CD44. HSPGs are required for high-affinity binding of fibroblast growth factor to its receptor. Furthermore, an EXT1

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -525- homologue in Drosophila (tout-velu, Ttv) has been shown to be required for diffusion of an important segment polarity protein called Hedgehog (Hh), a homologue of mammalian Indian Hedgehog (IHh). It was therefore hypothesized that EXT mutations affect FGF and IHh signalling within the normal growth plate. Indeed, diminished levels of the EXT1 and EXT2 protein and of their putative downstream effectors (IHh/PTHrP and FGF signalling pathway) were demonstrated in both sporadic and hereditary osteochondroma chondrocytes. Moreover, EXT mutations were described to induce cytoskeletal abnormalities (altered actin distribution) in osteochondroma chondrocytes. Mutations Germinal germline mutations of EXT1 and EXT2 in HME patients have been studied extensively in Caucasian as well as Asian populations Somatic One sporadic osteochondroma was described to harbour a deletion of one EXT1 gene combined with an inactivating mutation in the other EXT1 gene. No somatic mutations were found in the EXT1 and EXT2 gene in 34 sporadic and hereditary osteochondromas and chondrosarcomas tested

Gene EXT2 Name Location 11p11-p12

External links Orphanet Symphalangism brachydactyly craniosynostosis Bibliography Hereditary multiple exostoses; report of a family. Crandall BF, Field LL, Sparkes RS, Spence MA. Clin Orthop 1983; 190: 217-219.

Genetic heterogeneity in families with hereditary multiple exostoses. Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G, et al. Am J Hum Genet 1993; 53: 71-79.

A gene for hereditary multiple exostoses maps to chromosome 19p. Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A, Maroteaux P. Hum Mol Genet 1994; 3: 717-722.

Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Ahn J, Ludecke H, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -526- Nature Gen 1995; 11: 137-143.

Natural history study of hereditary multiple exostoses. Wicklund LC, Pauli RM, Johnston D, Hecht JT. Am J Med Genet 1995; 55: 43-46.

The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA. Nature Genet 1996; 14: 25-32.

Positional cloning of a gene involved in hereditary multiple exostoses. Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul E, De Boulle K, De Vries BBA, Hendrickx J, Herrygers I, et al. Hum Mol Genet 1996; 5: 1547-1557.

Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies Hecht JT, Hogue D, Wang Y, Blanton SH, Wagner M, Strong LC, Raskind W, Hansen MF, Wells D. Am J Hum Genet 1997; 60: 80-86.

An extension of the admixture test for the study of genetic heterogeneity in hereditary multiple exostoses. Legeai-Mallet L, Margaritte-Jeannin P, Lemdani M, Le Merrer M, Plauchu H, Maroteaux P, Munnich A, Clerget-Darpoux F. Hum Genet 1997; 99: 298-302.

Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M. Clin Genet 1997; 52: 12-16.

Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Philippe C, Porter DE, Emerton ME, Wells DE, Simpson AHRW, Monaco AP. Am J Hum Genet 1997; 61: 520-528.

Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Raskind WH, Conrad EU, III, Matsushita M, Wijsman EM, Wells DE, Chapman N, Sandell LJ, Wagner M, Houck J. Hum Mutat 1998; 11: 231-239.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -527- Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, Mollica F, Ludecke H, Sitki Sayli B, Pazzaglia UE, et al. Am J Hum Genet 1998; 62: 346-354.

EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Bovee JVMG, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AHM, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PCW. Am J Hum Genet 1999; 65: 689-698.

Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses. Park KJ, Shin K, Ku J, Cho T, Lee SH, Choi IH, Phillipe C, Monaco AP, Porter DE, Park J J Hum Genet 1999; 44: 230-234.

Mutation analysis of hereditary multiple exostoses in the Chinese. Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, Pan Q, Long Z, Fan C, Deng H. Hum Genet 1999; 105: 45-50.

Cytoskeletal abnormalities in chondrocytes with EXT1 and EXT2 mutations. Bernard MA et al. J.Bone Miner.Res.2000; 15 (3): 442-450.

Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Bovee JVMG et al. Lab.Invest.2000; 80: 1925-1933.

EXT 1 gene mutation induces chondrocyte cytoskeletal abnormalities and defective collagen expression in the exostoses. Legeai-Mallet L et al. J.Bone Miner.Res.2000; 15 (8): 1489-1500.

Clinical and radiographic analysis of osteochondromas and growth disturbance in hereditary multiple exostoses. Porter DE et al. J.Pediatr.Orthop.2000; 20 (2): 246-250.

Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Bernard MA et al. Cell Motil.Cytoskeleton 2001; 48 (2): 149-162.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -528- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications

Contributor(s) Written 01- Judith V.M.G. Bovee 2000 Updated 03- Judith V.M.G. Bovee 2002 Citation This paper should be referenced as such : Bovee JVMG . Hereditary multiple exostoses (HME). Atlas Genet Cytogenet Oncol Haematol. January 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/HeredMultExostosID10061.html Bovee JVMG . Hereditary multiple exostoses (HME). Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/HeredMultExostosID10061.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -529- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Costello syndrome Identity Other Noonan-like syndrome with nasal papillomata names Inheritance The vast majority of cases are sporadic. An increase in mean paternal age has been demonstrated, favouring the hypothesis of dominant de novo mutations, but a microdeletion is an alternative explanation. Clinics Note Costello syndrome is a multiple congenital anomalies/mental retardation syndrome characterised by severe growth abnormalities and a predisposition to develop childhood tumours, especially rhabdomyosarcomas. Phenotype Costello syndrome is characterised by and clinics Growth abnormalities: whereas new-born are often macrosomic and macrocephalic they exhibit severe feeding difficulties and failure to thrive during the first months of life, up to two years of age. After this marasmic period, growth velocity is restored but the final height is short. Ectodermal abnormalities are characterised by loose and dark- coloured skin, and a predisposition to develop multiple papillomata, which when present are highly suggestive of the diagnosis. Mental retardation is usually mild and most patients with CS have an happy, ongoing personality. Heart defects are present in one third of patients, either structural defects, hypertrophic cardiomyopathy or dysarrythmia. Neoplastic Patients with Costello syndrome are prone to develop both benign and risk malignant tumours. The risk of developing a cancer is up to 15%. Rhabdomyosarcoma, mostly of the embryonic subtype is the tumor the most frequently encountered in CS. Neuroblastomaand bladder cancer (very rare in children) have also been described in several patients. Treatment Symptomatic: surgery of congenital heart defects or tumors; tube feeding during the first months. Prognosis Apart from mental retardation, the prognosis of patients with Costello syndrome depends mainly on the occurrence of cardiac and/or tumoral complications. Genes involved and Proteins Note Unknown.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -530- External links OMIM 218040 Orphanet Syndrome de Costello Bibliography Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause. Johnson JP, Golabi M, Norton ME, Rosenblatt RM, Feldman GM, Yang SP, Hall BD, Fries MH, Carey JC J Pediatr. 1998; 133(3): 441-448. Review

Costello syndrome: two cases with embryonal rhabdomyosarcoma. Kerr B, Eden OB, Dandamudi R, Shannon N, Quarrell O, Emmerson A, Ladusans E, Gerrard M, Donnai D J Med Genet. 1998; 35(12): 1036-1039

Costello syndrome Philip N, Sigaudy S J Med Genet. 1998; 35(3): 238-240. Review

Costello syndrome: report and review van Eeghen AM, van Gelderen I, Hennekam RC Am J Med Genet. 1999; 82: 187-193. Review.

Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review Franceschini P, Licata D, Di Cara G, Guala A, Bianchi M, Ingrosso G, Franceschini D Am J Med Genet. 1999; 86: 174-179. Review

Second case of bladder carcinoma in a patient with Costello syndrome Gripp KW, Scott CI Jr, Nicholson L, Figueroa TE Am J Med Genet. 2000; 90: 256-259

Costello syndrome: a cancer predisposing syndrome? Moroni I, Bedeschi F, Luksch R, Casanova M, D'Incerti L, Uziel G, Selicorni A. Clin Dysmorphol 2000; 9: 265-268. Review

Costello syndrome: report of six patients including one with an embryonal rhabdomyosarcoma Sigaudy S, Vittu G, David A, Vigneron J, Lacombe D, Moncla A, Flori E, Philip N Eur J Pediatr. 2000; 59: 139-142

Screening for cancer in children with Costello syndrome. DeBaun MR Am J Med Genet 2002; 108: 88-90

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Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol Gripp KW, Scott CI Jr, Nicholson L, McDonald-McGinn DM, Ozeran JD, Jones MC, Lin AE, Zackai EH Am J Med Genet 2002; 108: 80-87

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 04- Nicole Philip 2002 Citation This paper should be referenced as such : Philip N . Costello syndrome. Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/CostelloID10075.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -532- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Functional organization of the genome: chromatin

