Atlas Journal

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 7, Number 3, Jul-Sep 2003 Previous Issue / Next Issue Genes EVI1 Ecotropic Viral Integration 1 Site (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1 (3q26.2). Soumen Chakraborty, Silvia Buonamici, Vitalyi Senyuk, Giuseppina Nucifora. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 337-343. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/EVI103q26ID19.html MARK4 (MAP/microtubule affinity-regulating kinase 4) (19q13.2). Alessandro Beghini. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 344-349. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MARK4ID419.html AF5q31 (ALL1 fused gene from chromosome 5q31) (5q31) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 350-353. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/AF5q31ID230.html ALEX1 (arm protein lost in epithelial cancers, X chromosome, 1) (Xq22.1). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 354-356. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ALEX1Xq22ID477.html ALEX2 (arm protein lost in epithelial cancers, X chromosome, 2) (Xq22.1). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 357-359. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ALEX2Xq22ID478.html ALEX3 (arm protein lost in epithelial cancers, X chromosome, 3) (Xq22.1). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 360-362. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 I URL : http://AtlasGeneticsOncology.org/Genes/ALEX3Xq22ID479.html CAGE-1 (cancer-associated gene-1) (6p24.3). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 363-365. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CAG1ID475.html MAML2 (mastermind-like 2) (11q21-22). Goran Stenman. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 366-369. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MAML2ID472.html MDS2 (1p36). Jean-Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 370-372. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MDS2ID476.html MECT1 (mucoepidermoid carcinoma translocated 1) (19p13). Goran Stenman. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 373-375. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MECT1ID471.html TCF12 (transcription factor 12) (15q21). Goran Stenman. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 376-381. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TCF12ID406.html NR4A3 (nuclear receptor subfamily 4, group A, member 3) (9q22). Goran Stenman. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 382-387. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TECID75.html Leukaemias dic(9;12)(p13;p13) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 388-391. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/dic0912.html ins(5;11)(q31;q13q23) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 392-393. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/ins511ID1167.html t(1;21)(p32;q22). Charles D. Bangs. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 394-396. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 II URL : http://AtlasGeneticsOncology.org/Anomalies/t0121p32q22ID1259.html + 19 or trisomy 19. Edmond SK Ma, Thomas SK Wan. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 397-398. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/tri19ID1039.html t(1;12)(p36;p13). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 399-400. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0112p36p13ID1170.html t(X;10)(p10;p10). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 401-402. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0X10p10p10ID1256.html Solid Tumours Bone: Chondroma. Roberta Vanni. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 403-407. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/ChondromaID5147.html Thyroid: Anaplastic (undifferentiated) carcinoma. Oluwole Fadare, Giovanni Tallini. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 408-411. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/AnaCarciThyroidID5069.html Bone: Giant cell tumour. Ramses G Forsyth, Pancras CW Hogendoorn. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 412-417. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/BoneGiantCellTumID5150.html Thyroid: Oncocytic tumors. Oluwole Fadare, Giovanni Tallini. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 418-423. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/OncocytThyroidID5068.html Kidney: Renal cell carcinoma. Eva van den Berg, Stephan Storkel. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 424-431. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/RenalCellCarcinID5021.html Bone: Chondroblastoma. Salvatore Romeo, Pancras CW Hogendoorn. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 432-437. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 III URL : http://AtlasGeneticsOncology.org/Tumors/ChondroblastomaID5148.html Bone: Chondromyxoid fibroma. Salvatore Romeo, Pancras CW Hogendoorn. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 438-441. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/ChondroMyxoidFibID5149.html Smooth muscle: Intravenous leiomyomatosis. Paola Dal Cin. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 442-443. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/IntravLeiomyomID5158.html Cancer Prone Diseases Deep Insights Case Reports A new case of t(8;14)(q11;q32) in an acute lymphoblastic leukemia. Benoit Quilichini, Helene Zattara, François Casalonga, Laure-Anne Bastide-Alliez, Catherine Curtillet, Chantal Fossat, Gérard Michel.. Atlas Genet Cytogenet Oncol Haematol 2003; 7 (3): 444-447. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/814QuilichiniID100007.html Educational Items

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Atlas Genet Cytogenet Oncol Haematol 2003; 3 IV Atlas of Genetics and Cytogenetics in Oncology and Haematology

EVI1 Ecotropic Viral Integration 1 Site (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1

Identity Other PRDM3 names Hugo EVI1 Location 3q26.2 DNA/RNA

Description EVI1 spans over 100 kb and contains 12 exons with alternative untranslated exons 1a and 1b. Of 12 exons, ten are coding exons. MDS1 is a small gene, 300-400 kb upstream of the first exon of EVI1. MDS1-EVI1 results from the splicing of the second exon of MDS1 to the second exon of EVI1. Transcription Telomere to centromere. Protein

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Description EVI1 has 1051 amino acids and is a 145-kDa DNA binding protein. It contains two domains of seven and three sets of repeats of the zinc finger motif, a repression domain between the two sets of zinc fingers, and an acidic domain at the C-terminal end. Predicted translation of MDS1-EVI1 adds 188 amino acids upstream of the start site of EVI1 in the third exon, of which 63 amino acids are derived from the untranslated second exon and from the untranslated part of the third exon of EVI1, and remaining 125 amino acids are from the MDS1 gene. MDS1-EVI1 contains the PR domain that is about 40% homologous to the N-terminus of retinoblastoma-binding protein, RIZ and the PRDI-BF1 transcription factor. Expression In the mouse embryo EVI1 is expressed at high level in the urinary system and Mullerian ducts, in the lung, and in the heart, but at low level in most of the adult tissues. In humans, EVI1 is expressed abundantly in kidney, lung, pancreas and ovaries, and to a lesser extent in several other tissues, including skeletal muscle. The pattern of expression of MDS1-EVI1 in adult tissues is identical to that of EVI1. Localisation Nuclear. Function Because of the spatial and temporal restricted pattern of expression of EVI1, it is suggested that this gene plays an important role in mouse development and could be involved in organogenesis, cell migration, cell growth, and differentiation. Homology The human EVI1 is highly homologous to the murine gene and shows 91% and 94% homology in nucleotide or amino acid sequence respectively. MDS1-EVI1 shares an overall homology with the C. elegans Egl 43 protein that includes the PR domain at the N-terminus and the two zinc-finger domains. Implicated in Entity t(3;3)(q21;q26) or inv(3)(q21q26) Note Syndrome 3q21q26. The EVI1 gene can be activated in

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -338- haematopoietic cells by chromosomal rearrangements either in the 5¹ of the gene by t(3;3)(q21;q26) or in the 3¹ of the gene by inv(3)(q21q26). Both these rearrangements juxtaposed the enhancer of the constitutively expressed housekeeping gene ribophorin 1 at 3q21 to the coding region of EVI1. Disease Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome (MDS), and Chronic Myelogenous Leukemia (CML). Prognosis Patients with 3q26 EVI1 rearrangement have elevated platelet counts, marked hyperplasia with dysplasia of megakaryocytes, and poor prognosis. Cytogenetics Rearrangements at 3q26 often occur with monosomy of chromosome 7 or deletion of the long arm of chromosome 7, and, less frequently, deletion in chromosome 5. Oncogenesis Inappropriate expression of the EVI1 in haematopoietic cells alters the terminal differentiation of bone marrow progenitor cells to granulocytes, erythrocytes and megakaryocytes.

Entity t(3;21)(q26;q22) Disease Therapy-related MDS/AML and CML during the blast crisis. Prognosis Poor. Cytogenetics Complex Abnormal AML1 -MDS1-EVI1 Protein Oncogenesis Chimeric transcription factor with the dual functions of AML1 and MDS1-EVI1.

Entity t(3;12)(q26;p13) Note The amino terminus of the ETS protein TEL is fused not in frame to EVI1. In the patients with t(3;12)(q26;p13) over expression of the EVI1 gene is driven by the TEL promoter. Disease CML during the blast crisis and MDS in transformation. Prognosis Poor. Cytogenetics Complex.

Breakpoints

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Note Other chromosomal rearrangements that results in the inappropriate expression of EVI1 include t(2;3)(p13;q26), t(2;3)(q23;q26), t(3;7)(q27;q22), t(3;13)(q26;q13-14), and t(3;17)(q26;q22). External links Nomenclature Hugo EVI1 GDB EVI1 Entrez_Gene EVI1 2122 ecotropic viral integration site 1 Cards Atlas EVI103q26ID19 GeneCards EVI1 Ensembl EVI1 CancerGene EVI1 Genatlas EVI1 GeneLynx EVI1 eGenome EVI1 euGene 2122 Genomic and cartography EVI1 - 3q26.2 chr3:170285252-170346795 - 3q26.2 (hg17- GoldenPath May_2004) Ensembl EVI1 - 3q26.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene EVI1 Gene and transcription

Genbank AF164155 [ SRS ] AF164155 [ ENTREZ ]

Genbank AF164156 [ SRS ] AF164156 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -340- Genbank AF164157 [ SRS ] AF164157 [ ENTREZ ]

Genbank AF487422 [ SRS ] AF487422 [ ENTREZ ]

Genbank AF487423 [ SRS ] AF487423 [ ENTREZ ]

RefSeq NM_005241 [ SRS ] NM_005241 [ ENTREZ ]

RefSeq NT_086642 [ SRS ] NT_086642 [ ENTREZ ] AceView EVI1 AceView - NCBI TRASER EVI1 Traser - Stanford

Unigene Hs.165830 [ SRS ] Hs.165830 [ NCBI ] HS165830 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q03112 [ SRS] Q03112 [ EXPASY ] Q03112 [ 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 Q03112 Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ]

Smart SM00355 ZnF_C2H2 [EMBL]

Prodom PD000003 Znf_C2H2[INRA-Toulouse] Prodom Q03112 EVI1_HUMAN [ Domain structure ] Q03112 EVI1_HUMAN [ sequences sharing at least 1 domain ] Blocks Q03112 Polymorphism : SNP, mutations, diseases OMIM 165215 [ map ] GENECLINICS 165215

SNP EVI1 [dbSNP-NCBI]

SNP NM_005241 [SNP-NCI]

SNP EVI1 [GeneSNPs - Utah] EVI1 [SNP - CSHL] EVI1] [HGBASE - SRS] General knowledge Family EVI1 [UCSC Family Browser] Browser SOURCE NM_005241 SMD Hs.165830 SAGE Hs.165830 Amigo function|DNA binding Amigo process|development Amigo component|nucleus Amigo component|nucleus Amigo function|zinc ion binding

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -341- PubGene EVI1 Other databases Probes Probe EVI1 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography Retroviral activation of a novel gene encoding a zinc finger protein in IL-3 dependent myeloid leukemia cell lines. Morishita K, Parkar DS, Mucenski ML, Jenkins NA, Copeland NG, Ihle JN. Cell 1988; 54: 831-840. Medline 2842066

Unique expression of the Evi-1 gene in an endrometrial carcinoma cell line: sequence of cDNAs and structure of alternatively spliced transcripts. Morshita K, Parganas E, Douglass EC, Ihle JN. Oncogene 1990; 5: 963-971. Medline 2115646

Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Nucifora G, Birn DJ, Espinosa R 3rd, Erickson P, LeBeau MM, Roulston D, McKeithan TW, Drabkin H, Rowley JD. Blood 1993; 81: 2728-2734. Medline 8490181

Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. Nucifora G, Begy CR, Kobayashi H, Roulston D, Claxton D, Pedersen-Bjergaard J, Parganas E, Ihle JN, Rowley JD. Proc Natl Acad Sci U S A 1994; 91: 4004-4008. Medline 8171026 t(2;3)(p23;q26) in a patient with AML M2. Levaltier X, Penther D, Bastard C, Troussard X. Br J Haematol 1996; 92: 1027. Medline 8616064

Fluorescence in situ hybridization analysis of t(3;12)(q26;p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, Dyer M, Fuzibet JG, Gratecos N, Taillan B, Ayraud N, Marynen P. Blood 1996; 88: 682-689. Medline 8695816

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -342-

Expression of EVI1 and the retinoblastoma genes in acute myelogenous leukemia with t(3;13)(q26;q13-14). Yufu Y, Sadamura S, Ishikura H, Abe Y, Katsuno M, Nishimura J, Nawata H. Am J Hematolol 1996; 53: 30-34. Medline 8813093

The EVI1 gene in myeloid leukemia. Nucifora G. Leukemia 1997; 11: 2022-2031. Review. Medline 9447815

Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P. Cancer Res 1997; 57: 564-569. Medline 9044825

The EVI-1 gene-its role in pathogenesis of human leukemias. Jolkowska J, Witt M. Leuk Res 2000; 24: 553-558. Review. Medline 10867128

Acute myelogenous leukemia with the t(3;12)(q26;p13) translocation: Case report and review of the literature. Voutsadakis IA, Maillard N. Am J Hematol 2003; 72: 135-137. Medline 12555218 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications

BiblioGene - INIST Contributor(s) Written 05- Soumen Chakraborty, Silvia Buonamici, Vitalyi Senyuk, 2003 Giuseppina Nucifora. Citation This paper should be referenced as such : Chakraborty S, Buonamici S, Senyuk V, Nucifora G. . EVI1 Ecotropic Viral Integration 1 Site (EVI1) and Myelodysplastic Syndrome 1 (MDS1)-EVI1. Atlas Genet Cytogenet Oncol Haematol. May 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/EVI103q26ID19.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -343- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MARK4 (MAP/microtubule affinity-regulating kinase 4)

Identity Other MARKL1 names KIAA1860 Hugo MARK4 Location 19q13.2

DNA/RNA

Description Spans 55,6 kb; 18 exons Transcription 3,6kb mRNA of MARK4S isoform, 3,22kb of MARK4L isoform (alternative splicing-skipping of exon 16, which leads to a change in the reading frame ). Protein

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -344-

Description 688 amino acids (aa) for MARK4S isoform and 752 aa for MARK4L isoform; belongs to the MARK family of protein kinases and contains from aa 59 to 314 a Serine-Threonine kinase catalytic domain with two activating phosphorylation sites. A short sequence (T region) contains a putative membrane-targeting motif. This region is followed by a ubiquitin-associated (UBA) domain. The spacer is the least-conserved region among MARKs proteins. This region is followed by a strikingly conserved C-terminal domain. In MARK4 the C-terminal domain differs between MARK4S and MARK4L isoforms. Expression The MARK4S isoform is predominantly expressed in the brain and at low levels in the heart. The MARK4L isoform is expressed ubiquitously in all tissues, with a highly abundant expression in testis, neural progenitors and glial tumors. MARK4L is downregulated during glial differentiation. Localisation Protein was detected homogeneously in cytoplasm. Function MARK4 is considered to play a role as a messenger of the Wnt- signaling pathway. MARK4L represents a mitogenic-associated isoform. Homology MARK1, MARK2 (Emk1), MARK3 (p78/C-TAK1), par1, kin1 Mutations Note Mutations have not been detected. Implicated in Entity Hepatocellular carcinogenesis Oncogenesis RT-PCR anaysis detected upregulated expression in nearly all clinical hepatocellular carcinoma cells in which nuclear accumulation of b- catenin was observed.

Entity Up-regulation and overexpression of MARK4 has been described in glial tumors and glioblastoma cell lines. Oncogenesis MARK4 gene activation (enhanced expression and/or amplification) may result from intrachromosomal duplication upon 19q rearrangements.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -345- External links Nomenclature Hugo MARK4 GDB MARK4 Entrez_Gene MARK4 57787 MAP/microtubule affinity-regulating kinase 4 Cards Atlas MARK4ID419 GeneCards MARK4 Ensembl MARK4 CancerGene MARK4 Genatlas MARK4 GeneLynx MARK4 eGenome MARK4 euGene 57787 Genomic and cartography MARK4 - 19q13.2 chr19:50446682-50500381 + 19q13.32 GoldenPath (hg17-May_2004) Ensembl MARK4 - 19q13.32 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MARK4 Gene and transcription

Genbank AC005581 [ SRS ] AC005581 [ ENTREZ ]

Genbank AC006126 [ SRS ] AC006126 [ ENTREZ ]

Genbank AB049127 [ SRS ] AB049127 [ ENTREZ ]

Genbank AB058763 [ SRS ] AB058763 [ ENTREZ ]

Genbank AB088047 [ SRS ] AB088047 [ ENTREZ ]

RefSeq NM_031417 [ SRS ] NM_031417 [ ENTREZ ]

RefSeq NT_086903 [ SRS ] NT_086903 [ ENTREZ ] AceView MARK4 AceView - NCBI TRASER MARK4 Traser - Stanford

Unigene Hs.34314 [ SRS ] Hs.34314 [ NCBI ] HS34314 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q96L34 [ SRS] Q96L34 [ EXPASY ] Q96L34 [ INTERPRO ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -346- PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 Prosite PROTEIN_KINASE_ST [ Expasy ]

Prosite PS50030 UBA [ SRS ] PS50030 UBA [ Expasy ]

Interpro IPR001772 Kinase_Cterm [ SRS ] IPR001772 Kinase_Cterm [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

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

Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ]

Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]

Interpro IPR000449 UBA [ SRS ] IPR000449 UBA [ EBI ]

Interpro IPR009060 UBA_like [ SRS ] IPR009060 UBA_like [ EBI ] CluSTr Q96L34

Pfam PF02149 KA1 [ SRS ] PF02149 KA1 [ Sanger ] pfam02149 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Pfam PF00627 UBA [ SRS ] PF00627 UBA [ Sanger ] pfam00627 [ NCBI-CDD ]

Smart SM00220 S_TKc [EMBL]

Smart SM00165 UBA [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom Q96L34 MRK4_HUMAN [ Domain structure ] Q96L34 MRK4_HUMAN [ sequences sharing at least 1 domain ] Blocks Q96L34 Polymorphism : SNP, mutations, diseases OMIM 606495 [ map ] GENECLINICS 606495

SNP MARK4 [dbSNP-NCBI]

SNP NM_031417 [SNP-NCI]

SNP MARK4 [GeneSNPs - Utah] MARK4 [SNP - CSHL] MARK4] [HGBASE - SRS] General knowledge Family MARK4 [UCSC Family Browser] Browser SOURCE NM_031417 SMD Hs.34314 SAGE Hs.34314 Enzyme 2.7.1.37 [ Enzyme-SRS ] 2.7.1.37 [ Brenda-SRS ] 2.7.1.37 [ KEGG ] 2.7.1.37 [ WIT ] Amigo function|ATP binding Amigo function|ATP binding Amigo component|centrosome

