LHCGR (Luteinizing Hormone/Choriogonadotropin Receptor); LPHN2 (Latrophilin 2) (1P31.1)

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Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 8, Number 1, Jan-Mar 2004 Previous Issue / Next Issue Genes ATBF1 (AT-binding transcription factor 1) (16q22.3-q23.1). Nadine Van Roy, Frank Speleman. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 1-7. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ATBF1ID357.html DIRC2 (3q21). Anita Bonné, Danièlle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel.. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 8-11. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/DIRC2ID497.html DIRC3 (2q35). Anita Bonné, Danièlle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel.. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 12-14. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/DIRC3ID498..html RAP1GDS1 (4q22.3). Franck Viguié. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 15-18. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RAP1GDS1ID400.html RET (REarranged during Transfection) (10q11.2). Patricia Niccoli-Sire. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 19-25. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RETID76.html LHCGR (luteinizing hormone/choriogonadotropin receptor); LPHN2 (latrophilin 2) (1p31.1). Jim Heighway. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 26-36. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 I URL : http://AtlasGeneticsOncology.org/Genes/LHRID288.html LPHN2 (latrophilin 2) (1p31.1). Jim Heighway. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 37-42. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/LPHH1ID313.html HLXB9 (homeo box HB9) (7q36.3). Anne RM von Bergh, H Berna Beverloo. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 43-47. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/HLXB9ID393.html SYNPO2 (4q27). Jian-Hua Luo. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 48-51. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SYNPO2ID488.html Leukaemias 11p15 rearrangements in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 52-53. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/11p15TreatRelLeukID1299.html 12p13 rearrangements in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 54-55. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/12p13TreatRelLeukID1301.html 21q22 rearrangements in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 56-57. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/21q22TreatRelLeukID1296.html inv(16)(p13q22) in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 58-59. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/inv16p13q22TreatRelID1297.html t(3;21)(q26;q22) in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 60-61. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0321q26q22TreatRelID1294.html t(8;16)(p11;p13) in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 62-63. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 II URL : http://AtlasGeneticsOncology.org/Anomalies/t0816p11p13TreatRelID1302.html t(8;21)(q22;q22) in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 64-65. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0821q22q22TreatRelID1293.html t(9;22)(q34;q11) in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 66-67. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0922q34q11TreatRelID1300.html t(15;17)(q22;q21) in treatment related leukemia. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 68-69. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1517q22q21TreatRelID1298.html Acute megakaryoblastic leukemia (AMegL); M7 acute non lymphocytic leukemia (M7- ANLL). Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 70-74. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/M7ANLLID1100.html Refractory anemia with excess blasts (RAEB). Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 75-78. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/RAEBID1105.html Refractory anemia (RA). Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 79-82. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/RAID1104.html Refractory anemia with ringed sideroblasts (RARS). Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 83-86. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/RARSID1106.html Solid Tumours Bladder: Urothelial carcinomas - updated. Angela van Tilborg, Bas van Rhijn. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 87-104. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/blad5001.html Soft tissue tumors: Elastofibroma. Roberta Vanni.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 III Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 105-109. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/ElastofibromaID5173.html Ovary: Sex cord-stromal tumors. Lisa Lee-Jones. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 110-124. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/OvarSexCordStromID5223.html Testis: Spermatocytic seminoma. Ewa Rajpert-De Meyts. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 125-131. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/SpermatSeminID5119.html Cancer Prone Diseases Familial clear cell renal cancer. Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel.. Atlas Genet Cytogenet Oncol Haematol 2004; 8 (1): 132-135. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/FamClearCellRenalID10081.html Deep Insights Case Reports Educational Items

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Atlas Genet Cytogenet Oncol Haematol 2004; 1 IV Atlas of Genetics and Cytogenetics in Oncology and Haematology

ATBF1 (AT-binding transcription factor 1)