Patricia Ridgway1,3, Christèle Maison2,3 and Geneviève Almouzni2 1. Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT 0200, Australia. 2. UMR 218 du CNRS, Institut Curie, 26 rue d'ULM, 75248 Paris Cedex 05, France. 3. equal contribution. May 2002 Introduction In eukaryotic cells the genetic material is organized into a complex structure composed of DNA and proteins and localized in a specialized compartment, the nucleus. This structure, detected with basic dyes, was called chromatin (from the Greek "khroma" meaning coloured and "soma" meaning body) at the end of the 19th centruy [Flemming, 1882 #24]. Close to two meters of DNA in each cell must be assembled into a small nucleus of some in diameter. Despite this enormous degree of compaction, DNA must be rapidly accessible to permit its interaction with protein machineries that regulate the functions of chromatin: replication, repair and recombination. The dynamic organization of chromatin structure thereby influences, potentially, all functions of the genome. The fundamental unit of chromatin, termed the nucleosome, is composed of DNA and histone proteins. This structure provides the first level of compaction of DNA into the nucleus. Nucleosomes are regularly spaced along the genome to form a nucleofilament which can adopt higher levels of compaction (Figures 1 and 3), ultimately resulting in the highly condensed metaphase chromosome. The combined approaches of cell biology and genetic studies have led to the discovery that within an interphase nucleus chromatin is organized into functional territories [Cockell, 1999 #2]. Historically, based on microscopic observations, chromatin has been divided into two distinct domains, heterochromatin and euchromatin. Heterochromatin was defined as a structure that does not alter in its condensation throughout the cell cycle whereas euchromatin is decondensed during interphase [Heitz, 1928 #1]. Typically in a cell, heterochromatin is localized principally on the periphery of the nucleus and euchromatin in the interior of the nucleoplasm. We can distinguish constitutive heterochromatin, containing few genes and formed principally of repetitive sequences located in large regions coincident with centromeres and telomeres, from facultative heterochromatin composed of transcriptionally active regions that can adopt the structural and functional characteristics of heterochromatin, such as the inactive of mammals [Lyon, 1999 #25] [Avner, 2001 #26]. In this review we will define the components of chromatin and outline the different levels of its organization from the nucleosome to domains in the nucleus. We will discuss how variation in the basic constituents of chromatin can impact on its activity and how stimulatory factors play a critical role in imparting diversity to this dynamic

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -533- structure. Finally we will summarize how chromatin influences the organization of the genome at the level of the nucleus. The nucleosome Historically, the periodic nature of chromatin was identified by biochemical and electron microscopic studies. The partial digestion of DNA assembled into chromatin, isolated from rat liver nuclei, generated fragments of 180-200 base pairs in length which were resolved by electrophoretic migration [Williamson, 1970 #3] [Hewish, 1973 #4]. This regularity of chromatin structure was later confirmed by electron microscope analysis that revealed chromatin as regularly spaced particles or "beads on a string" [Olins, 1974 #5] [Oudet, 1975 #7]. In parallel, chemical cross-linking analysis permitted the precise determination of the stoichiometry of DNA and histones in the nucleosome to be 1/1 based on their mass [Kornberg, 1974 #9]. Together these observations led to the proposition that the nucleosome was the fundamental unit of chromatin. Pierre Chambon's laboratory was the first to use the term "nucleosome" [Germont, 1976 #77]. It is composed of a core particle and a linker region (or internucleosomal region) that joins adjacent core particles (Figure 1). The core particle is highly conserved between species and is composed of 146 base pairs of DNA wrapped 1.7 turns around a protein octamer of two each of the core histones H3, H4, H2A and H2B. The length of the linker region, however, varies between species and cell type. It is within this region that the variable linker histones are incorporated. Therefore, the total length of DNA in the nucleosome can vary with species from 160 to 241 base pairs [Compton, 1976 #10] [Morris, 1976 #11] [Noll, 1976 #12] [Spadafora, 1976 #13] [Thomas, 1977 #14].

Figure 1. Defining elements of nucleosomes and chromatosome The first crystal structure of the core particle was obtained at a resolution of 7A by diffraction of X rays [Finch, 1977 #15]. More recently the structure of the octamer was resolved at 3.1A [Arents, 1993 #16]. Finally, crystalization that enabled a resolution of 2.8A was obtained using a unique sequence of DNA and purified recombinant proteins [Luger, 1997 #17]. This analysis revealed, firstly, the distortion of the DNA wound around the histone octamer and, secondly, that the histone/DNA and histone/histone interactions through their "histone fold domain" formed a configuration remniscent of a hand shake. This structural information has facilitated experimental approaches used to study the functions of specific regions of histones, with the exception of their N-terminal tails that are not visualized in the crystal.

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Histone proteins Core histones The core histones, H3, H4, H2A and H2B, are small, basic proteins highly conserved in evolution (Figure 2). The most conserved region of these histones is their central domain structurally composed of the "histone fold -helicies separated by two loop regions [Arents, domain" consisting of three 1991 #18]. In contrast, the N-terminal tails of each core histone is more variable and unstructured. The tails are particularily rich in lysine and arginine residues making them extremely basic. This region is the site of numerous post-translational modifications that are proposed to modify its charge and thereby alter DNA accessibility and protein/protein interactions with the nucleosome [Strahl, 2000 #19]. It is significant to note that other proteins that interact with DNA also contain the "histone fold domain" [Baxevanis, 1995 #20] [Wolffe, 1996 #21]. There is a web site that lists proteins containing a "histone fold domain" (http://genome.nhgri.nih.gov/histones/) [Baxevanis, 1998 #27] [Sullivan, 2002 #78].

Figure 2. Defining elements of nucleosomes and chromatosome The core histones. A. Structure of nucleosomal histones. B. Amino-terminal tails of core histones. The numbers indicate amino acid position. The post-translational modifications are indicated (red ac = acetylation sites ; blue p = phosphorylation sites ; green m = methylation sites ; purple rib = ADP ribosylation). Linker histones Linker histones associate with the linker region of DNA between two nucleosome cores and, unlike the core histones, they are not well conserved between species [Richmond, 2000 #22]. In higher eukaryotes, they are composed of three domains: a globular, non-polar central domain essential for interactions with DNA and two non- structured N- and C- terminal tails that are highly basic and proposed to be the site of post translational modifications. The linker histones have a role in spacing nucleosomes and can modulate higher order compaction by providing an interaction

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -535- region between adjacent nucleosomes. The precise role of the linker histones is still a controversial subject [Khochbin, 2001 #79] and a variety of models have been proposed [Pruss, 1996 #28] [Thomas, 1999 #29]. General steps in chromatin assembly The assembly of DNA into chromatin involves a range of events, beginning with the formation of the basic unit, the nucleosome, and ultimately giving rise to a complex organization of specific domains within the nucleus. This step-wise assembly is described schematically in Figure 3. The first step is the deposition onto the DNA of a tetramer of newly synthesized (H3-H4)2 to form a sub-nucleosomal particle, which is followed by the addition of two H2A-H2B dimers [Senshu, 1978 #32] [Cremisi, 1977 #31] [Worcel, 1978 #30]. This produces a nucleosomal core particle consisting of 146 base pairs of DNA wound around a histone octamer. This core particle and the linker DNA together form the nucleosome [Kornberg, 1974 #9]. Newly synthesized histones are specifically modified; the most conserved modification is the acetylation of histone H4 on lysine 5 and lysine 12 [Sobel, 1995 #34]. The next step is the maturation step that requires ATP to establish regular spacing of the nucleosome cores to form the nucleofilament. During this step the newly incorporated histones are de-acetylated. Next the incorporation of linker histones is accompanied by folding of the nucleofilament into the 30nm fibre, the structure of which remains to be elucidated. Two principal models exist : the solenoid model, an example of which is presented in Figure 3, and the zig zag [Woodcock, 2001 #23]. Finally, further successive folding events lead to a high level of organization and specific domains in the nucleus. At each of the steps described above, variation in the composition and activity of chromatin can be obtained by modifying its basic constituents and the activity of stimulatory factors implicated in the processes of its assembly and disassembly.

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Figure 3. General steps in chromatin assembly Assembly begins with the incorporation of the H3/H4 tetramer (1), followed by the addition of two H2A-H2B dimers (2) to form a core particle. The newly synthesized histones utilized are specifically modified; typically, histone H4 is acetylated at Lys5 and Lys12 (H3-H4*). Maturation requires ATP to establish a regular spacing, and histones are de-acetylated (3). The incorporation of linker histones is accompanied by folding of the nucleofilament. Here the model presents a solenoid structure in which there are six nucleosomes per gyre (4). Further folding events lead ultimately to a defined domain organization within the nucleus (5) (for details see [Ridgway, 2001 #89]). Variation in basic constituents In the first steps of chromatin assembly, the elementary particle can assume variations at the level of DNA (for example by methylation) or at the histone level by