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -347- Amigo function|gamma-tubulin binding Amigo function|microtubule binding Amigo process|microtubule bundle formation Amigo component|microtubule cytoskeleton Amigo process|neurogenesis Amigo component|neuronal cell projection Amigo process|positive regulation of programmed cell death Amigo process|protein amino acid phosphorylation Amigo process|protein amino acid phosphorylation Amigo function|protein serine/threonine kinase activity Amigo function|protein serine/threonine kinase activity Amigo function|protein-tyrosine kinase activity Amigo function|tau-protein kinase activity Amigo function|transferase activity Amigo function|ubiquitin binding PubGene MARK4 Other databases Probes Probe MARK4 Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography MAPs, MARKs and microtubule dynamics. Drewes G, Ebneth A, Mandelkow EM. TIBS 1998; 23: 307-311. Medline 9757832

Isolation of a novel human gene, MARKL1, homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Kato S, Satoh S, Okabe H, Kitahara O, Ono K, Kihara C, Tanaka T, Tsunoda T, Yamaoka Y, Nakamura Y, Furukawa Y. Neoplasia 2001; 3 (1): 4-9. Medline 11326310

Prediction of the coding sequence of unidentified human genes. XX. The complete sequence of 100 new cDNA clones from brain which code for large proteins in vitro. Nagase T, Nakayama M, Nakajima D, Kikuno R, Ohara O. DNA Research 2001; 8: 85-95. Medline 11347906

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -348- The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines. Beghini A, Magnani I, Roversi G, Piepoli T, Di Terlizzi S, Moroni RF, Pollo B, Conti AMF., Cowell JK, Finocchiaro G, Larizza L. Oncogene 2003; 22: 2581-2591. Medline 12735302

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Alessandro Beghini 2003 Citation This paper should be referenced as such : Beghini A. . MARK4 (MAP/microtubule affinity-regulating kinase 4). Atlas Genet Cytogenet Oncol Haematol. May 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MARK4ID419.html

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AF5q31 (ALL1 fused gene from chromosome 5q31) (updated: old version not available)

Identity Location 5q31

AF5q31 (5q31) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA Description at least 16 exons Transcription in a telomere to centromere direction; 4235 bp mRNA; open reading frame: 3491 bp Protein

Description 1163 amino acids; 127 kDa Expression mostly in fetal tissues (heart, lung, brain, liver); at a low level in adult tissues; therefore, AF5q31 may play a critical role in the fetal development Homology with AF4-related proteins: AF4, the gene involved int(4;11)(q21;q23), LAF4, FMR2 Implicated in Entity ins(5;11)(q31;q13q23)acute lymphoblastic leukemia (ALL) --> MLL- AF5q31 Note poorly defined: only 2 cases to date, infants with CD19+ ALL; complete remission, relapse and death Hybrid/Mutated AF5Q31 and MLL are transcribed in opposite directions, and inverted Gene insertion is required

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -350- External links Nomenclature GDB AF5Q31 Entrez_Gene AF5Q31 27125 ALL1 fused gene from 5q31 Cards Atlas AF5q31ID230 GeneCards AF5Q31 Ensembl AF5Q31 CancerGene AF5q31 Genatlas AF5Q31 GeneLynx AF5Q31 eGenome AF5Q31 euGene 27125 Genomic and cartography AF5Q31 - 5q31 chr5:132244244-132327181 - 5q31.1 (hg17- GoldenPath May_2004) Ensembl AF5Q31 - 5q31.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene AF5Q31 Gene and transcription

Genbank AF197927 [ SRS ] AF197927 [ ENTREZ ]

Genbank AF213987 [ SRS ] AF213987 [ ENTREZ ]

Genbank BC025700 [ SRS ] BC025700 [ ENTREZ ]

Genbank BC040454 [ SRS ] BC040454 [ ENTREZ ]

Genbank BC063007 [ SRS ] BC063007 [ ENTREZ ]

RefSeq NM_014423 [ SRS ] NM_014423 [ ENTREZ ]

RefSeq NT_086681 [ SRS ] NT_086681 [ ENTREZ ] AceView AF5Q31 AceView - NCBI TRASER AF5Q31 Traser - Stanford

Unigene Hs.519313 [ SRS ] Hs.519313 [ NCBI ] HS519313 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 604417 [ map ] GENECLINICS 604417

SNP AF5Q31 [dbSNP-NCBI]

SNP NM_014423 [SNP-NCI]

SNP AF5Q31 [GeneSNPs - Utah] AF5Q31 [SNP - CSHL] AF5Q31] [HGBASE - SRS]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -351- General knowledge Family AF5Q31 [UCSC Family Browser] Browser SOURCE NM_014423 SMD Hs.519313 SAGE Hs.519313 Amigo function|transcription factor activity Amigo process|transcription from Pol II promoter PubGene AF5Q31 Other databases Probes Probe Cancer Cytogenetics (Bari) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y. Proc Natl Acad Sci USA 1999; 96: 14535-14540. Medline 10588740

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 04- Jean-Loup Huret 2000 Updated 06- Jean-Loup Huret 2003

Citation This paper should be referenced as such : Huret JL . AF5q31 (ALL1 fused gene from chromosome 5q31). Atlas Genet

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -352- Cytogenet Oncol Haematol. April 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/AF5q31ID230.html Huret JL . AF5q31 (ALL1 fused gene from chromosome 5q31). Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/AF5q31ID230.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -353- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALEX1 (arm protein lost in epithelial cancers, X chromosome, 1)

Identity Location Xq22.1 DNA/RNA Description spans 4.2 kb; 4 exons; exon 4 is the only coding exon Transcription cDNA: 2141 bp Protein

Description 453 amino acids, 49 kDa.; contains a transmembrane domain in N term, an ATP/GTP binding site, 2 arm (armadillo) repeats, and potential phosphorylation sites Expression wide in normal tissues, except leucocytes; lost or significantly reduced in carcinomas Homology with ALEX2 and ALEX3 External links Nomenclature GDB ARMCX1 Entrez_Gene ARMCX1 51309 armadillo repeat containing, X-linked 1 Cards Atlas ALEX1Xq22ID477 GeneCards ARMCX1 Ensembl ARMCX1 CancerGene ALEX1 Genatlas ARMCX1 GeneLynx ARMCX1 eGenome ARMCX1 euGene 51309 Genomic and cartography ARMCX1 - Xq22.1 chrX:100611659-100615818 + Xq22.1 GoldenPath (hg17-May_2004) Ensembl ARMCX1 - Xq22.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -354- OMIM Disease map [OMIM] HomoloGene ARMCX1 Gene and transcription

Genbank CQ782722 [ SRS ] CQ782722 [ ENTREZ ]

Genbank AB039670 [ SRS ] AB039670 [ ENTREZ ]

Genbank AF248963 [ SRS ] AF248963 [ ENTREZ ]

Genbank AK074785 [ SRS ] AK074785 [ ENTREZ ]

Genbank BC002691 [ SRS ] BC002691 [ ENTREZ ]

RefSeq NM_016608 [ SRS ] NM_016608 [ ENTREZ ]

RefSeq NT_086963 [ SRS ] NT_086963 [ ENTREZ ] AceView ARMCX1 AceView - NCBI TRASER ARMCX1 Traser - Stanford

Unigene Hs.9728 [ SRS ] Hs.9728 [ NCBI ] HS9728 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 300362 [ map ] GENECLINICS 300362

SNP ARMCX1 [dbSNP-NCBI]

SNP NM_016608 [SNP-NCI]

SNP ARMCX1 [GeneSNPs - Utah] ARMCX1 [SNP - CSHL] ARMCX1] [HGBASE - SRS] General knowledge Family ARMCX1 [UCSC Family Browser] Browser SOURCE NM_016608 SMD Hs.9728 SAGE Hs.9728 Amigo function|binding PubGene ARMCX1 Other databases Probes PubMed PubMed 2 Pubmed reference(s) in LocusLink Bibliography ALEX1, a novel human armadillo repeat protein that is expressed differentially in normal tissues and carcinomas. Kurochkin IV, Yonemitsu N, Funahashi SI, Nomura H. Biochem Biophys Res Commun. 2001; 280: 340-347. Medline 11162520

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -355- REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . ALEX1 (arm protein lost in epithelial cancers, X chromosome, 1). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ALEX1Xq22ID477.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -356- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALEX2 (arm protein lost in epithelial cancers, X chromosome, 2)

Identity Location Xq22.1 DNA/RNA Description spans 4.6 kb Transcription main transcript: 2.7 kb; other transcripts: 1.4 and 7 kb. Protein

Description 632 amino acids; contains a transmembrane domain in N term, and a arm (armadillo) repeat Expression wide in normal tissues, except leucocytes; lost or significantly reduced in carcinomas Homology with ALEX1 and ALEX3 External links Nomenclature GDB ARMCX2 Entrez_Gene ARMCX2 9823 armadillo repeat containing, X-linked 2 Cards Atlas ALEX2Xq22ID478 GeneCards ARMCX2 Ensembl ARMCX2 CancerGene ALEX2 Genatlas ARMCX2 GeneLynx ARMCX2 eGenome ARMCX2 euGene 9823 Genomic and cartography ARMCX2 - Xq22.1 chrX:100716416-100720977 - Xq22.1 (hg17- GoldenPath May_2004) Ensembl ARMCX2 - Xq22.1 [CytoView]

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

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -357- HomoloGene ARMCX2 Gene and transcription

Genbank AB011084 [ SRS ] AB011084 [ ENTREZ ]

Genbank AL709063 [ SRS ] AL709063 [ ENTREZ ]

Genbank BC012541 [ SRS ] BC012541 [ ENTREZ ]

Genbank BC015926 [ SRS ] BC015926 [ ENTREZ ]

Genbank BC052628 [ SRS ] BC052628 [ ENTREZ ]

RefSeq NM_014782 [ SRS ] NM_014782 [ ENTREZ ]

RefSeq NM_177949 [ SRS ] NM_177949 [ ENTREZ ]

RefSeq NT_086963 [ SRS ] NT_086963 [ ENTREZ ] AceView ARMCX2 AceView - NCBI TRASER ARMCX2 Traser - Stanford

Unigene Hs.48924 [ SRS ] Hs.48924 [ NCBI ] HS48924 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 300363 [ map ] GENECLINICS 300363

SNP ARMCX2 [dbSNP-NCBI]

SNP NM_014782 [SNP-NCI]

SNP NM_177949 [SNP-NCI]

SNP ARMCX2 [GeneSNPs - Utah] ARMCX2 [SNP - CSHL] ARMCX2] [HGBASE - SRS] General knowledge Family ARMCX2 [UCSC Family Browser] Browser SOURCE NM_014782 SOURCE NM_177949 SMD Hs.48924 SAGE Hs.48924 Amigo function|binding PubGene ARMCX2 Other databases Probes PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography ALEX1, a novel human armadillo repeat protein that is expressed differentially in normal tissues and carcinomas. Kurochkin IV, Yonemitsu N, Funahashi SI, Nomura H. Biochem Biophys Res Commun. 2001; 280: 340-347.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -358- Medline 11162520

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . ALEX2 (arm protein lost in epithelial cancers, X chromosome, 2). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ALEX2Xq22ID478.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -359- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ALEX3 (arm protein lost in epithelial cancers, X chromosome, 3)

Identity Hugo RMCX3 Location Xq22.1 DNA/RNA Description spans 3.3 kb Transcription transcript: 2.0 kb Protein

Description 379 amino acids, 42.5 kDa; contains a transmembrane domain in N term, and a arm (armadillo) repeat Homology with ALEX1 and ALEX2 Mutations Note may be involved in tumorigenesis, but further studies are needed External links Nomenclature Hugo RMCX3 GDB ARMCX3 Entrez_Gene ARMCX3 51566 armadillo repeat containing, X-linked 3 Cards Atlas ALEX3Xq22ID479 GeneCards ARMCX3 Ensembl ARMCX3 Genatlas ARMCX3 GeneLynx ARMCX3 eGenome ARMCX3 euGene 51566 Genomic and cartography ARMCX3 - Xq22.1 chrX:100764776-100769487 + Xq22.1 GoldenPath (hg18-Mar_2006) Ensembl ARMCX3 - Xq22.1 [CytoView]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -360- NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ARMCX3 Gene and transcription

Genbank AB039669 [ ENTREZ ]

Genbank AF211175 [ ENTREZ ]

Genbank AK222655 [ ENTREZ ]

Genbank AY359079 [ ENTREZ ]

Genbank BC005194 [ ENTREZ ]

RefSeq NM_016607 [ SRS ] NM_016607 [ ENTREZ ]

RefSeq NM_177947 [ SRS ] NM_177947 [ ENTREZ ]

RefSeq NM_177948 [ SRS ] NM_177948 [ ENTREZ ] AceView ARMCX3 AceView - NCBI TRASER ARMCX3 Traser - Stanford

Unigene Hs.592225 [ SRS ] Hs.592225 [ NCBI ] HS592225 [ spliceNest ] Protein : pattern, domain, 3D structure Protein Interaction databases Polymorphism : SNP, mutations, diseases OMIM 300364 [ map ] GENECLINICS 300364

SNP ARMCX3 [dbSNP-NCBI]

SNP NM_016607 [SNP-NCI]

SNP NM_177947 [SNP-NCI]

SNP NM_177948 [SNP-NCI]

SNP ARMCX3 [GeneSNPs - Utah] ARMCX3] [HGBASE - SRS]

HAPMAP ARMCX3 [HAPMAP] General knowledge Family ARMCX3 [UCSC Family Browser] Browser SOURCE NM_016607 SOURCE NM_177947 SOURCE NM_177948 SMD Hs.592225 SAGE Hs.592225 Amigo binding Amigo membrane Amigo integral to membrane PubGene ARMCX3

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -361- Other databases Probes Probe RMCX3 Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in LocusLink Bibliography ALEX1, a novel human armadillo repeat protein that is expressed differentially in normal tissues and carcinomas. Kurochkin IV, Yonemitsu N, Funahashi SI, Nomura H. Biochem Biophys Res Commun. 2001; 280: 340-347. Medline 11162520

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . ALEX3 (arm protein lost in epithelial cancers, X chromosome, 3). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://AtlasGeneticsOncology.org/Genes/ALEX3Xq22ID479.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -362- Atlas of Genetics and Cytogenetics in Oncology and Haematology

CAGE-1 (cancer-associated gene-1)

Identity Hugo CAGE1 Location 6p24.3 DNA/RNA Description spans 63 kb; 11 exons; ORF: 1920 bp Protein

Description 639 amino acids; 73 kDa; carry 2 consensus glycosylation sites, 10 PKC dependent phosphorylation sites Expression testis-restricted in normal tissues; wide/high expression in various cancer tissues (lung, cervix, stomach) CAG1 is a probable member of the cancer/testis antigen family Localisation mainly nuclear Function may be involved in signaling pathway Homology with monkey genes with testis specific expression Mutations Somatic may be associated with tumor progression . External links Nomenclature Hugo CAGE1 GDB CAGE1 Entrez_Gene CAGE1 285782 cancer antigen 1 Cards Atlas CAG1ID475 GeneCards CAGE1 Ensembl CAGE1 Genatlas CAGE1 GeneLynx CAGE1 eGenome CAGE1 euGene 285782 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -363- CAGE1 - 6p24.3 chr6:7271890-7334638 - 6p24.3 (hg17- GoldenPath May_2004) Ensembl CAGE1 - 6p24.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene CAGE1 Gene and transcription

Genbank AF414185 [ SRS ] AF414185 [ ENTREZ ]

Genbank AK097760 [ SRS ] AK097760 [ ENTREZ ]

Genbank BC026188 [ SRS ] BC026188 [ ENTREZ ]

Genbank BC026194 [ SRS ] BC026194 [ ENTREZ ]

Genbank BC033545 [ SRS ] BC033545 [ ENTREZ ]

RefSeq NM_175745 [ SRS ] NM_175745 [ ENTREZ ]

RefSeq NM_205864 [ SRS ] NM_205864 [ ENTREZ ]

RefSeq NT_086686 [ SRS ] NT_086686 [ ENTREZ ] AceView CAGE1 AceView - NCBI TRASER CAGE1 Traser - Stanford

Unigene Hs.367936 [ SRS ] Hs.367936 [ NCBI ] HS367936 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q8N7R5 [ SRS] Q8N7R5 [ EXPASY ] Q8N7R5 [ INTERPRO ] CluSTr Q8N7R5 Blocks Q8N7R5 Polymorphism : SNP, mutations, diseases OMIM 608304 [ map ] GENECLINICS 608304

SNP CAGE1 [dbSNP-NCBI]

SNP NM_175745 [SNP-NCI]

SNP NM_205864 [SNP-NCI]

SNP CAGE1 [GeneSNPs - Utah] CAGE1 [SNP - CSHL] CAGE1] [HGBASE - SRS] General knowledge Family CAGE1 [UCSC Family Browser] Browser SOURCE NM_175745 SOURCE NM_205864 SMD Hs.367936 SAGE Hs.367936 PubGene CAGE1 Other databases

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -364- Probes Probe CAGE1 Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography Identification and characterization of a novel cancer/testis antigen gene CAGE- 1. Park S, Lim Y, Lee D, Cho B, Bang YJ, Sung S, Kim HY, Kim DK, Lee YS, Song Y, Jeoung DI. Biochim Biophys Acta. 2003; 1625: 173-182. Medline 12531476

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . CAGE-1 (cancer-associated gene-1). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/CAG1ID475.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -365- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAML2 (mastermind-like 2)

Identity Other hMam-3 names KIAA1819 Hugo MAML2 Location 11q21-22 DNA/RNA Description Spans 365 kb; 5 exons. Transcription a major transcript of 7.5 kb. Protein

Description 1153 aa, 125 kDa; conserved N-terminal basic domain (aa 29-92) which binds to the ankyrin repeat domain of Notch receptors; two acidic domains (aa 263-360 and 1124-1153) and a C-terminal transcriptional activation domain. Expression widely expressed Localisation nuclear granules Function Mastermind-like coactivator for all four Notch receptors; forms a complex with Notch ICD and the CSL family of transcription factors, resulting in activation of the Notch target genes HES1 and HES5; functions as a CSL-dependent transcriptional coactivator for ligand- stimulated Notch. Homology MAML1 and MAML3. Implicated in Entity mucoepidermoid carcinoma with t(11;19)(q21-22;p13). Disease most common type of malignant salivary gland tumor; second most frequent lung tumor of bronchial gland origin. Hybrid/Mutated MECT1-MAML2; exon 1 of MECT1 fused to exons 2-5 of MAML2. Gene Abnormal MECT1-MAML2; in the fusion protein, the first 171 aa including the Protein basic domain of MAML2 are replaced by 42 aa of MECT1; there are no sequence similarities in the N-terminal domains of MAML2 and MECT1; the fusion protein activates transcription of the Notch target gene HES1 independently of both Notch ligand and CSL.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -366-