Identity Other AT motif-binding factor 1 names Alpha-fetoprotein enhancer binding protein Hugo ATBF1 Location 16q22.3-q23.1 DNA/RNA Description 10 exons, DNA size: 261.32 kb. Transcription two isoforms ATBF1-A and ATBF1-B, due to alternative promotor usage combined with alternative splicing, mRNA-size: 11893 bp. Protein

Description 3703 amino acids; 404 kDa; four homeodomains and 23 zinc fingers including 1 pseudo zinc finger motif, one DEAD and one DEAH box, a RNA and an ATP binding site, two large RS domains and multiple phosphorylation sites. Expression Embryonic and neonatal brain. Localisation nuclear Function Transcription factor that binds to the AT-rich core sequence of the enhancer element of the AFP gene and downregulates AFP gene expression, possibly involved in neuronal differentiation (ATBF1-A). Homology mouse atbf1, drosophila zfh2 and C. Elegans ZC 123.3 Mutations Somatic Amplification, in one early neural crest derived cell line SJNB-12 under the form of extrachromosomally double minutes, non-syntenic co- amplification with MYC. Absence of ATBF1 expression in alpha-fetoprotein expressing gastric cancer cell lines, lack of ATBF1 expression not due to mutation, deletion or translocation but to strong repression at the transcriptional level. Implicated in Disease Early neural crest derived cell line (SJNB-12). Prognosis unknown Cytogenetics Several structural and numerical chromosomal aberrations and presence of extrachromosomally double minutes and homogenously staining regions, presence of a reciprocal unbalanced

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -1- t(8;16)(q24.3;q22.3). Oncogenesis Amplification in one neural crest derived cell line (SJNB-12), non- syntenic co-amplification with MYC.

Disease Alpha-fetoprotein producing gastric cancer cell lines (GCIY and Ist-I). Prognosis poor (very malignant and highly metastatic cancer) Oncogenesis Alpha-fetoprotein producing cancer cell lines show absence of ATBF1 expression, lack of ATBF1 expression not due to deletion mutation or translocation but to strong repression at the transcriptional level.

External links Nomenclature Hugo ATBF1 GDB ATBF1 Entrez_Gene ATBF1 463 AT-binding transcription factor 1 Cards Atlas ATBF1ID357 GeneCards ATBF1 Ensembl ATBF1 Genatlas ATBF1 GeneLynx ATBF1 eGenome ATBF1 euGene 463 Genomic and cartography ATBF1 - chr16:71378456-71639775 - 16q22.2 (hg17- GoldenPath May_2004) Ensembl ATBF1 - 16q22.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ATBF1 Gene and transcription

Genbank AC002044 [ SRS ] AC002044 [ ENTREZ ]

Genbank AC004943 [ SRS ] AC004943 [ ENTREZ ]

Genbank AY424268 [ SRS ] AY424268 [ ENTREZ ]

Genbank BC029653 [ SRS ] BC029653 [ ENTREZ ]

Genbank D10250 [ SRS ] D10250 [ ENTREZ ]

RefSeq NM_006885 [ SRS ] NM_006885 [ ENTREZ ]

RefSeq NT_086854 [ SRS ] NT_086854 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -2- AceView ATBF1 AceView - NCBI TRASER ATBF1 Traser - Stanford

Unigene Hs.461285 [ SRS ] Hs.461285 [ NCBI ] HS461285 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q15911 [ SRS] Q15911 [ EXPASY ] Q15911 [ INTERPRO ]

Prosite PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Expasy ]

Prosite PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Expasy ]

PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 Prosite ZINC_FINGER_C2H2_1 [ Expasy ]

PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 Prosite ZINC_FINGER_C2H2_2 [ Expasy ]

Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ]

Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ]

Interpro IPR003604 Znf_U1 [ SRS ] IPR003604 Znf_U1 [ EBI ] CluSTr Q15911

PF00046 Homeobox [ SRS ] PF00046 Homeobox [ Sanger Pfam ] pfam00046 [ NCBI-CDD ] Pfam PF00096 zf-C2H2 [ SRS ] PF00096 zf-C2H2 [ Sanger ] pfam00096 [ NCBI-CDD ]