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -537- differential post-translational modification and the incorporation of variant forms (for example CENP-A, a variant of H3). All of these variations are capable of introducing differences in the structure and activity of chromatin. The vast array of post- translational modifications of the histone tails summarized in Figure 2 (such as acetylation, phosphorylation, methylation, ubiquitination, polyADP-ribosylation), and their association with specific biological processes has led to a proposed hypothesis of a language, refered to as the "histone code", that marks genomic regions [Strahl, 2000 #19]. It must be emphasized that this code is a working hypothesis used to design experimental approaches that investigate the activity of chromatin. The code is "read"by other proteins or protein complexes that are capable of understanding and interpreting the profiles of specific modifications [Strahl, 2000 #19] [Jenuwein, 2001 #35]. The incorporation of histone variants such as H2A-X [Rogakou, 1999 #36], CENP-A [Sullivan, 1994 #37], macro H2A [Pehrson, 1992 #80] and H2A.Z [Clarkson, 1999 #38] may be important at specific domains of the genome. In this context, CENP-A, a variant of histone H3 is associated with silent centromeric regions [Sullivan, 1994 #37] and macro H2A on the inactive X chromosome of female mammals [Mermoud, 1999 #39]. H2A-X is implicated in the formation of foci containing DNA repair factors in the regions of DNA double-strand breaks [Paull, 2000 #81]. Growing evidence exists that H2A.Z has a role in modifying chromatin structure to regulate transcription [Santisteban, 2000 #40]. During the maturation step, incorporation of linker histones, non-histone chromatin associated proteins, called HMG (High Mobility Group), and other specific DNA- binding factors help to space and fold the nucleofilament. Therefore the early steps in assembly can have a great impact on the final characteristics of chromatin in specific nuclear domains [Marshall, 1997 #41]. Stimulatory Assembly Factors (for review see [Kaufman, 2000 #42]) Histone interacting factors Biochemical fractionation of extracts derived from cells or embryos permitted the identification of acidic factors that can form complexes with histones and enhance the process of histone deposition. They act as histone chaperones by facilitating the formation of nucleosome cores without being part of the final reaction product. These histone-interacting factors, also called chromatin-assembly factors, can bind preferentially to a subset of histone proteins. In Xenopus laevis, the proteins N1-N2 and nucleoplasmin are respectively associated with histones H3-H4 and histones H2A-H2B [Laskey, 1978 #43]. The situation is more complex for NAP-1 (Nucleosome Assembly Protein 1), depending on the system studied [Ito, 1997 #44]. Chromatin Assembly Factor-1 (CAF-1) interacts with newly synthesized acetylated histones H3 and H4 to preferentialy assemble chromatin during DNA replication [Smith, 1989 #45] [Kaufman, 1995 #46]. CAF-1 is also capable of promoting the assembly of chromatin specifically coupled to the repair of DNA [Gaillard, 1996 #47]. The recent demonstration of the interaction of CAF-1 with the protein PCNA (Proliferating Cell Nuclear Antigen) established a molecular link between the assembly of chromatin and the processes of replication and repair of DNA (see for review [Ridgway, 2000 #48] [Mello, 2001 #82]). The assembly of specialized structures in centromeric regions, by deposition of variant histones such as CENP-A, or telomeres may be a result of the specificity and the diversity of as yet uncharacterised histone chaperones. Remodelling machines and histone-modifying enzymes

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -538- Stimulatory factors also act during the chromatin maturation stage to organize and maintain a defined chromatin state. Their effects on chromatin can induce changes in conformation at the level of the nucleosome or more globally over large chromatin domains. These factors are of two types; one requiring energy in the form of ATP, generally refered to as chromatin remodelling machines, and the other that act as enzymes to post-translationally modify histones. Chromatin remodelling machines are multi-protein complexes which have now been characterized from yeast, humans and Xenopus laevis and are summarized in Table 1. Complexes sharing the same ATPase subunit are classified in the same family. The ATPase subunit, mating-type switching/sucrose non-fermenting (swi2/snf2) defines the first family, the ATPase ISWI the second family, also termed ISWI, and the last family is called Mi2/NuRD (nucleosome remodeling histone deacetylase) complex after the name of the ATPase subunit Mi2. The activity of the ATPase permits the complex to modify nucleosomal structure, driven by the liberation of energy during the hydrolysis of ATP [Travers, 1999 #53]. The study of factors that stimulate the regular arrangement of nucleosomes during the assembly of chromatin led to the identification of several multi-protein complexes such as ATP-utilizing chromatin assembly and remodelling factor (ACF) [Ito, 1997 #44] [Ito, 1999 #50], chromatin accessibility complex (CHRAC) [Varga-Weisz, 1997 #83] and remodeling and spacing factor (RSF) [LeRoy, 1998 #51]. These complexes are capable of "sliding" nucleosomes along DNA in vitro [Langst, 1999 #52] [Ito, 1999 #50]. The common feature of these chromatin remodelling factors is their large size and multiple protein subunits including the ATPase, however, they display differences in abundance and activity. Remodels the Structure of Chromatin (RSC), for example, is ten times more abundant than SWI/SNF and contains 15 subunits in contrast to the 11 in SWI/SNF but it has six subunits in common with SWI/SNF including a homologous ATPase (reviewed in Bjorklund et al., 1999). In contrast to the SWI/SNF complex, all the subunits of RSC are essential for viability of yeast [Cao, 1997 #84].

Table 1: Chromatin remodeling complexes divided into families based on the similarity of their ATPase subunit (see for review [Kingston, 1999 #85] [Fry, 2001 #55]). The "histone code" hypothesis has been proposed to explain the diversity of chromatin activity in the nucleus. The unstructured N-terminal histone tails extend outside the nucleosome core and are the sites of action for enzymes that catalyze with high specificity their post-translational modification. The most well characterized of these modifications is the acetylation of lysine residues. Acetylation is the result of an equilibrium between two opposing activities: histone acetyl transferase (HAT) and histone deacetylation (HDAC) (for review see [Taddei, 1997 #56]). An in gel electrophoretic protein separation method allowed the identification of the first protein with a histone acetyltransferase activity, HAT A, also called p55 in Tetrahymena [Brownell, 1995 #86]. The characterisation of specific inhibitors such as trapoxine resulted in the purification of the first histone deacetylase, human HDAC1 [Taunton, 1996 #57]. Numerous proteins that play a role in the regulation of transcription have intrinsic histone acetyltransferase activity such as GCN5, PCAF and TAFII250 [Brownell, 1996 #58] [Mizzen, 1996 #59]. Similarly, histone deacetylases have been

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -539- described as components of multi-protein complexes associated with repressive chromatin. Also within these complexes are the Mi-2 family of remodeling factors [Knoepfler, 1999 #61] [Ng, 2000 #60] providing a link between remodelling of nucleosomes and histone deacetylation during chromatin-mediated repression. Very recently it has been proposed that another modification, methylation of histones, plays a functionally important role [Jenuwein, 2001 #35]. The first histone- methyltransferase, called SUV39H1 in human, was only recently discovered [Rea, 2000 #62]. It specifically methylates histone H3 on lysine residue 9 and this methylation modifies the interaction of H3 with heterochromatin associated proteins [Bannister, 2001 #63] [Lachner, 2001 #64]. The two possible modifications (acetylation and methylation) on the same residue (lysine 9) of the N-terminal tail of H3 is a perfect illustration of the "histone code" hypothesis in action. Indeed, acetylated lysine in H3 and H4 N-terminal tail selectively interact with chromodomain present in numerous proteins having intrinsic histone acetyltransferase activity. However, H3 methylated on lysine residue 9 interact specifically with the chromodomain of an heterochromatin associated protein HP1. Therefore, in addition to producing alterations in the overall charge of the histone tails, proposed to physically destabilize the nucleosome, modifications appear to impart specificity to protein:protein interactions with the histones. They are associated with different regions of the genome and are correlated with precise nuclear functions [Strahl, 2000 #19]. Organization of the genome in the nucleus The higher level of compaction of chromatin is not as well characterized. The nucleofilament is compacted to form the 30nm fibre that is organized into folds of 150 to 200 Kbp (250nm during interphase) to obtain a maximum level of compaction in the metaphase chromosome (850nm). At interphase the organization of the genome relies on the structure of chromosomes that have been characterized into different regions based on a specific banding pattern revealed by Giemsa staining [Comings, 1974 #65] [Belyaev, 1996 #66]. The principle bands are G and C bands that are late replicating in S phase and correspond to heterochromatin and the R bands that replicate earlier in S-phase and represent euchromatin. The R bands are enriched in acetylated histones and this modification is conserved through mitosis suggesting that histone acetylation may serve as a marker for the memory of domain organization through the cell cycle [Turner, 1998 #67] [Sadoni, 1999 #68]. The localization of chromosomes in the interphase nucleus by Fluorsecence In Situ Hybridization (FISH) reveals that each chromosome occupies a defined space [Lamond, 1998 #69]. This observation is in accordance with the notion of chromosomal territories proposed, in 1885 by Rabl, for the organization of chromosomes in plants. The Rabl configuration, in which the telomeres are attached to the nuclear envelope beside the nucleus with the centromeres on the other side, has been described in a number of cell types [Marshall, 1997 #70]. However, in mammals, this configuration does not exist and the organization of the chromosomes in the nucleus varies as a function of cell type [He, 1996 #87]. During interphase, regions that correspond to the bands of metaphase chromosomes are located in the nucleus based on the timing of their replication. On the nuclear periphery are the later replicating regions, corresponding to G and C bands and the transcriptionally silent telomeres, while gene rich regions are preferentially localized more internally. Therefore, although each chromosome occupies a different territory, distinct parts of chromosomes can unite to form functional domains [Cockell, 1999 #2] [Croft, 1999 #72]. The localization of coincident and non-coincident regions by FISH suggests that

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -540- genes tend to be localized at the surface of chromosome territories. In the model proposed by Cremer, based on the localization of some genes, transcripts are released into interchromosomal channels, transferred to sites for processing, then exported to the cytoplasm after maturation [Cremer, 1993 #74] (and see for review [Cremer, 2001 #88]). Several studies have led to the proposal that the nucleus is organized into domains [van Holde, 1995 #76] [Lamond, 1998 #69] [Bridger, 1998 #75]. The localization of DNA in these domains is perhaps, in part, a consequence of the activities of chromatin. Targeting proteins might help to bring specialized proteins to specific domains in the nucleus [Sutherland, 2001 #91]. In a hypothetical model, the proteins associated with heterochromatin (for example HP1, Polycomb, Sir3p/Sir4p and ATRX), transcription factors (such as Ikaros) and assembly factors (such as CAF-1) may all be involved in the for establishment and maintenance of nuclear domains.