External links Nomenclature Hugo MAML2 GDB MAML2 Entrez_Gene MAML2 84441 mastermind-like 2 (Drosophila) Cards Atlas MAML2ID472 GeneCards MAML2 Ensembl MAML2 CancerGene MAML2 Genatlas MAML2 GeneLynx MAML2 eGenome MAML2 euGene 84441 Genomic and cartography MAML2 - chr11:95351088-95715992 - 11q21 (hg17- GoldenPath May_2004) Ensembl MAML2 - 11q21 [CytoView]

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

HomoloGene MAML2 Gene and transcription

Genbank AB058722 [ SRS ] AB058722 [ ENTREZ ]

Genbank AY040322 [ SRS ] AY040322 [ ENTREZ ]

Genbank AY186997 [ SRS ] AY186997 [ ENTREZ ]

Genbank CR627398 [ SRS ] CR627398 [ ENTREZ ]

RefSeq NM_032427 [ SRS ] NM_032427 [ ENTREZ ]

RefSeq NT_086787 [ SRS ] NT_086787 [ ENTREZ ] AceView MAML2 AceView - NCBI TRASER MAML2 Traser - Stanford

Unigene Hs.428214 [ SRS ] Hs.428214 [ NCBI ] HS428214 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q96JK6 [ SRS] Q96JK6 [ EXPASY ] Q96JK6 [ INTERPRO ] CluSTr Q96JK6 Blocks Q96JK6 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -367- OMIM 607537 [ map ] GENECLINICS 607537

SNP MAML2 [dbSNP-NCBI]

SNP NM_032427 [SNP-NCI]

SNP MAML2 [GeneSNPs - Utah] MAML2 [SNP - CSHL] MAML2] [HGBASE - SRS] General knowledge Family MAML2 [UCSC Family Browser] Browser SOURCE NM_032427 SMD Hs.428214 SAGE Hs.428214 PubGene MAML2 Other databases Probes Probe MAML2 Related clones (RZPD - Berlin) PubMed PubMed 5 Pubmed reference(s) in LocusLink Bibliography Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino G, Callahan R. Genes Dev 1992; 6: 345-355. Medline 1372276

Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma. Nordkvist A, Gustafsson H, Juberg-Ode M, Stenman G. Cancer Genet Cytogenet 1994; 74: 77-83. Medline 8019965

Conservation of the Notch signalling pathway in mammalian neurogenesis de la Pompa JL, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA. Development 1997; 124: 1139-1148. Medline 9102301

A child with a t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid carcinoma. Stenman G, Petursdottir V, Mellgren G, Mark J. Virchows Archiv 1998; 433; 579-581. Medline 9870694

MAML1, a human homologue of Drosophila Mastermind, is a transcriptional co-

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -368- activator for NOTCH receptors. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. Nat Genet 2000; 26: 484-489. Medline 11101851

Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling. Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M. J Biol Chem 2002; 277: 50612-50620. Medline 12386158

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Goran Stenman 2003 Citation This paper should be referenced as such : Stenman G . MAML2 (mastermind-like 2). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MAML2ID472.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -369- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MDS2

Identity Location 1p36 DNA/RNA Description spans 13 kb; 7 exons Transcription 4 alternate splicings; major splice: 281 bp, exons 1, 4, 6, 7 are constantly used Protein

Description The 4 alternate splicings give rise to 2 proteins, of 82 and 140 amino acids Expression wide Implicated in Entity t(1;12)(p36;p13) in myeloid disorders Prognosis unknown so far Hybrid/Mutated 5' ETV6 - 3' MDS2 Gene Abnormal truncated ETV6 Protein

External links Nomenclature GDB MDS2 Entrez_Gene MDS2 259283 myelodysplastic syndrome 2 Cards Atlas MDS2ID476 GeneCards MDS2 Ensembl MDS2 CancerGene MDS2 Genatlas MDS2 GeneLynx MDS2 eGenome MDS2 euGene 259283

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -370- Genomic and cartography GoldenPath MDS2 - 1p36 Ensembl MDS2 - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MDS2 Gene and transcription

Genbank AJ310434 [ SRS ] AJ310434 [ ENTREZ ]

Genbank BC041472 [ SRS ] BC041472 [ ENTREZ ] AceView MDS2 AceView - NCBI TRASER MDS2 Traser - Stanford

Unigene Hs.523369 [ SRS ] Hs.523369 [ NCBI ] HS523369 [ spliceNest ] Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 607305 [ map ] GENECLINICS 607305

SNP MDS2 [dbSNP-NCBI]

SNP MDS2 [GeneSNPs - Utah] MDS2 [SNP - CSHL] MDS2] [HGBASE - SRS] General knowledge Family MDS2 [UCSC Family Browser] Browser SMD Hs.523369 SAGE Hs.523369 PubGene MDS2 Other databases Probes PubMed PubMed 1 Pubmed reference(s) in LocusLink Bibliography A novel gene, MDS2, is fused to ETV6/TEL in a t(1;12)(p36.1;p13) in a patient with myelodysplastic syndrome. Odero MD, Vizmanos JL, Roman JP, Lahortiga I, Panizo C, Calasanz MJ, Zeleznik- Le NJ, Rowley JD, Novo FJ. Genes Chromosomes Cancer 2002; 35: 11-19. Medline 12203785

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

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -371- Contributor(s) Written 07- Jean-Loup Huret, Sylvie Senon 2003 Citation This paper should be referenced as such : Huret JL, Senon S . MDS2. Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MDS2ID476.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -372- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MECT1 (mucoepidermoid carcinoma translocated 1)

Identity Other KIAA0616 names Hugo MECT1 Location 19p13 DNA/RNA Description spans 99 kb; contains at least 14 exons Protein

Localisation predicted nuclear localization. Function unknown Implicated in Entity mucoepidermoid carcinoma with t(11;19)(q21-22;p13). . Disease Most common type of malignant salivary gland tumor; second most frequent lung tumor of bronchial gland origin. Hybrid/Mutated MECT1- MAML2; exon 1 of MECT1 fused to exons 2-5 of MAML2. Gene Abnormal MECT1-MAML2; in the fusion protein the first 171 aa including the Protein basic domain of MAML2 are replaced by 42 aa of MECT1; there are no sequence similarities in the N-terminal domains of MAML2 and MECT1; the fusion protein activates transcription of the Notch target gene HES1 independently of both Notch ligand and CSL.

External links Nomenclature Hugo MECT1 GDB MECT1 Entrez_Gene MECT1 23373 mucoepidermoid carcinoma translocated 1 Cards GeneCards MECT1 Ensembl MECT1 CancerGene MECT1

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -373- Genatlas MECT1 GeneLynx MECT1 eGenome MECT1 euGene 23373 Genomic and cartography MECT1 - 19p13 chr19:18655504-18749757 + 19p13.11 (hg17- GoldenPath May_2004) Ensembl MECT1 - 19p13.11 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MECT1 Gene and transcription

Genbank AC006123 [ SRS ] AC006123 [ ENTREZ ]

Genbank AB014516 [ SRS ] AB014516 [ ENTREZ ]

Genbank AK024089 [ SRS ] AK024089 [ ENTREZ ]

Genbank AY040323 [ SRS ] AY040323 [ ENTREZ ]

Genbank AY360171 [ SRS ] AY360171 [ ENTREZ ]

RefSeq NM_015321 [ SRS ] NM_015321 [ ENTREZ ]

RefSeq NM_025021 [ SRS ] NM_025021 [ ENTREZ ]

RefSeq NT_086897 [ SRS ] NT_086897 [ ENTREZ ] AceView MECT1 AceView - NCBI TRASER MECT1 Traser - Stanford

Unigene Hs.371096 [ SRS ] Hs.371096 [ NCBI ] HS371096 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O75114 [ SRS] O75114 [ EXPASY ] O75114 [ INTERPRO ] CluSTr O75114 Blocks O75114 Polymorphism : SNP, mutations, diseases OMIM 607536 [ map ] GENECLINICS 607536

SNP MECT1 [dbSNP-NCBI]

SNP NM_015321 [SNP-NCI]

SNP NM_025021 [SNP-NCI]

SNP MECT1 [GeneSNPs - Utah] MECT1 [SNP - CSHL] MECT1] [HGBASE - SRS] General knowledge Family MECT1 [UCSC Family Browser] Browser SOURCE NM_015321

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -374- SOURCE NM_025021 SMD Hs.371096 SAGE Hs.371096 PubGene MECT1 Other databases Probes Probe MECT1 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling. Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M. J Biol Chem 2002; 277: 50612-50620. Medline 12386158

Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Wu L, Sun T, Kobayashi K, Gao P, Griffin JD. Mol Cell Biol 2002; 22:7688-7700. Medline 12370315 t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O'Neil K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ. Nat Genet 2003; 33: 208-213. Medline 12539049 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Goran Stenman 2003 Citation This paper should be referenced as such : Stenman G . MECT1 (mucoepidermoid carcinoma translocated 1). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MECT1ID471.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -375- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TCF12 (transcription factor 12)

Identity Other HTF4 names HEB Hugo TCF12 Location 15q21 DNA/RNA Description spans 370 kb; 21 exons. Transcription two alternatively spliced transcripts of 4745 bp and 4077 bp. Protein

Description 682 aa, 73 kDa; serine rich N-terminus containing a potential leuzine zipper domain; C-terminus containing a bHLH-domain as well as a class A-specific domain. Expression ubiquitous Localisation nuclear Function basic helix-loop-helix (bHLH) transcription factor belonging to the class A family; acts as a general negative regulator of cell proliferation; binds specifically to oligomers of E-box motifs; forms heterodimers with other bHLH proteins of both class A and class B, e.g. E2A, TAL1, myogenin and MyoD; implicated in myogenesis, hematopoiesis and neurogenesis. Homology TCF3 and TCF4 Implicated in Entity Extraskeletal myxoid chondrosarcoma with t(9;15)(q22;q21). Disease rare type of sarcoma (2.3% of all soft tissue sarcomas) characteristically involving the deep, soft tissues of the extremities; morphological resemblance to embryonic cartilage. Hybrid/Mutated TCF12-TEC Gene Abnormal N-terminal domain of TCF12 fused to the entire TEC protein; the Protein translocation separates the N-terminal of TCF12 from the bHLH domain as well as from a potential leucine zipper domain; the N- terminal of TCF12 shows no sequence homology to the N-terminals of EWSR1 or TAF2N.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -376-

External links Nomenclature Hugo TCF12 GDB TCF12 TCF12 6938 transcription factor 12 (HTF4, helix-loop-helix Entrez_Gene transcription factors 4) Cards GeneCards TCF12 Ensembl TCF12 CancerGene TCF12 Genatlas TCF12 GeneLynx TCF12 eGenome TCF12 euGene 6938 Genomic and cartography TCF12 - 15q21 chr15:54998125-55368004 + 15q21.3 (hg17- GoldenPath May_2004) Ensembl TCF12 - 15q21.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TCF12 Gene and transcription

Genbank AF271609 [ SRS ] AF271609 [ ENTREZ ]

Genbank AF271610 [ SRS ] AF271610 [ ENTREZ ]

Genbank AF271611 [ SRS ] AF271611 [ ENTREZ ]

Genbank AF271612 [ SRS ] AF271612 [ ENTREZ ]

Genbank AF271613 [ SRS ] AF271613 [ ENTREZ ]

RefSeq NM_003205 [ SRS ] NM_003205 [ ENTREZ ]

RefSeq NM_207036 [ SRS ] NM_207036 [ ENTREZ ]

RefSeq NM_207037 [ SRS ] NM_207037 [ ENTREZ ]

RefSeq NM_207038 [ SRS ] NM_207038 [ ENTREZ ]

RefSeq NM_207040 [ SRS ] NM_207040 [ ENTREZ ]

RefSeq NT_086827 [ SRS ] NT_086827 [ ENTREZ ] AceView TCF12 AceView - NCBI TRASER TCF12 Traser - Stanford

Unigene Hs.511504 [ SRS ] Hs.511504 [ NCBI ] HS511504 [ spliceNest ] Protein : pattern, domain, 3D structure

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -377- SwissProt Q99081 [ SRS] Q99081 [ EXPASY ] Q99081 [ INTERPRO ]

Prosite PS50888 HLH [ SRS ] PS50888 HLH [ Expasy ]

Interpro IPR001092 HLH_basic [ SRS ] IPR001092 HLH_basic [ EBI ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ] CluSTr Q99081

Pfam PF00010 HLH [ SRS ] PF00010 HLH [ Sanger ] pfam00010 [ NCBI-CDD ] Blocks Q99081 Polymorphism : SNP, mutations, diseases OMIM 600480 [ map ] GENECLINICS 600480

SNP TCF12 [dbSNP-NCBI]

SNP NM_003205 [SNP-NCI]

SNP NM_207036 [SNP-NCI]

SNP NM_207037 [SNP-NCI]

SNP NM_207038 [SNP-NCI]

SNP NM_207040 [SNP-NCI]

SNP TCF12 [GeneSNPs - Utah] TCF12 [SNP - CSHL] TCF12] [HGBASE - SRS] General knowledge Family TCF12 [UCSC Family Browser] Browser SOURCE NM_003205 SOURCE NM_207036 SOURCE NM_207037 SOURCE NM_207038 SOURCE NM_207040 SMD Hs.511504 SAGE Hs.511504 Amigo function|DNA binding Amigo function|RNA polymerase II transcription factor activity Amigo process|development Amigo process|immune response Amigo process|muscle development Amigo component|nucleus Amigo process|regulation of transcription from Pol II promoter Amigo process|regulation of transcription, DNA-dependent PubGene TCF12 Other databases

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -378- Probes Probe TCF12 Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography HTF4: a new human helix-loop-helix protein. Zhang Y, Babin J, Feldhaus AL, Singh H, Sharp PA, Bina M. Nucl Acids Res 1991; 19: 4555. Medline 1886779

HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors. Hu JS, Olson EN, Kingston RE. Mol Cell Biol 1992; 12: 1031-1042. Medline 1312219

The nucleotide sequence of the human transcription factor HTF4a cDNA. Zhang Y, Bina M. DNA Sequence 1992; 2: 397-403. Medline 1446075

A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines. Sawada S, Littman DR. Mol Cell Biol 1993; 13: 5620-5628. Medline 8355705

Distinguishable patterns of protein-DNA interactions involving complexes of basic helix-loop-helix proteins. Doyle K, Zhang Y, Baer R, Bina MJ. J Biol Chem 1994; 269: 12099-12105. Medline 8163514

Oncogenic conversion of a novel orphan nuclear receptor by chromosome translocation. Labelle Y, Zucman J, Stenman G, Kindblom L-G, Knight J, Turc-Carel C, Dockhorn- Dworniczak B, Mandahl N, Desmaze C, Aurias A, Delattre O, Thomas G. Hum Mol Genet 1995; 4: 2219-2226. Medline 8634690

Localization of the human HTF4 transcription factors 4 gene (TCF12) to chromosome 15q21. Zhang Y, Flejter WL, Barcroft CL, Riviere M, Szpirer J, Szpirer C, Bina M. Cytogenet Cell Genet 1995; 68: 235-238. Medline 7842744

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -379- bHLH transcription factors and mammalian neuronal differentiation. Kageyama R, Ishibashi M, Takebayashi K, Tomita K. Int J Biochem Cell Biol 1997; 29; 1389-1399. Medline 9570134

Muscle differentiation: more complexity to the network of myogenic regulators. Arnold HH, Winter B. Curr Opin Genet Dev 1998; 8: 539-544. Medline 9794824

Fusion of the EWS-related gene TAF2N to TEC in extraskeletal myxoid chondrosarcoma. Sjogren H, Meis-Kindblom J, Kindblom LG, Aman P, Stenman G. Cancer Res 1999; 59: 5064-5067. Medline 10537274

Class A helix-loop-helix proteins are positive regulators of several cyclin- dependent kinase inhibitors' promoter activity and negatively affect cell growth. Pagliuca A, Gallo P, De Luca P, Lania L. Cancer Res 2000; 60: 1376-1382. Medline 10728702

Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21). Sjogren H, Wedell B, Meis-Kindblom JM, Kindblom LG, Stenman G. Cancer Res 2000; 6: 6832-6835. Medline 11156374

Genomic organization of human TCF12 gene and spliced mRNA variants producing isoforms of transcription factor HTF4. Gan TI, Rowen L, Nesbitt R, Roe BA, Wu H, Hu P, Yao Z, Kim UJ, O'Sickey T, Bina M. Cytogenet Genome Res 2002; 98: 245-248. Medline 12826747

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Goran Stenman 2003

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -380-

Citation This paper should be referenced as such : Stenman G . TCF12 (transcription factor 12). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TCF12ID406.html

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NR4A3 (nuclear receptor subfamily 4, group A, member 3)

Identity Other TEC names NR4A3 NOR1 MINOR CSMF CHN Hugo NR4A3 Location 9q22 DNA/RNA Description spans about 46 kb; 9 exons Transcription four transcript variants (6382 bp, 5635 bp, 4983bp and 2588 bp) Protein

Description three isoforms (637 aa, 626 aa and 443 aa); N-terminal activation domain; central bipartite zinc finger DNA-binding domain; C-terminal ligand binding domain. Expression most tissues, highest expression levels in the central nervous system. Localisation nuclear Function orphan nuclear receptor; implicated in the control of cell proliferation as an immediate-early protein and in differentiation and apoptosis; binds as a monomer to the DNA-response element NBRE; activate transcription constitutively when bound to NBRE; the homeotic protein Six3 is a coactivator of TEC. Homology belongs to the steroid/thyroid receptor gene super family; highly homologous to the nuclear receptors NGFI-B and NURR1. Implicated in Entity Extraskeletal myxoid chondrosarcoma with t(9;22)(q22;q12). Disease rare type of sarcoma (2.3% of all soft tissue sarcomas) characteristically involving the deep, soft tissues of the extremities; morphological resemblance to embryonic cartilage.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -382- Hybrid/Mutated EWSR1-TEC Gene Abnormal N-terminal transactivation domain of EWSR1 fused to the entire TEC Protein protein.