Table 2: Revised nomenclatrue for the HMG chromosomal proteins From: M. Bustin Trends Biochem Sci. 2001 Mar; 26(3):152-69 References

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -543- 50. Mermoud JE, Costanzi C, Pehrson JR, Brockdorff N. Histone macroH2A1.2 relocates to the inactive X chromosome after initiation and propagation of X- inactivation. Journal of Cell Biology 1999; 147: 1399-408. 51. Mizzen CA, Yang XJ, Kokubo T, et al. The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell 1996; 87: 1261-70. 52. Morris NR. A comparison of the structure of chicken erythrocyte and chicken liver chromatin. Cell 1976; 9: 623-32. 53. Ng H, Bird A. Histone deacetylases: silencers for hire. TIBS 2000; 25: 121- 126. 54. Noll M. Differences and similarities in chromatin structure of Neurospora crassa and higher eucaryotes. Cell 1976; 8: 349-55. 55. Olins AL, Olins DE. Spheroid chromatin units (v bodies). Sciences 1974; 183: 330-332. 56. Oudet P, Gross-Bellard M, Chambon P. Electron microscopic and biochemical evidence that chromatin structure is a repeating unit. Cell 1975; 4: 281-300. 57. Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol 2000; 10: 886-95. 58. Pehrson JR, Fried VA. MacroH2A, a core histone containing a large nonhistone region. Science 1992; 257: 1398-400. 59. Pruss D, Bartholomew B, Persinger J, et al. An asymmetric model for the nucleosome: a binding site for linker histones inside the DNA gyres [see comments]. Science 1996; 274: 614-7. 60. Rea S, Eisenhaber F, O'Carroll D, et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 2000; 406: 593-9. 61. Richmond TJ, Widom J. Nucleosome and chromatin structure. In: Elgin SCRW, J. L., ed. Chromatin Structure and Gene Expression. Oxford: IRL Press, 2000:1-19. 62. Ridgway P, Almouzni G. CAF-1 and the inheritance of chromatin states: at the crossroads of DNA replication and repair. J Cell Sci 2000; 113: 2647-58. 63. Ridgway P, Almouzni G. Chromatin assembly and organization. J Cell Sci 2001; 114: 2711-2. 64. Rogakou EP, Boon C, Redon C, Bonner WM. Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 1999; 146: 905-915. 65. Sadoni N, Langer S, Fauth C, et al. Nuclear organization of mammalian genomes: polar chromosome territories build up functionally distinct higher order compartments. J Cell Biol 1999; 146: 1211-1226. 66. Santisteban MS, Kalashnikova T, Smith MM. Histone H2A.Z regulats transcription and is partially redundant with nucleosome remodeling complexes. Cell 2000; 103: 411-22. 67. Senshu T, Fukuda M, Ohashi M. Preferential association of newly synthesized H3 and H4 histones with newly replicated DNA. J. Biochem. 1978; 84: 985=988. 68. Smith S, Stillman B. Purification and characterization of CAF-I, a human cell factor required for chromatin assembly during DNA replication in vitro. Cell 1989; 58: 15-25. 69. Sobel RE, Cook RG, Perry CA, Annunziato AT, Allis CD. Conservation of deposition-related acetylation sites in newly synthesized histones H3 and H4. Proc Natl Acad Sci USA 1995; 92: 1237-1241.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -544- 70. Spadafora C, Bellard M, Compton JL, Chambon P. The DNA repeat lengths in chromatins from sea urchin sperm and gastrule cells are markedly different. FEBS Letters 1976; 69: 281-5. 71. Strahl BD, Allis DC. The language of covalent histone modifications. Nature 2000; 403: 41-45. 72. Sullivan KF, Hechenberger M, Masri K. Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere. J Cell Biol 1994; 127: 581-92. 73. Sullivan S, Sink DW, Trout KL, et al. The histone database. Nucleic Acids Res 2002; 30: 341-2. 74. Sutherland HG, Mumford GK, Newton K, et al. Large-scale identification of mammalian proteins localized to nuclear sub-compartments. Hum Mol Genet. 2001; 10: 1995-2011. 75. Taddei A, Almouzni G. Histone acetyl-transferases and deacetylases, coregulators of transcription. Med Sci 1997; 13: 1205-1209. 76. Taunton J, Hassig CA, Schreiber SL. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 1996; 272: 408- 11. 77. Thomas JO, Thompson RJ. Variation in chromatin structure in two cell types from the same tissue: a short DNA repeat length in cerebral cortex neurons. Cell 1977; 10: 633-40. 78. Thomas JO. Histone H1: location and role. Curr Opin Cell Biol 1999; 11: 312- 317. 79. Travers A. An engine for nucleosome remodeling. Cell 1999; 96: 311-314. 80. Turner BM. Histone acetylation as an epigenetic determinant of long-term transcriptional competence. Cell Mol Life Sci 1998; 54: 21-31. 81. van Holde K, Zlatanova J. Chromatin higher order structure: chasing a mirage? J Biol Chem 1995; 270: 8373-6. 82. Varga-Weisz PD, Wilm M, Bonte E, Dumas K, Mann M, Becker PB. Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature 1997; 388: 598-602. 83. Williamson R. Properties of rapidly labelled deoxyribonucleic acid fragments isolated from the cytoplasm of primary cultures of embryonic mouse liver cells. J Mol Biol 1970; 51: 157-68. 84. Wolffe AP, Pruss D. Deviant nucleosomes: the functional specialization of chromatin. Trends Genet. 1996; 12: 58-62. 85. Woodcock CL, Dimitrov S. Higher-order structure of chromatin and chromosomes. Curr Opin Genet Dev 2001; 11: 130-5. 86. Worcel A, Han S, Wong ML. Assembly of newly replicated chromatin. Cell 1978; 15: 969-77.

Contributor(s) Written 05- Ridgway P., Maison C. and Almouzni G 2002 Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -545- Ridgway P., Maison C. and Almouzni G., Functional organization of the genome: chromatin. URL : http://www.infobiogen.fr/services/chromcancer/Deep/ChromatinDeep.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -546- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CASE REPORTS in HAEMATOLOGY

Pentasomy 21 as a sole abnormality in an atypical CML patient in chronic phase.

Shambhu K Roy, Sonal R Bakshi, Shailesh J Patel, Pina J Trivedi, Manisha M Brahmbhatt, Shwetal M Rawal, Pankaj M Shah, Devendra D Patel.

Clinics Age and sex : 65 yrs old female patient Previous history : no preleukemia; no previous malignant disease; -no inborn condition of note; Organomegaly : no hepatomegaly; splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 61.8 x 109/l; Hb : 11.5 g/dl; platelets : 348 x 109/l; blasts : 2%; (Myelocyte 13%, Meta Myelocyte 7%, Band cells 7%, P49/E4/B6/L12)% Bone marrow : Increased cellularity/ M:E ratio, Megakaryocytes present, Erythropoiesis normoblastic. Blasts-8%, Promyelocytes-5%, Myelocytes-41%, Metamyelocytes-10%, Band cells-9%, Polymorphs-14%, Eeosinophils-0%, Basophils-1%, Lymphocytes-05%, Monocytes-0%, Pronormoblasts-0%, Early normoblasts-0%, Internormoblasts-2%, Late normoblasts-5%.% Survival Date of diagnosis: March 1999 Treatment : Hydrea Complete remission : None Treatment related death : - Relapse : - Status : Dead Survival : 6 months Karyotype Sample : Bone marrow and Blood; culture time : Overnight; banding : G-banding Results : 49XX,+21, +21, +21. (Pentasomy 21) in all 20 karyotypes (Fig 1). Other molecular studies technics : Whole chromosome painting probe for chromosome 21, and BCR-abl gene

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -547- rearrangement (Vysis, USA). results : Pentasomy confirmed (Fig 2), BCR-abl gene rearrangement was not present (Fig 3).

A G-banded Metaphase showing five copies of chromosome 21 (arrows) as a sole abnormality and the partial karyotype of the metaphase

A DAPI-counterstained metaphase after fluorescence in situ hybridization using FITC-labeled whole chromosome painting probe for chromosome 21 from Vysis, USA

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -548-

A DAPI stained metaphase after fluorescence in situ hybridization using probe for detection of BCR- abl rearrangement from Vysis, USA Comments This is the first report of pentasomy 21 as a sole abnormality in a Philadelphia negative, bcr-abl negative i.e. atypical CML patient. Earlier this was reported in very young patients with; a congenital acute leukemia, a Diamond-Blackfan anemia, a neonatal AML, and acute leukemia patients with Down syndrome. One patient (72- year-old male) with AML without maturation has been reported recently. In majority of the cases pentasomy was due to isochromosome 21. To the best of our knowledge, this is the first case of atypical CML with pentasomy 21. Bibliography Pentasomy 21 characterizing spontaneously regressing congenital acute leukemia. Berghe HVD, Vermaelen K, Orshoven ABV, et al. Cancer Genet Cytogenet 1983; 9: 19-24. Nonrandom chromosomal aberrations and clonal chromosomal evolution in acute leukemia associated with DownÕs syndrome. Wang N, Leung J, Warrier P, et. al. Cancer Genet Cytogenet 1987; 28: 155-162. Pentasomy 21q in a neonatal case of acute myeloblastic leukemia. Brothman AR, Ghosn C, and Werner C. Cancer Genet Cytogenet 1990; 47: 135-137. Pentasomy 21 in leukemia complicating Diamond-Blackfan anemia. Mori PG, Haupt R, Fugazza G, et al. Cancer Genet Cytogenet 1992; 63: 70-72. Conference report. The World Health Organization classification of Harris NL, Jaffe ES, Diebold J, et. al. Histopathology 2000; 6: 69-87. Pentasomy 21 with two isochromosomes 21 in a case of acute myeloid leukemia without maturation. Salido M, Sole F, Espinet B, et. al. Cancer Genet Cytogenet 2002; 132: 71-73.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -549- Contributor(s) Written Shambhu K Roy, Sonal R Bakshi, Shailesh J Patel, Pina J 04- Trivedi, Manisha M Brahmbhatt, Shwetal M Rawal, Pankaj M 2002 Shah, Devendra D Patel. Citation This paper should be referenced as such : Roy SK, Bakshi SR, Patel SJ, Trivedi PJ, Brahmbhatt MM, Rawal SM, Shah PM, Patel DD . Pentasomy 21 as a sole abnormality in an atypical CML patient in chronic phase.. Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://AtlasGeneticsOncology.org/Reports/21CRRoyID100004.html

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Atlas Genet Cytogenet Oncol Haematol 2002; 3 -550- Atlas of Genetics and Cytogenetics in Oncology and Haematology

IMMUNOGLOBULIN GENES: CONCEPT OF DNA REARRANGEMENT * Introduction

I Historical questions

II Answers

II.1 Light chains (kappa or lambda)

II.1.1 Kappa chain: V- J rearrang ements II.1.2 Lambda chain: V- J rearrang ements II.1.3 Allele exclusio n and isotype

II.2 Heavy chains

II.2.1 V-D- J rearrang ements II.2.2 Isotype switchin g

II.3 Membrane and secreted Igs

III Conclusions

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -551- III.1. Germline diversity: multigene families III.2. Diversity due to DNA rearrangements III.3. Diversity as a result of somatic hypermutations * Introduction An immunoglobulin (Ig) consists of 2 identical light chains (L) and 2 identical heavy chains (H) (for example IgG-type); at the three-dimensional level, an Ig chain consists of one N-terminal variable domain, V, and one (for an L chain) or several (for an H chain) C-terminal constant domain(s), C. The cells of the B line synthesize immunoglobulins. They are either produced at a membrane (on the surface of the B-lymphocytes) or are secreted (by the plasmocytes).

See also : IMGT Education - Fig 1

I. Historical questions As soon as the main characteristics of the immunoglobulins were discovered, a number of questions arose: A The antigens are highly varied; to be able to respond to them, the immunoglobulins must be equally diverse (there are 1011 to 1012 different Igs!), which corresponds to the diversity of the amino acids of the N-terminal parts of the L and H chains (i.e. to the variable domains). Does this reflect extreme diversity of the genes responsible for coding the immunoglobulins? (in line with the model of the germline theory: 1 gene = 1 Ig chain; in which case many genes would have to be implicated; they may arise from the

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -552- duplication of ancestral genes; but the entire would not suffice to encode all the immunoglobulins!). Does this reflect an accumulation of mutations? (in line with the model of the theory of somatic mutations: in this case, only a few genes would be implicated, but numerous somatic mutations would then have to take place to produce the diversity of the immunoglobulins produced; however this model would run counter to the generally accepted principles of genetics). Does this reflect a mechanism specific to the immunoglobulin genes? B During its differentiation, a B cell, first produces membrane immunoglobulins on the surface of the B-lymphocyte, and then produces the immunoglobulins secreted by the plasmocyte. The amino acid sequence of the heavy chains of the membrane and secreted Igs differ only at their C-terminal end: are the same genes implicated in both cases? C A B-cell first expresses the IgM at its surface and then, during its differentiation, may express another class of Ig (IgG, IgE or IgA) (this mechanism is known as an isotype switch): how does this switch occur? How can we explain that regardless of the immunoglobulin isotype produced, the same specific antigen variable domain (same idiotype) is expressed? D A B-cell synthesizes a single type of heavy chain and light chain, even though its genome has 2 chromosomes (2 alleles) for each Ig locus; allele exclusion must therefore occur and a hemizygote phenotype is produced; how does this allele exclusion take place? E Finally, if the variable regions do undergo mutations, why aren’t there any in the constant regions? Various methods used in molecular biology and gene cloning in the mouse and in human beings have been used to answer these questions; we will limit our discussion to human immunoglobulins.

II. Answers II.1. Light chains (kappa or lambda)

II.1.1. Kappa chain: V-J rearrangements

IGK (kappa) genes at 2p11 on . Multiple IGKV genes for the variable region, V (76 genes, of which 31 to 35 are functional); 5 IGKJ genes for the junctional region, J; a single IGKC gene for the constant region, C; the V, J and C genes are separated in the DNA of the genome ('germline' configuration of the Ig genes). These are multigene families (also see the section on the families of genes, in Globin genes "... of the duplications of the ancestor gene have succeeded each other, and the mutations of each of the genes have led to some degree of diversity. Many of these duplicated genes are functional ..."). First the DNA is rearranged: this makes it possible to join 1 V and 1 J; the intermediate sequences are then deleted, The pre-messenger RNA is copied (transcription); this includes introns,

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -553- Then comes splicing: the elimination of the introns from the pre-messenger RNA , to yield mature, messenger RNA, This is followed by protein synthesis (known as 'translation'). N.B.: It is crucial not to confuse DNA rearrangements with RNA splicing. NOTE: Only the genes for the immunoglobulins and T-receptors undergo DNA rearrangement.

See also : IMGT Education - Fig 2 V-J rearrangements occur at the recombination signals (RS), which include a heptameric sequence (7 nucleotides) and a nonameric sequence (9 nucleotides), separated by a spacer. Each IGKV gene is followed downstream (in the 3' position) by an RS consisting of a CACAGTG heptamer, and then by a 12-bp spacer, and then an ACAAAAACC nonamer. Each IGKJ gene is preceded upstream (in the 5' position) by an RS consisting, between 5' and 3', of a GGTTTTTGT nonamer, a 23-bp spacer and a CACTGTG heptamer.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -554-

See also: : IMGT Education - Fig 3

II.1.2. Lambda chain: V-J rearrangements

IGL (lambda) genes at the 22q11 position on chromosome 22; the V-J rearrangement mechanism is the same as that described for the IGK genes: the rearrangements take place between one of the 29 to 33 functional IGLV genes and a J gene; it should be noted that there are 4 to 5 functional IGLC genes, each of which is preceded by a IGLJ gene.

II.1.3. Allele exclusion and isotype

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Allele exclusion can be explained in part by the timing of rearrangements, and partly by the surface expression of a functional immunoglobulin, which inhibits the rearrangements and therefore the expression of a second chain. Only one 14 chromosome and one 2 (or 22) chromosome are therefore productive (answer to question D).

II.2. Heavy chains IGH ('heavy') genes at 14q32 on chromosome 14. There are 11 IGHC genes, 9 of which are functional (IGHM, IGHD, IGHG1, IGHG2, IGHG3, IGHG4, IGHA1, IGHA2 and IGHE) and correspond respectively to 9 heavy chain isotypes        and 

II.2.1. V-D-J rearrangements

DNA rearrangements between one of the 38 to 46 functional variable IGHV genes, one of the 23 functional diversity IGHD genes, and one of the 6 functional junction IGHJ genes: there are also some RSs, which are located downstream (in position 3') of the V genes, either side of the D genes and upstream (at 5') of the J genes. During V-D-J rearrangement, a junction is first formed between 1 D and 1 J, and then one between 1 V and the D-J complex.

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See also: IMGT Education - Fig 4 Note: there are also 2 or 3 open reading frames for the D genes; each of which can code for 2 or 3 different peptide sequences. The V-D-J junctions are also characterized by nucleotide deletions (by an exonuclease) and by the random addition of nucleotides (by means of TdT, terminal deoxynucleotidyl transferase); the V regions which result are not, therefore, coded in the genome of the individual and considerably increase the diversity of the V-D-J junctions of the variable domains of the heavy chains of the immunoglobulins.

II.2.2. Isotype switching

In the pre-B lymphocyte, a mu chain is first synthesized, because the constant IGHM gene (CÊ) is located near to the V-D-J rearrangement. This mu chain is associated with the pseudo-light chain and the combination constitutes the pre-B receptor. The first complete Ig synthesized by the B-lymphocyte is an IgM, in which the mu chain is combined with a light kappa or lambda chain. During its differentiation, the B lymphocyte can express some other isotype or sub-isotype of Ig. This involves the replacement of an IGHC gene by another, as the result of DNA recombination (isotype switch), with the excision of the entire intermediate part of a deletion loop. This excision occurs at the switch sequences (role related to that of the RSs). The usual sequence is then as follows: synthesis of pre-messenger RNA, splicing of the introns, resulting in mature RNA, and then protein synthesis. This explains why 1) a B-lymphocyte can at first synthesize an IgM and then, during its differentiation, an IgG (IgG1, IgG2, IgG3 or IgG4), an IgA (IgA1 or IgA2) or an IgE, and 2) that it retains the same V-D-J rearrangement and therefore the same antigen recognition site (idiotype) (answer to question C).