Entity Extraskeletal myxoid chondrosarcoma with t(9;17)(q22;q11). Disease rare type of sarcoma (2.3% of all soft tissue sarcomas) characteristically involving the deep, soft tissues of the extremities; morphological resemblance to embryonic cartilage. Hybrid/Mutated TAF2N-TEC Gene Abnormal N-terminal transactivation domain of TAF2N fused to the entire TEC Protein protein.

Entity Extraskeletal myxoid chondrosarcoma with t(9;15)(q22;q21). Disease rare type of sarcoma (2.3% of all soft tissue sarcomas) characteristically involving the deep, soft tissues of the extremities; morphological resemblance to embryonic cartilage. Hybrid/Mutated TCF12-TEC Gene Abnormal N-terminal domain of TCF12 fused to the entire TEC protein; the N- Protein terminal of TCF12 shows no sequence homology to the N-terminals of EWSR1 or TAF2N.

Breakpoints

External links Nomenclature Hugo NR4A3 GDB NR4A3

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -383- Entrez_Gene NR4A3 8013 nuclear receptor subfamily 4, group A, member 3 Cards Atlas TECID75 GeneCards NR4A3 Ensembl NR4A3 CancerGene NOR1 Genatlas NR4A3 GeneLynx NR4A3 eGenome NR4A3 euGene 8013 Genomic and cartography NR4A3 - 9q22 chr9:99663692-99708728 + 9q31.1 (hg17- GoldenPath May_2004) Ensembl NR4A3 - 9q31.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NR4A3 Gene and transcription

Genbank D78579 [ SRS ] D78579 [ ENTREZ ]

Genbank D85241 [ SRS ] D85241 [ ENTREZ ]

Genbank D85242 [ SRS ] D85242 [ ENTREZ ]

Genbank S81243 [ SRS ] S81243 [ ENTREZ ]

Genbank U12767 [ SRS ] U12767 [ ENTREZ ]

RefSeq NM_006981 [ SRS ] NM_006981 [ ENTREZ ]

RefSeq NM_173198 [ SRS ] NM_173198 [ ENTREZ ]

RefSeq NM_173199 [ SRS ] NM_173199 [ ENTREZ ]

RefSeq NM_173200 [ SRS ] NM_173200 [ ENTREZ ]

RefSeq NT_086754 [ SRS ] NT_086754 [ ENTREZ ] AceView NR4A3 AceView - NCBI TRASER NR4A3 Traser - Stanford

Unigene Hs.279522 [ SRS ] Hs.279522 [ NCBI ] HS279522 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q92570 [ SRS] Q92570 [ EXPASY ] Q92570 [ INTERPRO ]

PS00031 NUCLEAR_REC_DBD_1 [ SRS ] PS00031 Prosite NUCLEAR_REC_DBD_1 [ Expasy ]

PS51030 NUCLEAR_REC_DBD_2 [ SRS ] PS51030 Prosite NUCLEAR_REC_DBD_2 [ Expasy ] Interpro IPR000536 Hrmon_recept_lig [ SRS ] IPR000536 Hrmon_recept_lig [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -384- Interpro IPR001723 Stdhrmn_receptor [ SRS ] IPR001723 Stdhrmn_receptor [ EBI ]

Interpro IPR008946 Str_ncl_receptor [ SRS ] IPR008946 Str_ncl_receptor [ EBI ]

Interpro IPR001628 Znf_C4steroid [ SRS ] IPR001628 Znf_C4steroid [ EBI ] CluSTr Q92570

PF00104 Hormone_recep [ SRS ] PF00104 Hormone_recep [ Sanger Pfam ] pfam00104 [ NCBI-CDD ]

Pfam PF00105 zf-C4 [ SRS ] PF00105 zf-C4 [ Sanger ] pfam00105 [ NCBI-CDD ]

Prodom PD000035 Znf_C4steroid[INRA-Toulouse] Prodom Q92570 NR43_HUMAN [ Domain structure ] Q92570 NR43_HUMAN [ sequences sharing at least 1 domain ] Blocks Q92570 Polymorphism : SNP, mutations, diseases OMIM 600542 [ map ] GENECLINICS 600542

SNP NR4A3 [dbSNP-NCBI]

SNP NM_006981 [SNP-NCI]

SNP NM_173198 [SNP-NCI]

SNP NM_173199 [SNP-NCI]

SNP NM_173200 [SNP-NCI]

SNP NR4A3 [GeneSNPs - Utah] NR4A3 [SNP - CSHL] NR4A3] [HGBASE - SRS] General knowledge Family NR4A3 [UCSC Family Browser] Browser SOURCE NM_006981 SOURCE NM_173198 SOURCE NM_173199 SOURCE NM_173200 SMD Hs.279522 SAGE Hs.279522 Amigo function|binding Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|steroid hormone receptor activity Amigo function|steroid hormone receptor activity Amigo function|thyroid hormone receptor activity Amigo function|transcription factor activity PubGene NR4A3 Other databases

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -385- Probes Probe NR4A3 Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography Molecular cloning of a novel thyroid/steroid receptor superfamily gene from cultured rat neuronal cells. Ohkura N, Hijikuro M, Yamamoto A, Miki K. Biochem Biophys Res Commun 1994; 205: 1959-1965. Medline 7811288

The isolation and characterization of MINOR, a novel mitogen-inducible nuclear orphan receptor. Hedvat CV, Irving SG. Mol Endocrinol 1995; 9: 1692-1700. Medline 8614405

Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma. Clark J, Benjamin H, Gill S, Sidhar S, Goodwin G, Crew J, Gusterson BA, Shipley J, Cooper CS. Oncogene 1996; 12: 229-235. Medline 96152889

Identification of a novel fusion gene involving hTAFII68 and CHN from a t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma. Attwooll C, Tariq M, Harris M, Coyne JD, Telford N, Varley JM. Oncogene 1999; 18: 7599-7601. Medline 20071145

The EWS/TEC fusion protein encoded by the t(9;22) chromosomal translocation in human chondrosarcomas is a highly potent transcriptional activator. Labelle Y, Bussieres J, Courjal F, Goldring MB. Oncogene 1999; 18:3303-3308. Medline 99286095

Fusion of the EWS-related gene TAF2N to TEC in extraskeletal myxoid

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -386- chondrosarcoma. Sjogren H, Meis-Kindblom J, Kindblom L-G, Aman P, Stenman G. Cancer Res 1999; 59: 5064-5067. Medline 20005666

Fusion of the NH2-terminal domain of the basic helix-loop-helix protein TCF12 to TEC in extraskeletal myxoid chondrosarcoma with translocation t(9;15)(q22;q21). Sjogren H, Wedell B, Meis-Kindblom JM, Kindblom L-G, Stenman G. Cancer Res 2000; 6: 6832-6835. Medline 11156374

The AF2 domain of the orphan nuclear receptor TEC is essential for the transcriptional activity of the oncogenic fusion protein EWS/TEC. Maltais A, Filion C, Labelle Y. Cancer Lett 2002; 183: 87-94. Medline 12049818

The EWS/NOR1 fusion gene product gains a novel activity affecting pre-mRNA splicing. Ohkura N, Yaguchi H, Tsukada T, Yamaguchi K. J Biol Chem 2002; 277: 535-543. Medline 11673470

The homeotic protein Six3 is a coactivator of the nuclear receptor NOR-1 and a corepressor of the fusion protein EWS/NOR-1 in human extraskeletal myxoid chondrosarcomas. Laflamme C, Filion C, Bridge JA, Ladanyi M, Goldring MB, Labelle Y. Cancer Res 2003; 63: 449-454. Medline 12543801

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 07- Goran Stenman 2003 Citation This paper should be referenced as such : Stenman G . NR4A3 (nuclear receptor subfamily 4, group A, member 3). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TECID75.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -387- Atlas of Genetics and Cytogenetics in Oncology and Haematology

dic(9;12)(p13;p13) (updated: old version not available)

Identity

dic(9;12)(p13;p13) diagram and breakpoints and C-banding (above) - Editor; G- banding (left) - Courtesy Jean-Luc Lai; R- banding with chr 12 up side down (right)- Editor

Clinics and Pathology Disease Acute lymphocytic leukemia (ALL)most often; rarely: chronic myelogenous leukemia (CML) in blast crisis, T-cell leukaemia or non Hodgkin lymphoma (NHL) Phenotype / ALLs with dic(9;12) are most often L1/L2 and CD10+, at times CIg+ cell stem ALL origin Epidemiology 1% of paediatric ALL; sex ratio: 2M/1F; children and young adults (>1yr, <25yrs); no infant case Clinics moderate organomegaly; blood data: moderate WBC

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -388-

Treatment bone marrow transplantation is not indicated; no high risk protocol Prognosis complete remission is obtained in all cases; 5 yrs survival > 95% Cytogenetics Cytogenetics dicentric with loss of parts of 9p and 12p --> ploidy: 45 chromosomes Morphological Additional +8, +21, ... anomalies Genes involved and Proteins Gene PAX5 Name Location 9p13 The PAX5 coding region extends over a genomic interval of approximately 200kb and comprises 10 exons. Two alternative Dna / Rna transcripts have been identified, originating from alternative promotor usage, containing exon 1A or 1B. Full length mRNA is 3650bp. Protein PAX5 belongs to the paired box family of transcription factors, involved in a multitude of developmental processes. PAX5 was originally identified as a B-cell specific transcription factor (B-cell-specific activator protein, BSAP. Recently, it has been shown that PAX5 expression is not only continuously required for B cell lineage commitment during early B cell development but also for B lineage maintenance. Contains a paired box (DNA binding) domain, a truncated homeo domain homology region, and a transactivation domain. Gene ETV6 Name Location 12p13 Dna / Rna alternative transcripts Protein contains a HLH domain and a ETS-DNA binding domain; ETS-related transcription factor, transcriptional repressor that binds to DNA sequence 5'- CCGGAAGT-3', can form homodimers or heterodimers with TEL2 or FLI1 Result of the

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -389- chromosomal anomaly Hybrid fusion of PAX5 to ETV6; constant breakpoints in PAX5 intron 4 and gene ETV6 intron 2, in the three cases described so far. Description Transcript 5'PAX5 - 3'ETV6 transcript, no reciprocal transcript due to deletion Detection RT-PCR, FISH

Fusion The PAX5/ETV6 chimeric transcript results in fusion of the paired box Protein domain (PRD) of PAX5 to the helix-loop-hel ix and ETS-binding Description domains of ETV6. Of note: the putative chimeric protein contains the DNA-binding domains of both fusion partners, namely the PRD and the ETS-domain.

External links Other dic(9;12)(p13;p13) Mitelman database (CGAP - NCBI) database To be noted Bone marrow transplantation should not be performed, as the prognosis of the dic(9;12)/ALL is excellent. Cases with dic(9;12) involvement are collected and analyzed for the presence of the PAX5/ETV6 fusion. If you are interested in participating in this study, please contact: [email protected] Bibliography Two cases of dic(9;12) in acute Iymphocytic leukaemia (ALL). Prognosis in ALL with dic(9;12). Huret JL, Heerema NA , Brizard A, Provisor AJ, Benz-Lemoine E, Guilhot F, Savage JRK, Tanzer J. Leukemia 1990; 4: 423-425. Medline 95147469

Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group. Behrendt H, Charrin C, Gibbons B, Harrison CJ, Hawkins JM, Heerema NA, Horschler-Botel B, Huret JL, Lai JL, Lampert F, et al Leukemia. 1995; 9: 102-106. Medline 95147469

The non-random dic(9;12) translocation in acute lymphoblastic leukemia is associated with B-progenitor phenotype and an excellent prognosis. Mahmoud H, Carroll AJ, Behm F, Raimondi SC, Schuster J, Borowitz M, Land V, Pullen DJ, Vietti TJ, Crist W. Leukemia. 1992; 6: 703-707.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -390- Medline 92326440

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

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

Contributor(s) Written 08- Jean-Loup Huret 1997 Updated 06- Jean-Loup Huret 2003 Updated 01- Sabine Strehl 2004 Citation This paper should be referenced as such : Huret JL . dic(9;12)(p13;p13). Atlas Genet Cytogenet Oncol Haematol. August 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/dic0912.html Huret JL . dic(9;12)(p13;p13). Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/dic0912.html Strehl S . dic(9;12)(p13;p13). Atlas Genet Cytogenet Oncol Haematol. January 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/dic0912.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -391- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ins(5;11)(q31;q13q23) (updated: old version not available)

Clinics and Pathology Disease acute lymphoblastic leukemia (ALL) and ALL evolving towards a M4- acute non lymphocytic leykemia (ANLL) Phenotype / cell stem CD19+ origin Epidemiology poorly defined: only 2 cases to date Clinics a girl aged 4 mths, who entered complete remission, relapsed and died 20 mths after diagnosis, and a 3 mth old boy who had a 18 mths remission, developped relapses and died. Prognosis yet unknown, likely to be poor Cytogenetics Cytogenetics the chromosomal rearrangement may be hidden if only a small portion Morphological of chromosome 11 (with MLL) is transferred into chromosome 5 (in the vicinity of AF5Q31) Cytogenetics the use of MLL probes can uncover the anomaly Molecular Additional i(17q) in one case, and a complex karyotype in the other case anomalies Variants a few cases of t(5;11)(q31;q23) have been described, but it is unknown if they involve the same genes Genes involved and Proteins Gene AF5q31 Name Location 5q31.1 Protein present homologies with AF4 Gene MLL Name Location in 11q23 Dna / Rna 13-15 kb mRNA Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -392- Result of the chromosomal anomaly Hybrid gene 5' MLL- 3' AF5q31 Description

External links Other ins(5;11)(q31;q13q23) Mitelman database (CGAP - 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 AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y. Proc Natl Acad Sci USA 1999; 96: 14535-14540.

Insertion of MLL sequences into chromosome band 5q31 results in an MLL- AF5Q31 fusion and is a rare but recurrent abnormality associated with infant leukemia. Deveney R, Chervinsky DS, Jani-Sait SN, Grossi M, Aplan PD. Genes Chromosomes Cancer. 2003; 37: 326-331. Medline 12759932 Contributor(s) Written 04- Jean-Loup Huret 2000 Updated 06- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . ins(5;11)(q31;q13q23). Atlas Genet Cytogenet Oncol Haematol. April 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/ins511ID1167 Huret JL . ins(5;11)(q31;q13q23). Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/ins511ID1167 © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -393- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(1;21)(p32;q22)

Clinics and Pathology Disease Acute myelomonoblastic leukemia (M4 by FAB subtype). Phenotype / CD34+,DR+,CD117+, CD15+, CD13+, CD33+, MPO+, CD64+ blast cell stem population consistent with ANLL-M4 by FAB subtype. origin Etiology Unknown, reported agricultural chemical exposure in single case. Epidemiology Single case involving 25 year old male. Clinics Patient presented w/o palpable adenopathy, gingival hyperplasia, systolic murmur, hepatosplenomegaly and petechia. WBC was normal with anemia and thrombocytopenia. Cytology Predominately large blasts with moderate cytoplasm, smooth nuclear chromatin, and prominent nucleoli, folded nuclear contours present in blast subset. Treatment Patient lost to treatment. Evolution Unknown Prognosis Unknown Cytogenetics Cytogenetics Single case presented with second copy of der(1)t(1;21). Morphological

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Chromosome and FISH images showing : 1) partial karyotype and ideogram of t(1;21)(p32;q22) including a second copy of the der(1)t(1;21) present in the clone; and 2) metaphase FISH showing red AML1 signal on the two copies of the der(t)t(1;21), the der(21)t(1;21) and the normal 21 homolog. Green TEL signal is present of both 12 homologs indicating that no cryptic TEL/AML1 gene rearrangement is present. The adjacent interphase nucleus shows four AML1 signals and two TEL signals consistent with the metaphase pattern.

Cytogenetics AML1 fusion suggested by partial translocation of 500kb probe signal Molecular to der(1)t(1;21). Probes Commercially available 500kb AML1 probe. Genes involved and Proteins Note The putative 1p32 gene partner is unknown. Cryptic t(12;21) TEL(ETV6)/AML1 rearrangement is unlikely due to normal TEL metaphase FISH signal using commercial TEL/AML1 probe. Gene AML1 Name

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -395- Location 21q22 Dna / Rna AML 1 is oriented 3' toward the centromere. Protein Contains a runt domain and at C-term a tranactivation domain; forms heterodimers, widely expressed; nuclear localization; transcription factor(activator) for various hematopoietic-specific genes. External links Other t(1;21)(p32;q22) Mitelman database (CGAP - NCBI) database Other t(1;21)(p32;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography A unique AML1 (CBF2A) rearrangement, t(1;21)(p32;q22), observed in a patient with acute myelomonocytic leukemia. Cherry AM, Bangs CD, Jones P, Hall S, Natkunam Y. Cancer Genetics and Cytogenetics 2001; 129:155-160. Medline 21450465

Contributor(s) Written 06- Charles D. Bangs 2003 Citation This paper should be referenced as such : Bangs CD . t(1;21)(p32;q22). Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0121p32q22ID1259.html

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Trisomy 19

Clinics and Pathology Disease Trisomy 19 (+19) as a sole karyotypic aberration is strongly associated with myeloid disorder. In a previously published literature review, among 31 patients with isolated +19, 25 were diagnosed with myeloid malignancy, including acute myeloid leukaemia (AML) in 14 cases and myelodysplastic syndrome (MDS) in 11 cases. Four out of the 14 AML patients had a preceding MDS phase, with +19 appearing at the time of leukaemic transformation. None of the MDS or AML cases, however, had a history of exposure to radiotherapy and chemotherapy. Hence isolated +19 is associated with a subgroup of de novo myeloid disorder, in which the clinical characteristics and prognostic impact require further delineation.

As a secondary or additional abnormality, +19 is frequently encountered in chronic myeloid leukaemia (CML). Though not as common as trisomy 8, i(17q) and extra Ph chromosome, +19 is nevertheless seen in up to 15% of CML patients with additional abnormalities.

Frequent gain of chromosome 19 or 19q was recently detected by comparative genomic hybridization in 4 out of 12 (33.3%) patients samples of acute megakaryoblastic leukaemia (AML-M7) and 9 out of 11 (81.8%) megakaryoblastic cell lines. In none of the primary patient samples was the abnormality detected by G-banding analysis. In another study on childhood and adult AML-M7, +19 was detected in 7 out of 53 patients, although as an additional abnormality in all cases. It appears +19 may play a role in the pathogenesis of megakaryoblastic leukaemia. Etiology Isolated +19 is probably associated with de novo myeloid disorders, as none of the AML and MDS cases with this abnormality reported had a history of prior radiotherapy or chemotherapy exposure. Prognosis Although isolated +19 is strongly associated with myeloid disorders, most probably de novo disease, its prognostic significance requires further elucidation. Bibliography Trisomy 19 in a patient with myelodysplastic syndrome and thrombocytosis. Humphries JE, Wheby MS. Cancer Genet Cytogenet 1990; 44: 187-191. Medline 2297677

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Trisomy 19 as the sole chromosomal anomaly in hematologic neoplasms. Johansson B, Billstrom R, Mauritzson N, Mitelman F. Cancer Genet Cytogenet 1994; 74: 62-65. Medline 8194050

Frequent gain of chromosome 19 in megakaryoblastic leukemias detected by comparative genomic hybridization. Alvarez S, MacGrogan D, Calasanz MJ, Nimer SD, Jhanwar SC. Genes Chromosomes Cancer 2001; 32: 285-293. Medline 11579469

Chromosome 19 abnormalities are commonly seen in AML, M7. Nimer SD, MacGrogan D, Jhanwar S, Alvarez S. Blood 2002; 100: 3838. Medline 12411327

Contributor(s) Written 06- Edmond S.K. Ma, Thomas S.K. Wan 2003 Citation This paper should be referenced as such : Ma ESK, Wan TSK. . Trisomy 19. Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/tri19ID1039.html

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t(1;12)(p36;p13)

Clinics and Pathology Disease Myeloid disorders: one chronic myelogenous leukemia with t(9;22) and one refractory anemiia with excee of blasts in transformation Epidemiology only 2 cases so far: 1 male and 1 female patient, aged 50 and 66 yrs Prognosis unknown so far Genes involved and Proteins Gene MDS2 Name Location 1p36 Dna / Rna 7 exons; alternate splicing Gene ETV6 Name Location 12p13 Dna / Rna 9 exons; alternate splicing Protein contains a Helix-Loop-Helix and ETS DNA binding domains; wide expression; nuclear localisation; ETS-related transcription factor Result of the chromosomal anomaly Hybrid 5' ETV6 - 3' MDS2; exons 1 and 2 of ETV6 are fused to exons 6 and 7 gene of MDS2; fusion is not in frame; the reciprocal fusion gene is not Description expressed

Fusion Protein truncated ETV6 lacking the PTN domain and the DNA binding domain Description

External links Other t(1;12)(p36;p13) Mitelman database (CGAP - NCBI) database Other t(1;12)(p36;p13) CancerChromosomes (NCBI)

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -399- 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 Granulocytic sarcoma of the larynx preceding chronic myeloid leukemia. Vassallo J, Altemani AM, Cardinalli IA, Crespo AN, Passos Lima CSP, Eid KA, Souza CA. Pathol Res Pract 1993; 189: 1084-1086.

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

Contributor(s) Written 07- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(1;12)(p36;p13). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0112p36p13ID1170.html

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t(X;10)(p10;p10)

Clinics and Pathology Disease Acute non lymphocytic leukemia (ANLL) (M1 and M5 ANLL) and biphenotypic leukemia Epidemiology only 3 cases available so far; 2 male and 1 female patients, aged 2, 27, and 86 yrs Prognosis unknown (one case died at 1 mth, another one is alive at 74 mths +) Genetics genes involved are unknown Cytogenetics Additional complex karyotypes were found in two of three cases, del(5q) and +8 in anomalies two cases each, -7 in one case External links Other t(X;10)(p10;p10) Mitelman database (CGAP - NCBI) database Other t(X;10)(p10;p10) 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 Bone marrow karyotypes in 94 children with acute leukemia. Heim S, Bekassy AN, Garwicz S, Heldrup J, Kritoffersson U, Mandahl N, Webe T, Mitelman F. Eur J Hematol 1990; 44: 227-233.

Translocation (X;10)(p10;p10). A rare but non random chromosomal abnormality in acute leukemia of myeloid differenciation. Wong KF, Hayes KJ, Huh YO, Albitar M, Glassman AB. Cancer Genet Cytogenet 1996; 86: 153-155.

Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -401- Written 07- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(X;10)(p10;p10). Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0X10p10p10ID1256.html

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Bone: Chondroma

Identity Note Chondroma is an uncommon benign tumour which characteristically forms mature cartilage. It is found mostly in the small bones of the hand and/or feet, although it can also occur in long, tubular bones, primarily the humerus, femur and ribs. Occasionally, focal areas of mixoid degeneration may result in a mistaken diagnosis of chondrosarcoma. Classification Chondromas are classified according to their location: enchondroma: within the bone (within the medullary cavity), periosteal chondroma: on the surface of the bone, soft tissue chondroma in the soft tissue. Clinics and Pathology Disease Enchondroma Note Fig: Enchondroma in the distal portion of the femur shaft. (courtesy of Dr Henry DeGroot at http://www.drdegroot.com)

Enchondroma is usually a solitary benign lesion in intramedullary bone. Usually asymptomatic, it is incidentally discovered as a palpable bony nodule. Rarely, causes soft tissue swelling and pain at the lesion site. Pain can be a sign of pathologic fracture. Both sex are equally affected, and any age group can be involved. It is thought to develop from epiphyseal cartilage rests that subsequently proliferate and slowly enlarge. Approximately 50% of solitary enchondromas are found in the hands, typically in the middle and distal portions of the metacarpals and the proximal portions of the phalanges, 10% in the feet, 20% in the proximal and distal parts of the femur and the proximal part of the humerus. On gross examination, the lesion is well circumscribed and has the pale bluish-gray appearance typical of cartilage. The nonerheditary syndrome of multiple enchondromas or enchondromatosis is known as Ollier's disease. Enchondromatosis associated with soft tissue hemangiomas is known as Maffucci's syndrome. Pathology Microscopically, enchondroma is hypocellular with few double-nucleated cells without cytologic atypia, but cellularity may vary. There is no permeation of morrow. The matrix does not show any myxoid change. Calcification and ossification are common. Histologic appearance of

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -403- enchondroma may recall that of a grade-1 chondrosarcoma. The permeation through the cortex into soft tissue must be identified before a diagnosis of chondrosarcoma is made. The chondromas in Ollier disease and Maffucci syndrome may demonstrate a greater degree of cellularity and cytologic atypia, and may be difficult to distinguish from chondrosarcoma. Fig: H&E 20x original magnification of an enchondroma: note lobules of benign cartilage cells and hyaline matrix. (courtesy of Dr Henry DeGroot at http://www.drdegroot.com).

Treatment No treatment is required for asymptomatic lesions. If fracture occurs it is usually treated with curretage and bone grafting. Evolution A small percentage of enchondromas will undergo malignant transformation, usually throught a slow process, occurring over decades. It is more common in long bones than short. Prognosis Prognosis for benign enchondroma is excellent. Solitary lesion in the hand rarely undergoes transformation. It has been suggested that Maffucci¹s syndrome is associated with a very high incidence of malignancy, either in the skeleton or in visceral organs.

Disease Periosteal chondroma Note a) Fig: Ankle periosteal chondroma; {courtesy of Dr Nick Ordall http://www.xray2000.f9.co.uk/) b) Fig: Chondroma of the right femur (courtesy of Dr Henry DeGroot at http://www.drdegroot.com/) Periosteal chondroma is a painful cartilaginous lesion that arises from surface of cortex deep to the periosteum, producing broad based cartilaginous mass that may extend into soft tissues; often develops after adolescence. It does not infiltrate the adjacent soft tissue but may increase in size. It is similar in appearance and location to periosteal osteosarcoma. The potential for confusion with periosteal and parosteal osteosarcoma mandates a thorough investigation and biopsy of this lesion. The most common location is adjacent to the metaphysis. The cortex may be involved to a variable degree, but the lesions do not involve the medullary space. Pathology It persists as mass of mature cartilage. Low power microscopy shows well circumscribed lobulated hyaline masses. Cellularity can vary, from hypo- to hyper-cellularity. The cartilage looks more active than enchondroma and the lesion may be confused with chondrosarcoma. Fig: Bone tumor images (courtesy of Dr Henry DeGroot at http://www.drdegroot.com)

Treatment Periosteal chondromas are treated with conservative excision. Prognosis Risk of recurrence after bloc marginal excision is less than 10%.

Disease Soft-tissue chondroma Note Soft-tissue chondroma is a benign cartilage-forming tumor,usually

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -404- arising from tenosynovial sheaths or the soft tissue adjacent to tendons in the hands and feet, usually without any connection to the underlying bone. Predominantly sited in the fingers, it is usually solitary, develops in adults, and may causes pain. It is composed entirely of mature hyaline cartilage. Infrequently, the tumor undergoes secondary changes and may exhibit morphologic features that result in diagnostic difficulty. Pathology Microscopically, soft-tissue chondromas vary considerably in appearence. Most consist of hyaline cartilage arranged in lobular pattern, and may show focal fibrosis, ossification, or myxoid change. Diffuse calcification may occur, completely obscuring the cartilagineous nature of the lesion. In some variants, the cartilage matrix becomes extensively mineralized, often associated with necrosis of chondrocytes, causing the tumor to resemble tumoral calcinosis. Hyaline cartilage may also undergo enchondral ossification, mimicking an osteogenic neoplasm or a reactive lesion. Myxoid degeneration may create confusion with extraskeletal myxoid chondrosarcoma. Treatment Local surgery is the treatment of choice. Genetics Note Cytogenetic studies of chondromas are scarse. A total of 16 cases with abnormal karyotypes have been reported: 6 enchondromas, 4 periosteal chondromas, and 6 soft part chondromas. No consistent abnormality has been detected, although chromosome or chromosomal region 4, 5, 6, 7 and 12q13-15 seems to be nonrandomly involved in changes. Bibliography Clonal karyotypic aberrationsin enchondromas. Bridge JA, Persons DL, Neff JR, Bhatia P. Cancer Detect Prev 1992; 16: 215-219. Medline 1458512

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. Medline 8402563

Rearrangement of band q13 on both chromosomes 12 in a periosteal chondroma. Mandahl N, Willen H, Rydholm A, Heim S, Mitelman F. Genes Chromosomes Cancer 1993; 6: 121-123. Medline 7680888

Rearrangement of band q13 on both chromosomes 12 in a periosteal chondroma Shadan FF, Mascarello JT, Newbury RO, Dennis T, Spallone P, Stock AD. Cancer Genet Cytogenet. 2000; 118 :144-147. Medline 10748295

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The Cytogenetics of bone and soft tissue tumors. Sandberg AA Bridge JA. Austin: R.G. Landes Company; 1994

Involvement of chromosomes 6 and 11 in a soft tissue chondroma. Dal Cin P, Qi H, Sciot R, Van den Bergh H. Cancer Genet Cytogenet 1997; 93: 177-178. Medline 9078305

Solitary enchondroma with clonal chromosomal abnormalities. Gunawan B, Weber M, Bergmann F, Wildberger J, Fuzesi L. Cancer Genet Cytogenet 1998; 104: 161-164. Medline 9666812

Maffucci's syndrome: clinical and radiological features of a rare condition McDermott AL, Dutt SN, Chavda SV, Morgan DW. J Laryngol Otol. 2001; 115: 845-847. Medline 11668006

Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. Tallini G, Dorfman H, Brys P, Dal Cin P, de Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Sciot R, Van den Bergh H, Vanni R, Willen H. J Pathol 2002; 196: 194-203. Medline 11793371

Cytogenetic findings in benign cartilaginous neoplasms. Buddingh EP, Naumann S, Nelson M, Neffa JR, Birch N, Bridge JA. Cancer Genet Cytogenet 2003; 141: 164-168 Medline 12606137

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: chondrosarcoma and other cartilaginous neoplasms. Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2003;143: 1-31. Medline 12742153

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Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -406- Written 05- Roberta Vanni 2003

Citation This paper should be referenced as such : Vanni R. . Bone: Chondroma. Atlas Genet Cytogenet Oncol Haematol. May 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/ChondromaID5147.html

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Thyroid: Anaplastic (undifferentiated) carcinoma

Identity Note Anaplastic (undifferentiated) carcinoma of the thyroid gland is a highly malignant tumor composed in part or wholly by undifferentiated malignant cells. Anaplastic (undifferentiated) thyroid carcinoma is a highly malignant tumor composed by undifferentiated malignant cells. Clinics and Pathology Epidemiology Anaplastic (undifferentiated) carcinoma of the thyroid gland is uncommon, accounting for less than 5% of all cases of thyroid carcinoma. The average age at diagnosis was 66.5 years, with a female to male ratio of 3.1:1 in one study of 70 cases. Clinics Most patients are euthyroid with a history of a rapidly enlarging neck mass. Sometimes, the tumor presents as a new-onset thyroid enlargement in a patient with longstanding thyroid nodule(s) or as the recurrence of a well-differentiated carcinoma. Tumor infiltration of surrounding structures results in secondary symptoms (dyspnea, dysphonia, dysphagia). Pathology Tumors are poorly defined, fleshy masses with areas of necrosis and hemorrhage. Microscopically they are composed of anaplastic cells with marked cytologic atypia and high mitotic activity. Tumor necrosis and vascular invasion are common. Histologic patterns include spindle, giant and squamoid cell types. Other patterns (e.g. angiomatoid, carcinosarcoma, lymphoepithelioma-like, adenosquamous) have been described. Undifferentiated (anaplastic) carcinoma of the thyroid must be differentiated from other high grade tumors with similar microscopic appearance originating from adjacent structures in the neck (e.g. larynx). Sometimes this distinction is only possible on clinical/anatomical grounds. Immunohistochemically, undifferentiated thyroid carcinoma is generally negative for thyroglobulin and calcitonin. Pankeratin and epithelial membrane antigen (EMA) are positive in about one-half and one-third of cases respectively. Thyroid transcription factor-1 (TTF-1) staining is present in 0-50% of cases.

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Treatment No effective treatment modalities are currently available. Prognosis Anaplastic (undifferentiated) carcinomas are highly aggressive neoplasms that are usually widely invasive at presentation. Regional and distant metastases are common. Most patients die within 1 year of the diagnosis with a median survival of 3.1 months in one study. The 5-year survival rate is around 5%, and the surviving cases are typically small tumors confined to the thyroid amenable to local resection. Cytogenetics Cytogenetics Anaplastic (undifferentiated) carcinoma represents not only Morphological morphologically but also in terms of somatic genetic alterations the extreme malignant form of thyroid cancer and as such it is characterized by complex chromosomal alterations. Cytogenetics LOH: Allelic loss has been identified at 1q (40%), 9p (58%), 11p Molecular (33%), 11q (33%), 17p (44%), 17q (43%), 19p (36%), 22q (38%). CGH: DNA unbalance can be demonstrated at a variety of chromosomal loci in 80% of undifferentiated carcinomas with a median number of chromosomal losses or gains of 10 per case with abnormal CGH profile. Gains were more common than DNA losses. Loss of chromosomal DNA was identified at 1p, 2q, 4q, 5q, 6q, 8p, 13q, 22q. Specific chromosomal DNA alterations (i.e. 3p13-14+, 5q11- 31-, 11q13+) may be associated with the transition from more differentiated phenotypes to anaplastic thyroid cancer. Genes involved and Proteins Note The genetic mechanisms involved with the development of anaplastic thyroid cancer are poorly understood. ATC are characterized by increased cell replication and high Ki67/Mib1 proliferation index, loss of

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -409- the apoptotic protein bcl-2 and of Fas and its ligand (usually highly expressed in well differentiated thyroid tumors), by an increase in the proapoptotic protein Bax, by Cyclin D1 over-expression and conversely by a fall in the CDK inhibitor p27. It is not clear whether these changes represent the cause or (more likely) the effect of disregulated cell differentiation and growth in anaplastic cancer. Mutational inactivation of p53 has been identified in 70-80% of anaplastic carcinomas while H-Ras, K-Ras, or N-Ras activating mutations are present in approximately 50% of the cases. Aberrant Wnt/beta-Catenin signaling appears to be a distinctive feature of anaplastic thyroid cancer since stabilizing mutations and/or aberrant beta-Catenin nuclear localization are present in 80% of ATC. beta- Catenin nuclear localization is accompanied by its cellular redistribution with marked decrease of the beta-Catenin membrane bound fraction.

Bibliography Anaplastic thyroid carcinoma: a study of 70 cases. Carcangiu ML, Steeper T, Zampi G, Rosai J. Am J Clin Pathol 1985; 83:135-158. Medline 2578727

Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Jenkins RB, Hay ID, Herath JF, Schultz CG, Spurbeck JL, Grant CS, Goellner JR, Dewald GW. Cancer 1990; 66:1213-1220. Medline 2400971

Tumors of the thyroid gland. Rosai J, Carcangiu ML, DeLellis RA Atlas of tumor Pathology 1992, 3rd series, fascicle 5.

Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. Donghi R, Longoni A, Pilotti S, Michieli P, Della Porta G, Pierotti MA. J Clin Invest 1993; 91:1753-1760. Medline 8473515

Treatment of 37 patients with anaplastic carcinoma of the thyroid. Kobayashi T, Asakawa H, Umeshita K, Takeda T, Maruyama H, Matsusuka F, Monden M. Head and Neck 1995; 18:36-41. Medline 8774920

DNA copy number changes in thyroid carcinoma.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -410- Hemmer S, Wasenius VM, Knuutila S, Franssila K, Joensuu H. Am J Pathol 1999; 154:1539-1547. Medline 10329606

Downregulation of p27KIP1 and Ki67/Mib1 labelling index support the classification of thyroid carcinoma into prognostically relevant categories. Tallini G, Garcia-Rostan G, Herrero A, Zelterman D, Viale G, Bosari S, Carcangiu ML. Am J Surg Pathol 1999; 23:678-685. Medline 10366150

Allelotyping of anaplastic thyroid carcinoma: frequent allelic losses on 1q, 9p, 11, 17, 19p, and 22q. Kitamura Y, Shimizu K, Tanaka S, Ito K, Emi M. Genes Chromosomes & Cancer 2000; 27: 244-251. Medline 10679913

Beta catenin dysregulation in thyroid neoplasms: down regulation, aberrant nuclear expression and CTNNBI exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis. Garcia-Rostan G, Camp RL, Herrero A, Carcangiu ML, Rimm DL, Tallini G. Am J Pathol 2001; 158:987-996. Medline 11238046

Genome-wide appraisal of thyroid cancer progression. Wreesmann VB, Ghossein RA, Patel SG, Harris CP, Schnaser EA, Shaha AR, Tuttle RM, Shah JP, Rao, PH, Singh B. Am J Pathol 2002; 161:1549-1556. Medline 12414503

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Oluwole Fadare, Giovanni Tallini 2003 Citation This paper should be referenced as such : Fadare O, Tallini G . Thyroid: Anaplastic (undifferentiated) carcinoma. Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/AnaCarciThyroidID5069.html

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Bone: Giant cell tumour

Identity Other Osteoclastoma. names Giant cell tumour of bone.