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -557- See also : IMGT Education - Fig 5 and: IMGT Education - Fig 6

II.3. Membrane and secreted Igs Alternative splicing of the pre-messenger RNA of the heavy chain can yield either a membrane heavy chain (membrane Ig of B lymphocytes), or a secreted heavy chain (plasmocyte secreted Ig), which retain the same V-D-J rearrangement (idiotype) and the same constant region (isotype) (answer to question B).

See also : IMGT Education - Fig 7 Note: the same mechanism (alternative splicing of a pre-messenger) expresses the IgMs and IgDs in the same B cell (situation in mature B cells leaving the bone marrow and reach the lymph nodes via the circulation).

III. Conclusions III.1. Germline diversity: multigene families 'Germline' diversity depends on the number of genes at each locus. These are families of genes, offering the possibility of a choice between similar? functional sequences. Possible intergene recombinations permit the long-term evolution of the locus with duplication or deletion of the genes. These genes undergo intragene conversions and recombinations, leading to mixing and diversity (polymorphism) between individuals. The presence of several open reading frames, in the case of IGHD genes, further increases the possibility of choice between similar functional sequences.

III.2. Diversity due to DNA rearrangements Combination diversity - in the mathematical sense of the term - permits the potential synthesis of a million immunoglobulins. The IGH genes permit the synthesis of about 6000 heavy chains, the IGK or IGL genes of about 160 light chains, which is equivalent to about a million possible combinations 6 x 10 3 x 160).

In addition to this, during the rearrangements of the IGH of the heavy chains, the acquisition of the N regions, and using one or other of the reading frames for the D

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -558- genes at the V-D-J junctions, and during the IGK or IGL rearrangements of the light chains, flexibility of the V-J junctions. These mechanisms contribute to increasing the diversity by a factor 103 to 104 (potential synthesis of 109 Ig chains).

III.3.Diversity as a result of somatic hypermutations Finally, somatic mutations are extremely numerous (somatic hypermutations) and produce very targeted characterization of the rearranged V-J and V-D-J genes of the Ig, but their mechanism of onset is not yet known. AID (activation-induced cytidine deaminase) may be implicated both in the occurrence of the mutations and the switch mechanism. The mutations appear during the differentiation of the B lymphocyte in the lymph glands and contribute to increasing the diversity of the Igs by a further factor of 103, which makes it possible to achieve a potential diversity of 1012 different Igs (answer to question A). These different mechanisms of diversity make it possible to obtain 1012 different immunoglobulins, capable of responding to the several million known antigens (answer to question A). The number of different Igs is in fact limited by the number of B cells in a given species.

For further details, see: IMGT Génétique Moléculaire des Immunoglobulines and: The Immunoglobulin FactsBook, MP Lefranc and G Lefranc, Academic Press, 2001. ISBN 0-12-441351-X.

• Contributor(s) Written 03-2002 Marie-Paule Lefranc, Jean-Loup Huret Citation This paper should be referenced as such : Lefranc MP, Huret JL . Immunoglobulin Genes. Atlas Genet Cytogenet Oncol Haematol. March 2002 . URL : http://AtlasGeneticsOncology.org/Educ/PolyIgEng.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -559- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Chromatin: functional organization of the genome

I. Introduction II. The nucleosome III. Histone proteins III.1. Core histones III.2. Linker histones IV. General steps in chromatin assembly V. General steps in chromatin assembly VI. Stimulatory Assembly Factors VI.1. Histone interacting factors VI.2. Remodelling machines and histone-modifying enzymes VII. Organization of the genome in the nucleus Long version French version

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I- Introduction In eukaryotic cells the genetic material is organized into a complex structure composed of DNA and proteins and localized in a specialized compartment, the nucleus. This structure was called chromatin (from the Greek "khroma" meaning coloured and "soma" meaning body). Close to two meters of DNA in each cell must be assembled into a small nucleus of some m in diameter. Despite this enormous degree of compaction, DNA must be rapidly accessible to permit its interaction with protein machineries that regulate the functions of chromatin: replication, repair and recombination. The dynamic organization of chromatin structure thereby influences, potentially, all functions of the genome. The fundamental unit of chromatin, termed the nucleosome, is composed of DNA and histone proteins. This structure provides the first level of compaction of DNA into the nucleus. Nucleosomes are regularly spaced along the genome to form a nucleofilament which can adopt higher levels of compaction (Fig 1 and 3), ultimately resulting in the highly condensed metaphase chromosome. Within an interphase nucleus chromatin is organized into functional territories. Chromatin has been divided into:

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -560- • euchromatin and • heterochromatin.

Heterochromatin was defined as a structure that does not alter in its condensation throughout the cell cycle whereas euchromatin is decondensed during interphase. Heterochromatin is localized principally on the periphery of the nucleus and euchromatin in the interior of the nucleoplasm. We can distinguish:

• constitutive heterochromatin, containing few genes and formed principally of repetitive sequences located in large regions coincident with centromeres and telomeres, from • facultative heterochromatin composed of transcriptionally active regions that can adopt the structural and functional characteristics of heterochromatin, such as the inactive X chromosome of mammals.

In this review we will define the components of chromatin and outline the different levels of its organization from the nucleosome to domains in the nucleus. We will discuss how variation in the basic constituents of chromatin can impact on its activity and how stimulatory factors play a critical role in imparting diversity to this dynamic structure. Finally we will summarize how chromatin influences the organization of the genome at the level of the nucleus.

II- The nucleosome The partial digestion of DNA assembled into chromatin, generated fragments of 180- 200 base pairs in length which were resolved by electrophoretic migration. This regularity of chromatin structure was later confirmed by electron microscope analysis that revealed chromatin as regularly spaced particles or "beads on a string". The stoichiometry of DNA and histones in the nucleosome was found to be 1/1 based on their mass. The nucleosome is the fundamental unit of chromatin. It is composed of:

• a core particle and • a linker region (or internucleosomal region) that joins adjacent core particles (Fig 1).

The core particle is highly conserved between species and is composed of 146 base pairs of DNA wrapped 1.7 turns around a protein octamer of two each of the core histones H3, H4, H2A and H2B. The length of the linker region, however, varies between species and cell type. It is within this region that the variable linker histones are incorporated. Therefore, the total length of DNA in the nucleosome can vary with species from 160 to 241 base pairs. Analyses revealed, firstly, the distortion of the DNA wound around the histone octamer and, secondly, that the histone/DNA and histone/histone interactions through their "histone fold domain" formed a configuration remniscent of a hand shake.

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Figure 1. Defining elements of nucleosomes and chromatosome III- Histone proteins III-1. Core histones The core histones, H3, H4, H2A and H2B, are small, basic proteins highly conserved in evolution (Figure 2). The most conserved region of these histones is their central domain structurally composed of the "histone fold domain" consisting of three a- helicies separated by two loop regions. In contrast, the N-terminal tails of each core histone is more variable and unstructured. The tails are particularily rich in lysine and arginine residues making them extremely basic. This region is the site of numerous post-translational modifications that are proposed to modify its charge and thereby alter DNA accessibility and protein/protein interactions with the nucleosome. It is significant to note that other proteins that interact with DNA also contain the "histone fold domain" Figure 2. The core histones. A. Structure of nucleosomal histones. B. Amino-terminal tails of core histones. The numbers indicate amino acid position. The post-translational modifications are indicated (red ac = acetylation sites ; blue p = phosphorylation sites ; green m = methylation sites ; purple rib = ADP ribosylation).

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III-2. Linker histones Linker histones associate with the linker region of DNA between two nucleosome cores and, unlike the core histones, they are not well conserved between species. In higher eukaryotes, they are composed of three domains: a globular, non-polar central domain essential for interactions with DNA and two non-structured N- and C- terminal tails that are highly basic and proposed to be the site of post translational modifications. The linker histones have a role in spacing nucleosomes and can modulate higher order compaction by providing an interaction region between adjacent nucleosomes. IV- General steps in chromatin assembly The assembly of DNA into chromatin involves a range of events, beginning with the formation of the basic unit, the nucleosome, and ultimately giving rise to a complex organization of specific domains within the nucleus. This step-wise assembly is described schematically in Fig 3. The first step is the deposition onto the DNA of a tetramer of newly synthesized (H3-H4)2 to form a sub-nucleosomal particle, which is followed by the addition of two H2A-H2B dimers. This produces a nucleosomal core particle consisting of 146 base pairs of DNA wound around the histone octamer. This core particle and the linker DNA together form the nucleosome. Newly synthesized histones are specifically modified (e.g.the acetylation of histone H4). The next step is the maturation step that requires ATP to establish regular spacing of the nucleosome cores to form the nucleofilament. During this step the newly incorporated histones are de-acetylated. Next the incorporation of linker histones is accompanied by folding of the nucleofilament into the 30nm fibre, the structure of which remains to be elucidated. Two principal models exist : the solenoid model and the zig zag. Finally, further successive folding events lead to a high level of organization and specific domains in the nucleus.

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -563- At each of the steps described above, variation in the composition and activity of chromatin can be obtained by modifying its basic constituents and the activity of stimulatory factors implicated in the processes of its assembly and disassembly.