A characteristic well-defined eccentric, lytic subchondral lesion involving the epiphysis and metaphysis. The borders are well defined and usually not sclerotic. Pathologic fracture is present in 5-10% of giant cell tumours. Dynamic MRI shows a fast uptake and a slow wash out of contrast. Clinics and Pathology Disease Locally destructive, benign and mono-ostotic tumoral lesion, typically presenting in the meta-epiphysis of long tubular bones with predilection for the knee region of skeletally mature patients (more than 95% of the

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -412- patients is older than 25 years). Poly-ostotic lesions are exceptionally rare, counting for less than 1% of all cases. In these cases especially brown tumour of hyperparathyreoidism should be considered, which may look histologically identical. Although defined as a benign lesion, adjacent soft tissue invasion, angiovascular invasion and pulmonary metastases (1%) may occur. Phenotype / cell stem Not yet determined. origin Embryonic Mesoderm. origin Etiology The exact origin is still unknown, but data obtained from ultrastructural analyses and cell cultures, suggest that the "stromal" cell, or mononuclear spindle cell, is neoplastic. The mononuclear rounded cells and the osteoclastic giant cells are seen as reactive. Therefore, some suggest that "stromal cell tumour" is a better name, because this fits more precisely the concept of the mononuclear spindled cell (stromal cell) as neoplastic. Epidemiology This tumour represents 8% of all primary and approximately 20% of benign primary bone tumours. Mostly affecting adults in the third, fourth and fifth decade of life (72%). It is very rarely seen under the age of 10 years (1,3%). There is a slight female predominance (male/female ratio: 46,6%/53,4%). Clinics Pain of several weeks to months duration and a constantly expanding mass on X-ray, primary in the epiphysis, leading to cortex destruction, pathological fracture and soft tissue invasion. Finally ulceration of the skin occurs if not threatened. A pathological fracture could occasionally be the first sign of this tumour.

Mixture of three cellular components composites the tumour: tumoral spindle shaped mononuclear cells, reactive rounded mononuclear cells and diffusely scattered osteoclast type giant cells. Note that mitoses are strictly limited to the first cell type.

Pathology A mixture of four components can be distinguished: spindled-shaped and rounded mononuclear cells, osteoclastic-type giant cells and small blood vessels.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -413- The spindle-shaped mononuclear cells are regarded as neoplastic on results from electron microscopy and cell cultures. The origin of this cell type is still unknown, but it is thought to arise from the primitive mesenchymal stromal cell. Conventional mitotic figures are restricted to mononuclear cells. If atypical forms or strong nuclear atypia is noted, a secondary sarcomatous malignancy is almost always present. Secondary changes may be present like osteoid deposits, foci of fibrosis, collections of foamy cells or cystic degeneration. Secondary aneurysmal bone cyst formation is present in 6,5% of the cases. Mostly this is restricted to younger patients (median of 14 years) and low histological grade giant cell tumours.

As mentioned earlier, this tumour can histological be graded into 3 grades according to Jaffe (1940) or into 4 grades (Netherlands Committee on Bone Tumours). According to the latter grading system, grade 1 en 2 are considered as being benign, grade 3 as borderline malignant and grade 4 as malignant tumours. Grade 4 tumours show histological overlap with malignant fibrous hystiocytoma of bone. Although many authors are sceptic about grading giant cell tumours, this shows a good correlation with clinical outcome.

In that time no adjuvant chirurgical treatment, like cryosurgery or phenol additive was used. Nowadays the usefulness of grading in relation to recurrences is highly influenced by more effective surgical adjuvant techniques. According to literature still 20% of the giant cell tumours will recur, despite of these new surgical techniques. Together with the risk of developing pulmonal metastases, grading of giant cell tumours is in our view still valuable. In this grading system mitoses, pleiomorphism of the spindled mononuclear cells, giant cells and the individual size of the giant cells will be taken into account. Most important is the mitotic activity. When mitoses are occasional observed the risk of developing recurrences and pulmonal metastases is neglectable. If more than 1 mitosis is present per 1 high power field, patients are significantly at risk for developing recidives and pulmonal metastases (23%). Grade 2 tumours do have the highest prevalency (grade 1: 4%, grade 2: 88%, grade 3: 5%, grade 4: 3%).

Table : Grading of giant cell tumours according to the Netherlands Committee on

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -414- Bone Tumors.

Treatment Surgical intervention is the only treatment of choice. Mostly a curettage followed by local adjuvant cryosurgery or phenol instillation is sufficient to eradicate this lesion and to save the joint. The use of polymethylmetacrylate for filling the cavity after curettage additively decreases the percentage of recurrences. An added advantage of using cement is that recurrences are detected sooner. Sometimes 'en bloc' resection is needed to be curative. Pulmonal metastases are treated by local excision. Evolution Non-treatment always leads to destruction of cortical bone, to soft tissue invasion and finally to ulceration of the skin. Local recurrences can occur following proper treatment, mostly indicating less radical initial resection. Prognosis Good, despite of recurrences and pulmonary metastases. In general much is depending on the surgical technique and expertise in combination with the histological grade of this tumour. Although pulmonary metastases may occur in rare cases, angiovascular invasion does not have any significant influence on its prognosis. The mortality rate due to giant cell tumour is about 4%. Cytogenetics Note No recurrent chromosomal structural or numeric aberrations of importance have been detected yet. When confronted with a rearrangement, especially concerning 16q22 or 17p3, an associated aneurysmal bone cyst should be excluded. Cytogenetics The most frequent chromosomal anomaly is telomeric association. Morphological Comparing telomere length of giant cell tumours to this of leukocytes of the same patient, a reduction has been demonstrated. Most commonly affected telomeres are 11p, 13p, 14p, 15p, 19q, 20q and 21p. Bibliography Cytogenetic findings and biological behaviour of giant cell tumors. Bridge JA, Neff JR, Bathia PS, Sanger WG, Murpey MD. Cancer 1990; 65: 2697-2703. Medline 90254548

Giant cell tumor of bone. Chromosomal analysis of 48 specimens and review of the literature. Bridge JA, Neff JR, Mouron BR. Cancer Genet Cytogenet 1992; 58: 150-151. Medline 92103606

Cytogenetic study of 249 consecutive patients examined for a bone tumor. Tarkkanen M, Kaipainen A, Karaharju E, Böhling T, Szymanska J, Helio H, Kivioja A, Elomaa I, Knuutila S.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -415- Cancer Genet Cytogenet 1993; 68: 1-21. Medline 93321187

Telomere reduction in giant cell tumor of bone and with aging. Schwartz HS, Dahir GA, Butler MG. Cancer Genet Cytogenet 1993; 71: 132-138. Medline 94108877

Radiologic Atlas of Bone Tumors. Mulder JD, Kroon HM, Schütte HE, Taconis WK. Amsterdam: Elsevier, 1993.

Cytogenetics of fine needle aspiration biopsies of sarcomas. Molenaar WM, van den Berg E, Dolfin AC, Zorgdrager H, Hoekstra HJ. Cancer Genet Cytogenet 1995; 84: 27-31. Medline 96102250

Chromosomal anomalies exclusive of telomere associations in giant cell tumor of bone. McComb E, Johansson SC, Neff JR, Nelson M, Bridge JA. Cancer Genet Cytogenet 1996; 88: 163-166. Medline 96257783

Giant cell tumor of bone: a clinicopathologic study of prognostic factors. Masui F, Ushigome S, Fujii K. Pathol Int 1998; 48: 723-729. Medline 98449560

Giant cell tumor of bone metastasising to the lungs. A long-term follow-up. Siebenrock KA, Unni KK, Rock MG. J Bone Joint Surg Br 1998; 80: 43-47. Medline 98120849

Telomeric fusion is major cytogenetic aberration of giant cell tumors of bone. Zheng MH, Siu P, Papadimitriou JM, Wood DJ, Murch AR. Pathology 1999; 31: 373-378. Medline 10107621

Cytogenetic-morphological correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report form the CHAMP study group. Sciot R, Dorfman H, Brys P, Dal Cin P, de Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mittelman F, Rosai J, Rydholm A, Samson I, Tallini G, van den Berghe H, Vanni R, Willén H Mod Pathol 2000; 13: 1206-1210 Medline 20555664

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -416- Clonality studies in giant cell tumor of bone. Schwartz HS, Esken JD, Butler MG J Orthop Res 2002; 20(2): 387-390 Medline 21915254

Giant cell tumour Reid R, Banerjee SS, Sciot R Pathology and genetics of tumours of soft tissue and bone (WHO 2002)

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Ramses G Forsyth, Pancras CW Hogendoorn 2003 Citation This paper should be referenced as such : Forsyth RG, Hogendoorn PCW. . Bone: Giant cell tumour. Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/BoneGiantCellTumID5150.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -417- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Thyroid: Oncocytic tumors

Identity Note Oncocytes (from the greek word "swell"), also known as Hurthle cells, oxyphilic cells or Askanazy cells, are characterized by abundant granular cytoplasm due to aberrant accumulation of mitochondria. The cause for the mitochondria accumulation is unknown. The increased number of mithochondria may be a compensatory to intrinsic defects in the energy production machinery of the cell. Cells that fit this basic description may be identified in a variety of non-neoplastic lesions as well as in the affected tissues of patients with mitochondrial myopaties. Tumors composed of oncocytes are not restricted to the thyroid gland and may arise in a variety of locations, most commonly in the kidney and salivary gland and may be benign or malignant. By convention, thyroid tumors are designated as oncocytic if at least 75% of their constituent cells can be described as oncocytes. In the context of the traditional classification of differentiated thyroid tumors of follicular cell derivation into follicular and papillary histotypes, the majority of oncocytic neoplasms represent a distinct subtype of thyroid follicular tumors. Papillary carcinomas, as well as a few medullary thyroid carcinomas, may also be oncocytic but for the purpose of this brief review, "oncocytic tumors" will refer to the follicular cell derived neoplasm that lacks nuclear features of papillary carcinoma. Thyroid oncocytic tumors are neoplasms composed by a majority of cells with the morphologic features of oncocytes. Classification Note Oncocytic (Hurthle cell, oxyphilic cell, askanazi cell) adenoma: transcapsular and/or vascular invasion absent. Oncocytic (Hurthle cell, oxyphilic cell, askanazi cell) carcinoma: transcapsular and/or vascular invasion present.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -418-

Note Widely invasive oncocytic thyroid carcinoma

Clinics and Pathology Etiology Unknown. The precise cellular derangements that lead to the abnormal accumulation of mitochondria in oncocytes and tumor development are obscure. Alterations of nuclear genetic material (marked aneuploidy) and of mitochondrial DNA are a feature of thyroid oncocytic tumors. Epidemiology The mean age at diagnosis was 43 years for adenomas and 52 for oncocytic carcinomas in a recent series. There is a female preponderance in both subgroups, with a female-to-male ratio of 8:1 in adenomas and 2:1 in carcinomas. Thyroid oncocytic tumors represent approximately 5-10% of thyroid neoplasms. Clinics Most patients with oncocytic neoplasms are euthyroid and present with a thyroid nodule. Secondary syntoms due to compression of the adjacent structures in the neck (e.g. dysphonia, dysphagia) may be present, particularly in patients with malignant tumors. Pathology Grossly, oncocytic adenomas are encapsulated, solid nodules with a characteristic brown cut surface. Secondary changes, including infarction and hemorrhage are common (particularly after fine needle aspiration), possibly as a result of the low tolerance to ischemia displayed by the oncocytes. Histologically, the follicular growth pattern is most common but cells may also be arranged in trabeculae, solid sheets or papillary formations. The colloid is typically purple (amphophilic) rather than pink on conventional histology sections stained with hematoxylin and eosin. Oncocytes have round uniform nuclei with prominent nucleoli but may display scattered areas of

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -419- marked nuclear atypia and anisonucleosis. The gross appearance of a minimally invasive oncocytic carcinoma is indistinguishable to that of an adenoma, while widely invasive oncocytic carcinomas are obviously invasive macroscopically and display pervasive vascular invasion with multifocal involvement of the thyroid gland. There are no reliable cytologic features which distinguish oncocytic adenomas from carcinomas and the only criteria for a diagnosis of malignancy is the identification of transcapsular and/or vascular invasion.

Fig 1 : Oncocytic cells showing abundant granular cytoplasm and prominent

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -420- nucleoli (arrowheads) Fig 2 : Mitochondria accumulation in oncocytic cells. Some mitochondria have abnormal architecture with electrondense deposits (inset)

Treatment Oncocytic adenomas are treated with a simple lobectomy or nodulectomy, which is curative but should not be enucleated, as an evaluation of their capsule is essential for the pathologist to determine whether the tumor is benign or malignant. Carcinomas are treated with total/subtotal thyroidectomy followed by radioactive iodine therapy. Oncocytic carcinomas tend to have lower iodide uptake compared with non-oncocytic cancers and are often therefore less responsive to radioactive iodide administration. Prognosis The extent of tumor invasion determines the prognosis in oncocytic carcinomas. Patients with widely invasive tumors (defined as having 2 or more foci of capsular and/or vascular invasion) have a mortality of approximately 50% with median disease specific survival of 7 years. Patients with minimally invasive carcinoma have excellent prognosis with no tumor recurrences or disease related deaths reported in a recent series. Extrathyroidal extension and nodal metastases are adverse predictors of survival after multivariate analysis in widely invasive oncocytic carcinoma. Cytogenetics Cytogenetics Relatively few cases of oncocytic thyroid tumors have been studied by Morphological convential cytogenetic analysis, usually in general reports dealing with chromosomal alterations of thyroid neoplasia. 42-47 chromosomes with structural and numerical changes have been demonstrated in one oncocytic carcinoma. Cytogenetics CGH: Chromosomal DNA unbalance and aneuploidy are present in Molecular 70-80% of oncocytic thyroid neoplasms. Chromosomal DNA gains (+5, +7, +12, +17 , +19, +20) are more common than losses (-2, -9). Although aneuploidy is a feature of both oncocytic adenomas and carcinomas, sequential acquisition of numerical chromosomal changes (possibly beginning with trisomy 7) appears associated with tumor progression. Carcinomas tend to have more chromosomal gains and losses then adenomas and a statistical association has been demonstrated between the degree of aneuploidy and loss of differentiation, extent of tumor invasion, and recurrence. Genes involved and Proteins Note Nuclear genes and proteins: ATP production appears defective in oncocytic thyroid tumors but no specific alterations have been demonstrated in the nuclear genes which code for most of the proteins involved in the mitochondrial oxidative phosphorylation process or which control mtDNA replication. RAS mutations (frequently observed in follicular adenomas and carcinomas) and PAX8/ rearrangement (frequently observed in follicular carcinomas) are uncommon in oncocytic neoplasms. A gene predisposing to the familial development

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -421- of oncoytic thyroid neoplasms has been mapped at 19p13.2 NOTE Mitochondrial DNA (mtDNA) and proteins: The "common" mitochondrial DNA (mtDNA) deletion is a 4977 bp deletion frequently present in a variety of ageing human tissues. This deletion has been identified in 100% of oncocytic thyroid tumors but only at low level and in 20-30% of the non neoplastic thyroid parenchyma surrounding the tumor. Not only the prevalence but also the amount of the common mtDNA deletion is statistically higher in oncocytic thyroid tumors compared with non oncocytic ones. The proportion of mtDNA harbouring the common deletion appears to be higher in oncocytic carcinomas compared with oncocytic adenomas. Oncoytic tumors (benign or malignant) have a higher prevalence of mutations in the non coding displacaement-loop (D-loop) region of their mtDNA compared with non oncoytic tumors. Although mutations have been identified in the coding portions of the mtDNA, these mutations do not appear different from those observed in thyroid tumors lacking oncocytic features. No specific alterations have been identified in the mtDNA genes coding for the components of the oxidative phosphorylation process.

Bibliography Frequent occurrence of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Jenkins RB, Hay ID, Herath JF, Schultz CG, Spurbeck JL, Grant CS, Goellner JR, Dewald GW. Cancer 1990; 66:1213-1220. Medline 2400971

Follicular Hurthle cell tumors of the thyroid gland. Carcangiu ML, Bianchi S, Savino D, et al. Cancer 1991;68:1944-53. Medline 1913544

Tumors of the thyroid gland. Rosai J, Carcangiu ML, DeLellis RA. Atlas of Tumor Pathology. Third series, Fascicle 5. Washington DC: Armed Forces Institute of Pathology; 1992.

Frequent chromosomal DNA unbalance in thyroid oncocytic (Hurthle cell) neoplasms detected by comparative genomic hybridization. Tallini G, Hsueh A, Liu S, et al. Lab Invest 1999;79:547-555. Medline 10334566

Hurthle cell carcinoma: a critical histopathologic appraisal. Stojadinovic A, Ghossein RA, Hoos A, Urist MJ, Spiro RH, Shah JP, Brennan MF,

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -422- Shaha AR, Singh B. J Clin Oncol. 2001; 19:2616-2625. Medline 11352953

Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hurthle cell tumors. Maximo V, Soares P, Lima J, Cameselle-Teijeiro J, Sobrinho-Simoes M. Am J Pathol 2002; 160:1857-1865. Medline 12000737

Chromosomal aberrations by comparative genomic hybridization in hurthle cell thyroid carcinomas are associated with tumor recurrence. Wada N, Duh QY, Miura D, Brunaud L, Wong MG, Clark OH. Clin Endocrinol Metab 2002; 87:4595-4601. Medline 12364440

Prognostic factors in patients with Hurthle cell neoplasms of the thyroid. Lopez-Penabad L, Chiu AC, Schultz P, et al. Cancer 2003;97:1186-1194. Medline 12599224

RAS point mutations and PAX8-PPARy rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. Nikiforova MN, Lynch RA, Biddinger PW, et al. J Clin Endocrin Metab 2003;88:2318-2326 Medline 12727991

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Oluwole Fadare, Giovanni Tallini 2003 Citation This paper should be referenced as such : Fadare O, Tallini G . Thyroid: Oncocytic tumors. Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/OncocytThyroidID5068.html

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -423- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Kidney: Renal cell carcinoma

Classification Note Renal cell cancer (RCC) constitutes a group of epithelial tumors that are highly heterogeneous with respect to morphology and clinical behaviour. The major morphological classifications (WHO/AFIP; modified Mainz classification, and the Heidelberg classification) discriminate eight subtypes of renal cell tumors related to the basic cell types of the nephron from which they are derived, and in line with the genetic facts as presently understood: 1) metanephric adenoma and metanephric adenofibroma, 2) papillary adenoma, 3) renal oncocytoma, all three benign parenchymal neoplasms. Malignant parenchymal neoplasms are: 4) common or conventional (clear cell) renal carcinoma, 5) papillary (formerly chromophilic or tubulopapillary) renal carcinoma, 6) chromophobe renal carcinoma, 7) collecting duct carcinoma, and 8) renal cell carcinoma, unclassified. Clinics and Pathology Note Although common RCC and papillary RCC both are derived from the same part of the renal tubule and have a similar antigenic phenotype, they differ in genetic changes. This might be explained by the fact that common RCC arises from mature renal tubular cells, whereas papillary tumors are from embryonal origin. Embryonic In former times it was believed that certain clear cell epithelial renal origin tumors are derived from ectopic adreno-cortical elements as expressed by Virchow and advocated by Grawitz. This has led to the term "hypernephroma" or Grawitz tumor. Nowadays, there is evidence that the usual (nonembryonic) RCC in all its variants derives, in principle, from the mature uriniferous tubule (nephron). This evidence is corroborated by animal experiments and observation of pre-stages and early stages of epithelial renal tumors in human kidneys. Etiology A specific factor in the etiology of RCC is not known at the moment, although a number of dietary, environmental factors, hormonal, celllular and genetic factors associated with increased risk. RCC consists of a number histologically defined entities which may occur either non-hereditary or hereditary, e.g. the influence of genetic factors in VHL disease, in hereditary papillary RCC and familial RCC.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -424- Epidemiology RCC is the most common malignant tumor arising in the kidney and accounts for 2% of all new cancers diagnosed, representing 85% all primary renal neoplasms in adults. RCC affects males twice as often as females and shows a peak in the sixth decade. Although rarely, RCC can occur in children and adolescents. There is no clear geographical or ethnic preference. An increased incidence of RCC has been associated with end-stage renal disease and with acquired cystic kidney disease. RCCs are often large at detection and frequently already have metastasized. Pathology The present classification is primarily based on cytologic appearance and the cell type of origin in combination with growth pattern and genetic alterations.

Common (or non papillary or clear cell) RCC is the most common form of RCC, comprising 70-75% of cases.They show a male preponderance of 2:1. The tumor mass of common RCC is multicolored, with a predominantly yellow cur surface with white or gray foci. The tumor shows a solid growth pattern, but in some cases cystic appearance is seen. The cytoplasm is clear, due to an intensive intracytoplasmatic accumulation of glycogen and lipids. Usually, the nuclei are condensed and hyperchromatic. Electronmicroscopical features resembling the proximale tubule can be found i.e. brush border formation and basal infoldings. Tumor cells express antigens of the proximal tubule.

Papillary (or chromophilic) cell tumors (thought to arise from the proximal tubule) comprise 10-15% of RCC cases. Papillary RCC can be devided in adenomas and carcinomas. The adenomas tend to beige- to white colored small tumor masses whereas the carcinomas show an extensive greasy-brown colored central necrosis resulting from consecutive hemorrhages. The tumor cells exhibit centrally located small nuclei and the cytoplasm is contains few organelles only, especially endoplasmatic reticulum. As a rule the tumor cells are arranged in a (tubulo) papillary architecture. For both common and papillary RCC, hereditary as well as sporadic cases of papillary RCC have been found. Hereditary RCC is characterized by the appearance of multiple and bilateral tumors and an early age of onset. The chromophobic type (2-5%) resembles the intercalated cells type B from the cortical collecting duct. The antigen profiles of the chromophobic tumor exhibit collecting duct phenotypic features. No male preponderance is found. Chromophobic RCC consists of one or more solid tumor nodules with a slightly lobulated surface and the cut surface appears orange. The tumor cells are polygonal with a transparent, not clear, but reticulated cytoplasm. Nuclei are moderate with clear nucleoli. Ultrastructurally, the cytoplasm is crowded with glycogen deposits and numerous, sometimes invaginated, vesicles. Chromophobic RCC is diagnosed by a positive Hale's acid iron colloid stain and is positive for carbonic anhydrase C, but does not express band-3 protein.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -425- Renal oncocytoma (thought to arise from the distal nephron) comprises 5% of RCC and shows a 2.5:1 male to female ratio. Renal oncocytomas are solitary, well circumscribed, slightly lobulated solid tumors with a tan-brown cut surface and in larger tumors a central scar. The tumor cells show abundant granular eosinophilic cytoplasm and arranged in solid nests.The nuclei are generally round. Ultrastructurally, the cytoplasm is packed with numerous mitochondria. Renal oncocytomas find their origin in the intercalated cells type A of the cortical collecting tubule, which is substantiated by the shared expression of carbonic anhydrase C and band-3 protein. Collecting duct (duct Bellini) RCC comprises 1% and is closely related to the princi-pal cells of the medullary collecting duct. These tumors are usually localized in the renal medulla and white colored. The growth pattern is mainly tubular. The tumor cells have a basophilic cytoplasm due to pronounced formation of endoplasmatic reticulum and glycogen deposits. Nuclei are anaplastic.

Variants can be assigned to all these basic types which are characterized by augmentation of mitochondria leading to a stronger eosinophilia or granularity, respectively, of the cytoplasm. Spindle- shaped/pleomorphic variants as a result of sarcomatoid transformation can also be deduced from all the basic types. The differential diagnosis between renal cell adenomas and carcinomas has been a matter of controversy for long time. Although initially Bells' rule generally was followed (<3 cm: adenoma; >3 cm: carcinoma), this appeared unreliable and is still a matter of debate. Treatment The standard treatment for RCC is surgery by radical or partial nephrectomy. At present there is no effective therapy for metastatic RCC and patients with irresectable disease have a poor prognosis. Evolution About 50% of patients with localized disease progress with distant metastasis. Prognosis The anatomic extent of the disease represented by stage of disease is the single most important indicator of prognosis in RCC. Cytogenetics Note Cytogenetically, no differences are observed between hereditary tumors (usually presenting as multiple/bilateral tumors at an early age of onset) and sporadic papillary tumors. Increasing evidence exists on the presence of clonal, mostly numerical, chromosomal changes in apparantly normal kidney tissue from patients with a normal constitutional karyotype like trisomy 7, 5, 8, 10, 18 and loss of the Y chromosome. These changes are not an in vitro artefact and are independent of the length of cell culture. The presence of clonal and non clonal aberrations in apparantly normal kidney tissue merely indicates a chromosome instability pattern or mosaicism, and this condition should not be considered as strictly neoplastic. Cytogenetics The most frequently encountered RCC subtype is common or Morphological conventional type renal cell cancer characterized by loss of (part of)

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -426- the short arm of chromosome 3 due to (a) deletion(s) or unbalanced translocation(s). Regions frequently lost are are 3p12-14, 3p21 and 3p25. Loss of at least two of these regions are necessary for kidney cells to develop into common type renal cell carcinoma, and loss of 3p21 is obligatory. Therefore, if a tumor shows only one deletion at 3p, either 3p14 or 3p25, it should be designated common type renal cell adenomas. Other aberrations frequently found incommon RCC are (partial) trisomy of chromosome 5, especially the 5q22-qter segment. Trisomy 12, and 20, and loss of chromosomes 8, 9, 13q, 14q, and structural abnormalities of the long arm of chromosomes 6 and 10 are also found and correlated with progression.

Most papillary renal adenomas and carcinomas are characterized by a unique combination of autosomal trisomies with trisomy 17. Papillary adenomas specifically show a -Y,+7,+17 chromosomal pattern as well as trisomy 3 or gain of the long arm of chromosome 3, probably reflecting malignant transformation. Trisomy of chromosomes 12, 16, 20 as well as loss of the extra copy of chromosome 17 or loss of 17p are associated with progression from the adenoma into the carcinoma stage, i.e. papillary renal cell carcinomas. The high incidence of loss of the Y chromosome combined with the strong male preponderance suggests that loss of specific sequences harboured on the Y chromosome probably is important for developing this subtype.

A small subset of papillary RCC is characterized by X; autosome translocations. The t(X;1)(p11.2;q21), resulting in a fusion of the transcription factor TFE3 on the X chromosome, with a novel gene, designated PRCC, on chromosome 1, appears to be a specific primary anomaly characterizing a distinct subgroup of papillary RCC with common RCC like features as clear cytoplasma. These tumors occur preferentially in young (male) adults and children.

Metanephric adenoma or adenofibroma shows gain of chromosomes 7 and 17 with Y chromosome loss suggesting a relationship with papillary renal cell adenomas and carcinomas.

In renal oncocytoma several genetic subsets can be distinghuished: one with mixed populations of normal and abnormal karyotypes without any cytogenetic similarity (yet), a group defined by (variant) translocations involving 11q13, and one with specifically defined numerical anomalies, in particular loss of chromosomes 1, and Y/X.

The finding of mitochondrial DNA changes and the loss of Y/X in both renal oncocytoma and chromophobe carcinoma might indicate progression from renal oncocytoma to chromophobe renal cell carcinomas through additional chromosome losses, also explaining the occasionally malignant behavior of renal oncocytomas.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -427- Chromophobe renal carcinomas show multiple losses of entire chromosomes, i.e. loss of chromosomes 1, 2, 6, 10, 13, 17, 21, and the Y or X chromosome, leading to a low chromosome number.

Collecting duct carcinomas do not show consistent chromosomal abnormalities as yet: probably involvement of the short arm of chromosome 8 related to poor prognosis and loss of the long arm of chromosome 13 as well as loss of part of the long arm of chromosome 1q32. Losses of chromosome1 material seem to be a hallmark for all distal nephron tumors.

Sarcomatoid transformation in RCC represents the highest form of dedifferentiation and can in principle be derived from all the basic cell types. Cytogenetic data on sarcomatoid RCC is scarce: some show structural abnormalities of chromosomes 1, 5, 16, and 19 and losses of 3p, 4(q), 6q, 8p, 9, 13, 14, 17p, and gain of 5, 12, and 20 as well as TP53 mutations. Genes involved and Proteins Note The most frequent occurring RCC is common RCC characterized by loss of (part) of the short arm of chromosome 3 due to a deletion or unbalanced translocation and restricted to this type. Until today no tumor suppressor gene responsible for, or at least contributing to, cRCC has been identified -except for VHL-, in the different regions, although many candidate genes have been suggested such as FHIT(fragile histidine triad); TTRC1 (two-three-renal-cancer-1); DUTT1 (deleted in U- twenty twenty); locus NCR-1 (nonpapillary renal cell carcinoma 1) and RASSF1A (RAS association family 1). In papillary RCC, the TP53 gene most likely does not play an important role, since no mutations of TP53 have been observed in this subtype. Microsatellite analysis revealed allelic duplications a.o. at 20q11.2 and 20q13.2 suggesting new tumor genes in papillary renal carcinoma. The MET proto oncogene, assigned to 7q31 and encoding the hepatocyte growth factor receptor/scatter factor implicated in the proliferation and invasiveness, has been found mutated in germline and somatic mutations in papillary renal tumors. Loss of heterozygosity on chromosomes 8p or 9p provide prognostic significance in patients with locally advanced cRCC. PTEN/MMAC1 (chromosome 10) inactivation may play a role in the progression of cRCC.

To be noted Animal model Eker rats with a germline inactivation of the TSC-2 tumor suppressor gene, develop RCC. Using this model, it was found that overexpression of transforming growth factor a is an early event in the

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -428- development of RCC as it is seen in dysplasia and adenomas. Bibliography Tumors of the kidney, bladder, and related urinary structures. Murphy WM, Beckwith JB, Farrow GM. Armed Forces Institute of Pathology, Washington, DC 1994.

Renal-cell carcinoma. Motzer RJ, Bander NH, Nanus DM. N Engl J Med 1996; 335: 865-875. Medline 8778606

The Heidelberg classification of renal cell tumours. Kovacs G, Akhtar M, Beckwith BJ, et al. J Pathol 1997; 183: 131-133. Medline 9390023

Classification of renal cell carcinoma: Workgroup No.1 Union Internationale Contre Le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Stîrkel S, Eble JN, Adlakha K, et al. Cancer 1997; 80: 987-989. Medline 9307203

Involvement of multiple loci on chromosome 3 in renal cell cancer development. van den Berg A, Buys CHCM. Genes Chromosome Cancer 1997; 19: 59-76. Medline 9171996

Normal FHIT transcripts in renal cell cancer- and lung cancer-derived cell lines, including a cell line with a homozygous deletion in the FRA3B region. van den Berg A, Draaijers TG, Kok K, et al. Genes Chromosomes Cancer 1997; 19: 220-227. Medline 9258656

Cytogenetic classification of renal cell tumors. van den Berg E, Dijkhuizen T, Oosterhuis JW, Geurts van Kessel A, de Jong B, Stîrkel S. Cancer Genet Cytogenet 1997; 95: 103-107. Medline 9140459

Classification of renal cell cancer based on (cyto)genetic analysis. van den Berg E, Dijkhuizen T. Contrib Nephrol 1999; 128: 51-61. Medline 10597377

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -429- Combined LOH/CGH analysis proves the existence of interstitial 3p deletions in renal cell carcinoma. Alimov A, Kost-Alimova M, Liu J, et al. Oncogene 2000; 19: 1392-1399. Medline 10723130

Precancerous lesions in the kidney. Van Poppel H, Nilsson S, Algaba F, Bergerheim U, Dal Cin P, Fleming S, Hellsten S, Kirkali Z, Klotz L, Lindblad P, Ljungberg B, Mulders P, Roskams, Ross RK, Walker C, Wers˜ll P. Scand J Urol Nephrol Suppl 2000; 205: 136-165. (REVIEW). Medline 11144893

Identification and classification of differentially expressed genes in renal cell carcinoma by expression profiling on a global human 31,500 element cDNA arrray. Boer JM, Huber WK, Sultmann H, et al Genome Res 2001; 11: 1861-1870. Medline 11691851

The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. Dreijerink K, Braga E, Kuzmin I, et al. Proc Natl Acad Sci USA 2001; 98: 7504-7509. Medline 11390984

The genetic basis of renal epithelial tumors: advances in research and its impact on prognosis and therapy. Phillips JL, Pavlovich CP, Walther M, Ried T, Linehan WM. Curr Opin Urol 2001; 11: 463-469. Medline 11493766

Gene expression profiling of clear cell renal carcinoma: gene identification and prognostic classification. Takahashi M, Rhodes DR, Furge KA, et al Proc Natl Acad Sci USA 2001; 98: 9754-9759. Medline 11493696

Expression profiling of renal epithelia; neoplasms: a method for tumor classification and discovery of diagnostic molecular markers. Young AN, Amin MB, Moreno CS, et al. Am J Pathol 2001; 158: 1639-1651. Medline 11337362

Renal cancer: cytogenetic and molecular genetic aspects. Meloni-Ehrig AM.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -430- Am J Med Genet 2002; 30: 164-172. (REVIEW). Medline 12407697

Genetic progression of renal cell carcinoma. Moch H, Mihatsch MJ. Virchows Arch 2002; 44: 320-327. (REVIEW). Medline 12404056

Molecular genetics and histopathologic features of adult distal nephron tumors. Polascik TJ, Bostwick D, Cairns P. Urology 2002; 60: 941-946. (REVIEW). Medline 12475646

Allelic loss on chromosomes 8 and 9 correlates with clinical outcome in locally advanced clear cell carcinoma of the kidney. Presti JC Jr, Reuter WM, Russo P, Motzer R, Waldman F. J Urol 2002; 167: 1464-1468. Medline 11832771

Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis. Velickovic M, Delahunt B, McIver B, Grebe SK. Mod Pathol 2002; 15: 479-485. Medline 12011252

Hereditary renal cancers. Choyke PL, Glenn GM, Walther MM, Zbar B, Linehan WM. Radiology 2003; 226: 33-46. (REVIEW). Medline 12511666

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 06- Eva van den Berg, Stephan Storkel 2003 Citation This paper should be referenced as such : van den Berg E, Storkel S . Kidney: Renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. June 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/RenalCellCarcinID5021.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -431- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Bone: Chondroblastoma

Identity Note Chondroblastoma is a benign bone tumour typically affecting the epiphyses of long bones from individuals with an immature skeleton.

Radiology of Chondroblastoma. FIG. 1,2,3: Typical radiological findings of a lytic eccentric lesion affecting the epyphysis of the humerus (1 RX, 2 NMR and 3 bone scan) Clinics and Pathology Epidemiology Chondroblastoma is a rare neoplasm accounting for less than 1% of all bone tumors. Age of occurrence is usually between 10 and 25 years

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -432- with a male predominance. Older age of presentation for skull lesions is reported. Clinics Usual symptom at presentation is mild localized pain. Radiologically it occurs more often as an eccentric lytic lesion, with sclerotic borders, involving epiphyses of the long bones. Pathology The tumour is composed of cellular and matrix rich areas. Cellular areas are made up of so called ³chondroblasts²: round-,or polygonal cells, with an oval to round nucleus and with well defined eosinophilic cytoplasm. Mainly in non-decalcified sections the chondroblasts appear focally delimited by a thin calcification rim, so called ³chicken wire². Matrix rich areas are composed of different types of matrix: chondroid, osteoid, fibrous and rarely mature hyaline cartilage. Mitoses, always typical, are quite frequent, especially in the cellular areas. Immunohistochemical stainings show reactivity of the neoplastic cells for S-100 protein and Vimentin; although several other antigens are reported to be expressed (i.e. Smooth muscle actin and Cytokeratin). Multinucleated giant cells, especially at the periphery of matrix-rich areas, are almost always found. An associated aneurysmal bone cyst occurs in about 1/3 of the cases.

Histological features of chondroblastoma. Fig.4: The cellular areas are made up of polygonal cells with scattered multinucleated giants cells (Haematoxylin-Eosin stain). Fig.5: The polygonal cells are positive for S-100 immunostain.