Figure 3. General steps in chromatin assembly. Assembly begins with the incorporation of the H3/H4 tetramer (1), followed by the addition of two H2A-H2B dimers (2) to form a core particle. The newly synthesized histones utilized are specifically modified; typically, histone H4 is acetylated at Lys5 and Lys12 (H3-H4*). Maturation requires ATP to establish a regular spacing, and histones are de-acetylated (3). The incorporation of linker histones is accompanied by folding of the nucleofilament. Here the model presents a solenoid structure in which there are six nucleosomes per gyre (4). Further folding events lead ultimately to a defined domain organization within the nucleus (5). V- Variation in basic constituents

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -564- In the first steps of chromatin assembly, the elementary particle can assume variations:

• at the level of DNA (for example by methylation) or • at the histone level by differential post-translational modification and the incorporation of variant forms (for example CENP-A, a variant of H3).

All of these variations are capable of introducing differences in the structure and activity of chromatin. The vast array of post-translational modifications of the histone tails summarized in Fig 2 (such as acetylation, phosphorylation, methylation, ubiquitination, polyADP-ribosylation), and their association with specific biological processes has led to a proposed hypothesis of a language, refered to as the "histone code", that marks genomic regions (It must be emphasized that this code is a working hypothesis)). The code is "read"by other proteins or protein complexes that are capable of understanding and interpreting the profiles of specific modifications. The incorporation of histone variants may be important at specific domains of the genome: in this context, CENP-A, a variant of histone H3 is associated with silent centromeric regions and macro H2A on the inactive X chromosome of female mammals. H2A-X is implicated in the formation of foci containing DNA repair factors in the regions of DNA double-strand breaks. Growing evidence exists that H2A.Z has a role in modifying chromatin structure to regulate transcription. During the maturation step, incorporation of linker histones, non-histone chromatin associated proteins, called HMG (High Mobility Group), and other specific DNA- binding factors help to space and fold the nucleofilament. Therefore the early steps in assembly can have a great impact on the final characteristics of chromatin in specific nuclear domains.

VI- Stimulatory Assembly Factors VI-1. Histone interacting factors Acidic factors can form complexes with histones and enhance the process of histone deposition. They act as histone chaperones by facilitating the formation of nucleosome cores without being part of the final reaction product. These histone- interacting factors, also called chromatin-assembly factors, can bind preferentially to a subset of histone proteins. For instance, Chromatin Assembly Factor-1 (CAF-1) interacts with newly synthesized acetylated histones H3 and H4 to preferentialy assemble chromatin during DNA replication. CAF-1 is also capable of promoting the assembly of chromatin specifically coupled to the repair of DNA. The recent demonstration of the interaction of CAF-1 with the protein PCNA (Proliferating Cell Nuclear Antigen) established a molecular link between the assembly of chromatin and the processes of replication and repair of DNA. The assembly of specialized structures in centromeric regions, by deposition of variant histones such as CENP-A, or telomeres may be a result of the specificity and the diversity of as yet uncharacterised histone chaperones.

VI-2. Remodelling machines and histone-modifying enzymes Stimulatory factors also act during the chromatin maturation stage to organize and maintain a defined chromatin state. Their effects on chromatin can induce changes in conformation at the level of the nucleosome or more globally over large chromatin domains. These factors are of two types; one requiring energy in the form of ATP,

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -565- generally refered to as chromatin remodelling machines, and the other that act as enzymes to post-translationally modify histones. Chromatin remodelling machines: are multi-protein complexes (SWI/SNF, ISWI, Mi2/NuRD families).The activity of the ATPase permits the complex to modify nucleosomal structure, driven by the liberation of energy during the hydrolysis of ATP. The study of factors that stimulate the regular arrangement of nucleosomes during the assembly of chromatin led to the identification of several multi-protein complexes, capable in vitro of "sliding" nucleosomes along DNA. The common feature of these chromatin remodelling factors is their large size and multiple protein subunits including the ATPase, however, they display differences in abundance and activity. post-translational modifications: the "histone code" hypothesis has been proposed to explain the diversity of chromatin activity in the nucleus. The unstructured N- terminal histone tails extend outside the nucleosome core and are the sites of action for enzymes that catalyze with high specificity their post-translational modification. The most well characterized of these modifications is the acetylation of lysine residues. Acetylation is the result of an equilibrium between two opposing activities: histone acetyl transferase (HAT) and histone deacetylation (HDAC) (e.g. HAT A, with a histone acetyltransferase activity and HDAC1, a histone deacetylase). Numerous proteins that play a role in the regulation of transcription have intrinsic histone acetyltransferase activity. Similarly, histone deacetylases have been described as components of multi-protein complexes associated with repressive chromatin. Also within these complexes are the Mi-2 family of remodeling factors providing a link between remodelling of nucleosomes and histone deacetylation during chromatin- mediated repression. Methylation of histones plays a functionally important role. A histone- methyltransferase specifically methylates histone H3 on lysine residue 9 and this methylation modifies the interaction of H3 with heterochromatin associated proteins. The two possible modifications (acetylation and methylation) on the same residue (lysine 9) of the N-terminal tail of H3 is a perfect illustration of the "histone code" hypothesis in action. Indeed, acetylated lysine in H3 and H4 N-terminal tail selectively interact with chromodomain present in numerous proteins having intrinsic histone acetyltransferase activity. However, H3 methylated on lysine residue 9 interact specifically with the chromodomain of an heterochromatin associated protein HP1. Therefore, in addition to producing alterations in the overall charge of the histone tails, proposed to physically destabilize the nucleosome, modifications appear to impart specificity to protein:protein interactions with the histones. They are associated with different regions of the genome and are correlated with precise nuclear functions. VII- Organization of the genome in the nucleus The higher level of compaction of chromatin is not as well characterized. The nucleofilament is compacted to form the 30nm fibre that is organized into folds of 150 to 200 Kbp (250nm during interphase) to obtain a maximum level of compaction in the metaphase chromosome (850nm). At interphase the organization of the genome relies on the structure of chromosomes that have been characterized into different regions based on a specific banding pattern. The principle bands are:

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -566- • G and C bands that are late replicating in S phase and correspond to heterochromatin and the • R bands that replicate earlier in S-phase and represent euchromatin. The R bands are enriched in acetylated histones and this modification is conserved through mitosis suggesting that histone acetylation may serve as a marker for the memory of domain organization through the cell cycle.

The localization of chromosomes in the interphase nucleus reveals that each chromosome occupies a defined space. In mammals, the organization of the chromosomes in the nucleus varies as a function of cell type. During interphase, regions that correspond to the bands of metaphase chromosomes are located in the nucleus based on the timing of their replication:

• on the nuclear periphery are the later replicating regions, corresponding to G and C bands and the transcriptionally silent telomeres, while • gene rich regions are preferentially localized more internally.

Therefore, although each chromosome occupies a different territory, distinct parts of chromosomes can unite to form functional domains. The localization of coincident and non-coincident regions by FISH suggests that genes tend to be localized at the surface of chromosome territories. In the model based on the localization of some genes, transcripts are released into interchromosomal channels, transferred to sites for processing, then exported to the cytoplasm after maturation. Several studies have led to the proposal that the nucleus is organized into domains. The localization of DNA in these domains is perhaps, in part, a consequence of the activities of chromatin. Targeting proteins might help to bring specialized proteins to specific domains in the nucleus. In a hypothetical model, the proteins associated with heterochromatin (for example HP1, Polycomb, Sir3p/Sir4p and ATRX), transcription factors (such as Ikaros) and assembly factors (such as CAF-1) may all be involved in the for establishment and maintenance of nuclear domains.

Table Revised nomenclature for the HMG chromosomal proteins List of Abbreviations ATP: adenosine triphosphate C-terminal: carboxy-terminal CAF-1: Chromatin Assembly Factor-1 CENP-A: CENtromere Protein-A HAT: Histone Acetyl Transferase HDAC: Histone DeACetylase HMG: High Mobility Group HP1: Heterochromatin Protein 1 N-terminal: amino-terminal

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -567- PCNA: Proliferating Cell Nuclear Antigen SWI/SNF: mating type SWItching/Sucrose Non-Fermenting

List of Definitions Chromatin: is the carrier of genetic information. It is a complex structure composed of DNA and proteins and localized in the cellular nucleus. Chromatin remodeling machines: require energy in the form of ATP and induce changes in conformation at the level of the nucleosome or more globally over large chromatin domains. Constitutive heterochromatin: is formed principally of repetitive sequences and contains few genes. It is usually located in large regions coincident to centromeres and telomeres. Euchromatin: represents chromatin that is decondensed during interphase. Facultative heterochromatin: is composed of transcriptionally active regions that can adopt the structural and functional characteristics of heterochromatin. G, C and R bands: correspond to the metaphase chromosome organization in bands. Heterochromatin: represents a condensed form of chromatin that does not alter in its condensation throughout the cell cycle. Histone chaperones: are acidic factors that can form complexes with histones and enhance the process of histone deposition. They act as histone chaperones by facilitating the formation of nucleosome cores without being part of the final reaction product. Histone code: is the hypothesis of a language linked to the vast array of post- translational modifications to the histone tails and their association in specific biological activities. The functional significance of the interplay between these modified histones is the subject of intense investigation. This code is "read" by other proteins or protein complexes that are capable of understanding and interpreting the profiles of specific modifications. HMG (High Mobility Group) proteins: are non-histone chromatin associated proteins. These DNA-binding proteins can help to space and fold the nucleofilament. Nucleosome: is the fundamental unit of chromatin. It is composed of DNA and histone proteins. It provides the first level of compaction of DNA into the nucleus.

• Contributor(s) Written 04-2002 Patricia Ridgway, Christèle Maison, Geneviève Almouzni Citation This paper should be referenced as such : Ridgway P, Maison C, Almouzni G . Chromatin. Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://AtlasGeneticsOncology.org/Educ/ChromatinEducEng.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -568- Atlas of Genetics and Cytogenetics in Oncology and Haematology

SELECTION

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I- Introduction

II- Modeling and selective values

III- Basic model

IV- Equation of the recurrence of allele frequencies

V- Change in the selective values

VI- Change in populations

VI- 1. Homozygote A1A1 is the most advantaged; VI- 2. Homozygote A1A1 is the most disadvantaged; VI- 3. Heterozygote A1A2 is the most advantaged; VI- 4. Heterozygote A1A2 is the most disadvantaged;

VII- Conclusions

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I- Introduction We are going to consider a panmictic population, sufficiently large for the allele frequencies to be unaffected by any factor other than selection. We will also assume that the impact of selective factors remains constant over the generations, and that there is no overlapping of generations. In this population, let us assume that gene A is present in 2 allele forms, A1 and A2, of which the frequencies in generation n are p and q respectively. NB: in the context of selection involving only the haploid phase, it can be shown that the allele that confers the greatest advantage on the gametes carrying it will establish itself in the population. In this straightforward situation, selection during the haploid

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -569- phase will not be sufficient to preserve genetic polymorphism. We will see that the situation is different if selection occurs during the diploid phase; and this is what we are going to look at.

II- Modeling and selective values Many studies have attempted to model the effects of natural selection on changes in allele frequencies over the generations. The basic parameter used to quantify the effect of selection is known as the selective value (or "adaptative value") of the phenotype (Darwinian fitness), and it is conventionally represented as w. In practice, the phenotype and genotype are linked by the rules of genetic determinism, and the genotype is directly linked to the selective value of the phenotype that it determines. We shall also be discussing the selective values of the various genotypes. So, in the case of a diallele autosomal locus….

In the simplest model that we are going to consider here, these values represent all the constituents of the selective value of each genotype for the pre-reproductive period: embryonic survival, larval or juvenile survival …). This corresponds to the mean number of descendants contributed to the next generation by each of the genotypes. Only the situation in which the selection operates between fertilization and the moment when the product of fertilization itself reaches the age of reproduction is considered here; this component of selection is the viability (v). according to this model, all the mature individuals have the same reproductive potential, and contribute the same mean number of descendants (f) to the next generation. An individual with a survival probability of vi therefore contributes vi.f descendants to the next generation. Many different components can contribute to the selective value of an individual, but it is the global effect that is taken into consideration by these models. In the end, the selective value depends on the probability of survival of the genotype concerned and on its fecundity. The Table below shows how the selective values can be estimated if we know the number of descendants of each genotype.

In practice, it is often the ratio between these values that is what matters for the change in allele frequencies. In this case, what is used is the relative selective values, calculated by relating the absolute values to the "best" value of the genotype,

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -570- hence here w1 = 1, w2 = 0,9, w3 = 0,75. It should also be noted that it is possible to express these values either as a difference from value 1, or in the form w = 1-s. In this case, the parameter s is known as the selective coefficient. In the example below, we therefore have w1 = 1, w2 = 1-s (with s = 0,1), w3 = 1 — t (with t = 0,25) III- Basic model

We will consider a panmictic population, of infinite size, with non-overlapping generations, and which is not affected by any factors for evolutionary change other than selection. It is assumed that the effect of the selective factors remains constant over time (constant selective values model), and that these factors only affect the survival of individuals between the zygote stage and the reproductive adult stage. This basic model, therefore excludes selective differences that could involve various possible crosses between individuals of different genotypes. It can be seen that if the three selective values are equal to one another, in terms of their relative values w1 = w2 = w3, there is no selection differential, and the model corresponds to the Hardy-Weinberg model. In this population, let us assume that a gene A exists in 2 allele forms, A1 and A2, of which the frequencies in generation n are p and q respectively. In the simplest situation, it is only the probabilities of survival of the genotypes that differ. In this case, how will the allele frequencies evolve? IV- Equation of the recurrence of allele frequencies between two successive generations The Table below summarizes the steps in the calculation, showing the values of the genotype frequencies before and after selection.

2 2 Still: W = w1p + 2w2pq + w3q

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -571- W corresponds to the mean selective value of the population. It is proportional to the mean number of descendants contributed by a given individual to the nith generation. This is the weighted mean of the selective values of the different genotypes. This is an important value that will crop up again.

V- Change in the selective values between two successive generations Another important value for studying selection if the change in allele frequencies between two successive generations: p = p’- p, where p is the frequency of allele A1 in the nith generation. The sign of p tells us whether the frequency of allele A1 has increased, decreased or remained the same. If it has remained the same, then we are in a situation of steady-state (or equilibrium). p can be expressed as follows:

However, 1 — p = q and 1 — 2 p = q — p And hence we can deduce:

VI- Change in populations subjected to the effects of selection We will now look at how p and q evolve, towards what W tends, and what is the sign of p in the 4 fundamental situations: Homozygote A1A1 is the most advantaged w1 > w2 > w3 Homozygote A1A1 is the most disadvantaged w1 < w2 < w3 Heterozygote A1 is the most advantaged w2 > (w1; w3) Heterozygote A1 is the most disadvantaged w2 < (w1; w3) VI-1. Homozygote A1A1 is the most advantaged w1 > w2 > w3 p = pq/W [(w1 - w2) p + (w2 - w3)q] Note: w1 - w2 > 0 et w2 - w3 > 0 ---> p > 0 regardless of the values of p and q --> establishment of the allele A1 Outcome of a simulation, where: w1 = 1, w2 = 0.9, w3 = 0.3:

Atlas Genet Cytogenet Oncol Haematol 2002; 3 -572-

p = f (n) with the situation of the six different frequencies of p in the 0 generation The frequency of allele A1 always increases and tends towards 1.

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The maximum value of W tends towards 1

p is always within the range [ 0 ; 1 ] If the homozygote A1A1 is the most advantaged genotype, allele A1 becomes established in the population, and allele A2 is eliminated. VI-2. Homozygote A1A1 is the most disadvantaged: w1 < w2 < w3

p = pq/W [(w1 - w2) p + (w2 - w3)q] Note: w1 - w2 < 0 et w2 - w3 < 0 ---> p < 0, regardless of the values of p and q --> establishment of the allele A2 Outcome of a simulation, where: w1 = 0.6, w2 = 0.9, w3 = 1:

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p = f (n) with the situation of the six different frequencies of p in the 0 generation If homozygote A1A1 is the most disadvantaged, the frequency of allele A1 always falls and tends towards 0

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Point p = 0 et q = 1 is an equilibrium point known as "trivial", the value of W is maximum at the equilibrium point.

p is alwaysnegative over the range [ 0 ; 1] VI-3. Heterozygote A1A2 is the most advantaged w2 > (w1; w3) p = pq/W [(w1 - w2) p + (w2 - w3)q] Note: w1 - w2 < 0 ---> p > 0 from 0 to equilibrium p w2 - w3 > 0 ---> p < 0 from equilibrium p to 1 --> Genetic polymorphism conserved / Stable equilibrium Outcome of a simulation, where: w1 = 0.9, w2 = 1, w3 = 0.95:

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p = f (n) with the situation of the six different frequencies of p in the 0 generation When the heterozygote genotype A1A2 is more advantaged than either of the homozygotes, the population tends towards a state of stable, polymorphic equilibrium (and both the A1 and A2 alleles are conserved). p at equilibrium corresponds to (w3 — w2)/(w1-2w2+w3) = 0.33

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The equilibrium frequency of allele A1(0.33) corresponds to a maximum value of W. W equilibrium = W1 p2 equilibrium + 2 W2 p q equilibrium + W3 q2 equilibrium = 0.966 Obviously, it is for this value that p is zero In the range [ 0 ; 1 ].

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VI-4. Heterozygote A1A2 is the most disadvantaged: w2 < (w1; w3) p = pq/W [(w1 - w2) p + (w2 - w3)q]

Note: w1 - w2 > 0 ---> p < 0 from 0 to p equilibrium w2 - w3 <0 ---> p > 0 from p equilibrium to 1 --> so either allele A1 or allele A2 will become established: Unstable equilibrium Outcome of a simulation, where: w1 = 0.9, w2 = 0.8, w3 = 1:

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p = f (n) with the situation of the six different frequencies of p in the 0 generation When the heterozygote genotype is the most disadvantaged of all the genotypes, the population tends to fix either allele A1, or allele A2. There is a specific point, the equilibrium point p, where p is cancelled out in the range [ 0 ;1] .

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This is an unstable equilibrium point, which cannot actually exist unless the population is infinite in size. In a real population, random variations of p will be observed.

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VII- Conclusions In the model of selection with constant selective values, the population always develops towards a situation in which W is a maximum. This is a characteristic of the "fundamental theory " of natural selection. However, it is only exactly true in this model. Despite this, in general, natural selection tends to maximize the mean number of descendants of the population. If there are different constraints (as, for instance, in the model with variable selective values), it may simply tend towards an optimum close to, but less than the highest value of W.

• Contributor(s) Written 04-2002 Robert Kalmes Citation This paper should be referenced as such : Kalmes R . Selection. Atlas Genet Cytogenet Oncol Haematol. April 2002 . URL : http://AtlasGeneticsOncology.org/Educ/SelectionID30040ES.html

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