Treatment Simple curettage is the standard treatment. Evolution Rate of recurrence is between 14-18% mainly occurring within 2 years, and showing a higher occurrence rate in case of temporal bone location. Rare lung metastases in benign chondroblastomas, are documented. However they are not progressive, and therefore simple observation is sufficient, if necessary followed by simple surgical resection. Prognosis The prognosis is good. Rare and doubtful malignant progression are described, but no universal criteria for this event are currently available, and several authors consider this as cases of a misdiagnosis.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -433- Cytogenetics Cytogenetics DNA flow cytometry studies show chondroblastoma mainly to be a low Morphological proliferative diploid neoplasm, however aneuploid near-diploid populations have been reported. Karyotypic results of 7 cases are available in the literature. No specific cytogenic abnormalities neither specific type of aberrations are reported sofar. However some chromosomes seem to be more often involved: 3 cases for chromosome 5, 2 for chromosome 8, 2 for chromosome 11 and 2 for chromosome 17. Bibliography Cytophotometric studies of the nuclear DNA content in cartilaginous tumors. Cuvelier C, Roels HJ. Cancer 1979; 44: 1363-1374. Medline 80044542

Chondroblastoma: a clinical and radiological study of 104 cases. Bloem JL, Mulder JD. Skeletal Radiol 1985; 14(1): 1-9. Medline 4023729

S-100 protein immunostaining in the differential diagnosis of chondroblastoma. Monda L, Wick MR. Hum Pathol 1985; 16(3): 287-293. Medline 2579018

Chondroblastoma. A review of seventy cases. Springfield DS, Capanna R, Gherlinzoni F, Picci P, Campanacci M. J Bone Joint Surg Am 1985; 67(5): 748-755. Medline 3997927

Histology and biology of metastatic chondroblastoma. Report of a case with a review of the literature. Kunze E, Graewe T, Peitsch E. Pathol Res Pract 1987; 182(1): 113-123. Medline 3588400

Radiologic case study. Chondroblastoma. Monticciolo DL, Brown NL. Orthopedics 1987; 10(8): 1197, 1199-1201. Medline 3628108

Chondroblastoma of the temporal bone. Blaauw G, Prick JJ, Versteege C. Neurosurgery 1988; 22: 1102-1107. Medline 3047595

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Chondroblastoma: an immunohistochemical study. Brecher ME, Simon MA. Hum Pathol 1988; 19(9): 1043-1047. Medline 3417289

Immunohistochemical distribution of S-100 protein in tumors and tumor-like lesions of bone and cartilage. Okajima K, Honda I, Kitagawa T. Cancer 1988; 61: 792-799. Medline 88109271

Chondroblastoma of bone. Kurt AM, Turcotte RE, McLeod RA, Unni KK, Sim FH. Orthopedics 1990; 13(7): 787-790. Medline 2197612

Cytokeratin expression in chondroblastoma. Semmelink HJF, Pruszczynski M, Wiersma-van Tilburg AJM., Smedts F, Ramaekers FCS. Histopathology 1990; 16: 257-263. Medline 90236432

Epiphyseal chondroblastoma of bone. Long-term effects on skeletal growth and articular function in 15 cases treated surgically. Caterini R, Manili M, Spinelli M, Santori FS, Ippolito E. Arch Orthop Trauma Surg 1992; 111(6): 327-332. Medline 1449941

Chondroblastoma of bone. A clinical, radiological, light and immunohistochemical study. Edel G, Ueda Y, Nakanishi J, Brinker KH, Roessner A, Blasius S, Vestring T, Muller- Miny H, Erlemann R, Wuisman P. Virchows Arch A Pathol Anat Histopathol 1992; 421(4): 355-366. Medline 1384228

Human benign chondroblastoma with a pseudodiploid stemline characterized by a complex and balanced translocation. Mark J, Wedell B, Dahlenfors R, Grepp C, Burian P. Cancer Genet Cytogenet 1992; 58(1): 14-17. Medline 1728944

Chondroblastoma of the temporal bone. Case report and literature review. Varvares MA, Cheney ML, Goodman ML, Ceisler E, Montgomery WW. Ann Otol Rhinol Laryngol 1992; 101(9): 763-769. Medline 1514755

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Chondroblastoma. Pflueger P, Heinrich SD, Craver R. Orthopedics 1993; 16(3): 339-342. Medline 8464774

Chondroblastoma. Turcotte RE, Kurt AM, Sim FH, Unni KK, McLeod RA. Hum Pathol 1993; 24(9): 944-949. Medline 8253461

Ultrastructural cytochemical demonstration of proteoglycans and calcium in the extracellular matrix of chondroblastomas. Mii Y, Miyauchi Y, Morishita T, Miura S, Honoki K, Aoki M, Tamai S. Hum Pathol 1994; 25(12): 1290-1294. Medline 8001922

Chondroblastoma: classic and confusing appearance at MR imaging. Weatherall PT, Maale GE, Mendelsohn DB, Sherry CS, Erdman WE, Pascoe HR. Radiology 1994; 190(2): 467-474. Medline 8284401

Benign cartilage tumors. Scarborough MT, Moreau G. Orthop Clin North Am 1996; 27(3): 583-589. Medline 8649739

Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology and clinical biology. I. The intramedullary cartilage tumors. Brien EW, Mirra JM, Kerr R. Skeletal Radiol 1997; 26(6): 325-353. Medline 9229417

Ring chromosome 4 as the sole cytogenetic anomaly in a chondroblastoma: a case report and review of the literature. van Zelderen-Bhola SL, Bovee JV, Wessels HW, Mollevanger P, Nijhuis JV, van Eendenburg JD, Taminiau AH, Hogendoorn PC. Cancer Genet Cytogenet 1998; 105(2): 109-112. Medline 9723025

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Cartilage-forming tumours of bone and soft tissue and their differential diagnosis. Bovee JV, Hogendoorn PC. Current Diagnostic Pathology 2002; 7[4]: 223-234.

Chondroblastoma. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Kilpatrick SE, Parisien M, Bridge JA. Lyon: IARC Press 2002; 241-242

Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Sciot R, Van Den Berghe H, Vanni R, Willen H. Journal of Pathology 2002; 196[2]: 194-203. Medline 21653061

Cytogenetic findings in benign cartilaginous neoplasms. Buddingh EP, Naumann S, Nelson M, Neffa JR, Birch N, Bridge JA. Cancer Genet Cytogenet 2003; 141(2): 164-168. Medline 12606137

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: osteosarcoma and related tumors. Sandberg AA, Bridge JA. Cancer Genet Cytogenet 2003; 145(1): 1-30. Medline 12885459

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 07- Salvatore Romeo, Pancras CW Hogendoorn 2003 Citation This paper should be referenced as such : Romeo S, Hogendoorn PCW . Bone: Chondroblastoma. Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/ChondroblastomaID5148.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -437- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Bone: Chondromyxoid fibroma

Identity Note Chondromyxoid fibroma is a benign cartilaginous bone tumour composed of lobules of chondroid and myxoid matrix formed by spindle or stellate shaped cells.

Radiology of Chondromyxoid fibroma. Fig. 1: Plain film radiograph shows lytic, oval, bubbly lesion with sclerotic rims. Clinics and Pathology Epidemiology Chondromyxoid fibroma is a very rare neoplasm accounting for less than 1% of all bone tumours, and less of 2% of all benign bone tumours. Despite 75% of the cases occur in patients younger than 30 years of age, a wide range is reported (4-79 year) Males are slightly more commonly affected.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -438- Clinics A long story of mild pain is reported at the first clinical examination. Bones of the lower extremity are more often affected, with a peculiar predilection for the metaphyseal region. Radiology shows an eccentric lytic lesion (wide size range: 1-14 cm), with a sclerotic rim, and ovoid shape (paralleling the long axis of the bone) with bubbly appearance. Pathology Histologically the tumours shows a multilobular pattern. The size of the lobules varies from tumour to tumour as well as from field to field. They are composed of fibrous, myxomatous and chondroid areas. However frank hyaline cartilage is less often recognized. The neoplastic cells vary in shape from spindle to stellate, focally atypical nuclei are recognized in 20-30% of the cases. Usually the centre of the lobules is less cellular than the periphery. At the edge of the latter, giant cells can often be recognised. Chunky calcification can be present, especially in older patients.

Histological features of Chondromyxoid fibroma. Fig. 2: Lobules of myxoid matrix are evident at low magnification (Alcian blue stain). Fig. 3: At higher magnification the neoplastic cells show spindle to stellate shape (Haematoxylin-Eosin stain)

Treatment Simple curettage is the standard treatment. Evolution The rate of recurrence is 15%. Prognosis The prognosis is excellent. Cytogenetics Cytogenetics Karyotypes of 12 cases are reported in the literature. Complex Morphological cytogenic abnormalities are reported. In ten cases chromosome 6 appears to be involved and non-random clonal abnormalities involving 6p25, 6q13 and 6q23 are reported. Of interest 4 cases with peri- centromeric inversion are described [3 cases inv(6)(p13q25) and 1 case inv(6)(p13q23)]. Bibliography Cytophotometric studies of the nuclear DNA content in cartilaginous tumors. Cuvelier C, Roels HJ. Cancer 1979; 44: 1363-1374. Medline 80044542

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Chondromyxoid fibroma. The experience at the Istituto Ortopedico Rizzoli. Gherlinzoni F, Rock M, Picci P. J Bone Joint Surg [Am] 1983; 65: 198-204. Medline 83109172

Chondromyxoid fibroma of bone: thirty-six cases with clinicopathologic correlation. Zillmer DA, Dorfman HD. Hum Pathol 1989; 20: 952-964. Medline 90007503

A recurrent chondromyxoid fibroma with chromosome aberrations ins(5;2)(q13;p21p25) and 2p deletion: A case report. Tarkkanen M, Böhling T, Heliö H, Karaharju E, Kaipainen A, Szymanska J, Elomaa I, Knuutila S. Cancer Genet Cytogenet 1993; 65: 141-146. Medline 93201512

Benign cartilage tumors. Scarborough MT, Moreau G. Pediatr Orthop Onc 1996; 27(3): 583-589. Medline 96238985

Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology and clinical biology I. The intramedullary cartilage tumors. Brien EW, Mirra JM, Kerr R. Skeletal Radiol 1997; 26: 325-353. Medline 97373388

Cytogenetic analysis of a scapular chondromyxoid fibroma. Halbert AR, Harrison WR, Hicks MJ, Davino N, Cooley LD. Cancer Genet Cytogenet 1998; 104: 52-56. Medline 98312365

Evidence of an association between 6q13-21 chromosome aberrations and locally aggressive behavior in patients with cartilage tumors. Sawyer JR, Swanson CM, Lukacs JL, Nicholas RW, North PE, Thomas JR. Cancer 1998; 82(3): 474-483 Medline 98112643

Cartilage-forming tumours of bone and soft tissue and their differential diagnosis. Bovee JV, Hogendoorn PC. Current Diagnostic Pathology 2002; 7(4): 223-234.

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Chondromyxoid fibroma. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Ostrowski ML, Spjut HJ, Bridge JA. Lyon: IARC Press 2002: 243-245

Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumours. A report from the Chromosomes and Morphology (CHAMP) Collaborative Study Group. Tallini G, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Sciot R, Van Den Berghe H, Vanni R, Willen H. Journal of Pathology 2002; 196(2), 194-203. Medline 21653061

Cytogenetic findings in benign cartilaginous neoplasms. Buddingh EP, Naumann S, Nelson M, Neffa JR, Birch N, Bridge JA. Cancer Genet Cytogenet 2003; 141: 164-168 Medline 22494383

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 07- Salvatore Romeo, Pancras CW Hogendoorn 2003 Citation This paper should be referenced as such : Romeo S, Hogendoorn PCW . Bone: Chondromyxoid fibroma. Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/ChondroMyxoidFibID5149.html

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Smooth muscle: Intravenous leiomyomatosis

Clinics and Pathology Etiology Intravenous leiomyomatosis (IVL) is a rare smooth muscle proliferation of special interest because of its quasi-malignant behavior. Clinics IVL is a smooth muscle proliferation that arises from the uterus with vermiform extensions in some cases into the inferior vena cava and ultimately into the right heart. Pathology The neoplastic smooth muscle of intravenous leiomyomatosis resembles that of benign uterine leiomyomata and may include the same histological variants found in the uterus. Furthermore, the neoplastic smooth cells of IVL express estrogen and progesterone receptors and tumor growth appears to respond to hormonal manipulation. Treatment Although benign, its hemodynamic effects may require invasive extirpation. Cytogenetics Cytogenetics There are only two cytogenetic reports in IVL and both exhibited a Morphological karyotype with a der(14)t(12;14)(q15;q24) and two normal copies of chromosome 12. Fluorescence in situ hybridization revealed three copies of HMGA2 (a.k.a. HMGIC): two signals were detected on the normal chromosomes 12 at 12q15, as well as another on the der(14) in the breakpoint region, suggesting that the 12q breakpoint occurred 5' (centromeric) to HMGA2, as has been commonly observed and previously described in uterine leiomyoma with a t(12;14). Based on these findings, it has been suggested that the pathogenesis of IVL is more similar to that of typical uterine leiomyoma than it is to leiomyosarcoma. Bibliography Intravenous leiomyomatosis of the uterus. A clinicopathological analysis of 16 cases with unusual histologic features. Clement PB, Young RH, Scully RE. Am J Surg Pathol 1988; 12: 932-945. Medline 3202247

Intravenous leiomyomatosis: molecular and cytogenetic analysis of a case. Quade B J, Dal Cin P, Neskey D M, Weremowicz S, Morton C C.

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -442- Mod Pathol 2002; 15: 351-356. Medline 11904348

Intravenous leiomyomatosis is characterized by a der(14) t(12;14) (q15;q24). Dal Cin P, Quade BJ, Neskey DM, Kleinman MS, Weremowicz S, Morton CC. Genes Chromosomes Cancer 2003; 36(2): 205-206. Medline 12508249

Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Quade BJ, Weremowicz S, Neskey DM, Vanni R, Ladd C, Dal Cin P, Morton CC. Cancer Res 2003; 63(6):1351-1358. Medline 12649198

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 07- Paola Dal Cin 2003 Citation This paper should be referenced as such : Dal Cin P . Smooth muscle: Intravenous leiomyomatosis. Atlas Genet Cytogenet Oncol Haematol. July 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/IntravLeiomyomID5158.html

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CASE REPORTS in HAEMATOLOGY

A new case of t(8;14)(q11;q32) in an acute lymphoblastic leukemia

Benoit Quilichini, Helene Zattara, François Casalonga, Laure-Anne Bastide- Alliez, Catherine Curtillet, Chantal Fossat, Gérard Michel.

Clinics Age and sex : 13 yrs old male patient Previous history : no preleukemia; no previous malignant disease; -no inborn condition of note; Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 21 x 109/l; Hb : : 9.1 g/dl; platelets : 32 x 109/l; blasts : 79% Survival Date of diagnosis: April 2003 Complete remission was obtained Karyotype Sample : Blood and bone marrow.; culture time : Overnight unstimulated culture; banding : R-BANDING Results : 45, X, - Y, t(8;14)(q11;q32) [ 16 ] / 46, XY [ 4 ] Other molecular cytogenetics technics : 1- Fluorescence in situ hybridization ( FISH ) was performed using a probe specific for the IgH locus (14q32) and a chromosome 8 specific labelled Spectrum Orange painting probe ( Abott ) according to the manufacturer¹s instructions. FISH confirmed translocation t (8 ;14)(q11;q32) and reveals an IgH rearrangement. (Figure 3) Other molecular studies results : BCR/ABL : negative TEL /AML1 : negative MLL gene : no rearrangement

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Figure 1: Bone marrow (MGG-stained ) x 50: Increased cellularity, no megakaryocyte. Blasts : 97 % ; Neutrophils : 3%

Figure 2: Karyotype ( R-bands) : 45, X, -Y, t(8;14)(q11;q32)

Figure 3: Fluorescence in situ hybridization using WCP 8 probe ( Spectrum Orange) and LSI-IgH locus probe ( FITC): partial karyotype results ( R-banding and FISH ). Comments To our knowledge, the number of t(8 ;14)(q11;q32) cases reported in the literature is 44. In 10 cases, it was the sole acquired abormality. In 34 cases, the t(8;14)(q11;q32) is associated with others numerical or structural abnormalities. 12 patients showed a constitutional trisomy 21. This case, an eleven year old boy represents an additional case. He does not present Down syndrome (this association is further strengthened).

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -445- Using EGIL classification, bone marrow immunophenotypage classified this case as a common ALL ( negative c mu and CD10 positive expression though a low level). It is the first report showing association of a t(8 ;14)(q11 ;q32) and loss of chromosome Y. Splitting of the IgH gene was demonstrated in our case by FISH technique. As in translocations described in leukemias and lymphomas implicating the locus 14q32, the rearrangement could be crucial in this leukemic event. The breakpoint at 8q11 has not yet been cloned. Internal links Atlas Card t(8;14)(q11;q32) Case A case of pre-B ALL with t(8;14)(q11;q32) Report Case A case of Down syndrome with acute lymphoblastic leukemia and Report t(8;14)(q11;q32) Bibliography Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, van¹t Veer MB. Leukemia 1995; 9(10): 1783-1786. Medline 7564526 World health organization classification of neoplastic diseases of 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 HK, Vardiman J, Lister TA, Bloomfield CD. Journal of clinical oncology 1999; 17(12): 3835-3849. Medline 10577857 Acute lymphoblastic leukemia with an usual t(8;14)(q11;q32) : a Pediatric Oncology Group study. Kaleem Z, Shuster JJ, Carroll AJ, Borowitz MJ, Pullen DJ, Camitta BM, Zutter MM, Watson MS. Leukemia 2000; 14: 238-240. Medline 12581891 Acute lymphoblastic leukemia characterized by t(8 ;14)(q11;q32). Moore S, Suttle J, Bain S, Story C, Rice M. Cancer Genetics and Cytogenetics 2003; 141: 1-4. Medline 12581891 WEB : Atlas of Genetics and Cytogenetics in Oncology and Haematology The Cancer Genome Anatomy Project Mitelman Cases Quick Searcher Contributor(s) Written Benoit Quilichini, Helene Zattara, François Casalonga, Laure- 05- Anne Bastide-Alliez, Catherine Curtillet, Chantal Fossat, 2003 Gérard Michel. Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2003; 3 -446- Quilichini B, Zattara H, Casalonga F, Bastide-Alliez LA, Curtillet C, Fossat C, Michel G. . A new case of t(8;14)(q11;q32) in an acute lymphoblastic leukemia. Atlas Genet Cytogenet Oncol Haematol. May 2003 . URL : http://AtlasGeneticsOncology.org/Reports/814QuilichiniID100007.html

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