Smart SM00389 HOX [EMBL]

Smart SM00355 ZnF_C2H2 [EMBL]

Smart SM00451 ZnF_U1 [EMBL]

Prodom PD000010 Homeobox[INRA-Toulouse] Prodom Q15911 ATBF_HUMAN [ Domain structure ] Q15911 ATBF_HUMAN [ sequences sharing at least 1 domain ] Blocks Q15911 Polymorphism : SNP, mutations, diseases OMIM 104155 [ map ] GENECLINICS 104155

SNP ATBF1 [dbSNP-NCBI]

SNP NM_006885 [SNP-NCI]

SNP ATBF1 [GeneSNPs - Utah] ATBF1 [SNP - CSHL] ATBF1] [HGBASE - SRS] General knowledge Family ATBF1 [UCSC Family Browser] Browser SOURCE NM_006885 SMD Hs.461285 SAGE Hs.461285

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -3- function|RNA polymerase II transcription factor activity, enhancer Amigo binding Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|zinc ion binding PubGene ATBF1 Other databases Probes Probe ATBF1 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers. Morinaga T, Yasuda H, Hashimoto T, Higashio K, Tamaoki T. Mol Cell Biol 1991; 11(12): 6041-6049. Medline 92049333

ATBF1, a multiple-homeodomain zinc finger protein, selectively downregulates AT-rich elements of the human alpha-fetoprotein gene. Yasuda H, Mizuno A, Tamaoki T, Morinaga T. Mol Cell Biol 1994; 14(2): 1395-1401. Medline 94119090

Cloning and characterization of an ATBF1 isoform that expresses in a neuronal differentiation-dependent manner. Miura Y, Tam T, Ido A, Morinaga T, Miki T, Hashimoto T, Tamaoki T. J Biol Chem 1995; 270(45): 26840-26848. Medline 96070776

Automated fluorescent dye-terminator sequencing of G+C-rich tracts with the aid of dimethyl sulfoxide. Scheidl TM, Miura Y, Yee HA, Tamaoki T. Biotechniques 1995; 19(5): 691-694. Medline 96146888

Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3-q23.1. Yamada K, Miura Y, Scheidl T, Yoshida MC, Tamaoki T. Genomics 1995; 29(2): 552-553. Medline 96115612

[ZFH/ATBF1 gene family: transcription factors containing both homeo- and zinc finger-domains]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -4- Tamaoki T, Hashimoto T. Tanpakushitsu Kakusan Koso 1996; 41(11): 1550-1559. Medline 96425447

Developmental changes in expression of the ATBF1 transcription factor gene. Watanabe M, Miura Y, Ido A, Sakai M, Nishi S, Inoue Y, Hashimoto T, Tamaoki T. Brain Res Mol Brain Res 1996; 42(2): 344-349. Medline 97165899

Regulation and activities of alpha-fetoprotein. Chen H, Egan JO, Chiu JF. Crit Rev Eukaryot Gene Expr 1997; 7(1-2): 11-41. Medline 97187260

Myb-interacting protein, ATBF1, represses transcriptional activity of Myb oncoprotein. Kaspar P, Dvorakova M, Kralova J, Pajer P, Kozmik Z, Dvorak M. J Biol Chem 1999; 274(20): 14422-14428. Medline 99254009

AT motif binding factor 1-A (ATBF1-A) negatively regulates transcription of the aminopeptidase N gene in the crypt-villus axis of small intestine. Kataoka H, Joh T, Miura Y, Tamaoki T, Senoo K, Ohara H, Nomura T, Tada T, Asai K, Kato T, Itoh M. Biochem Biophys Res Commun 2000; 267(1): 91-95. Medline 20090598

Characterization of trinucleotide- and tandem repeat-containing transcripts obtained from human spinal cord cDNA library by high-density filter hybridization Kaushik N, Malaspina A, de Belleroche J. DNA Cell Biol 2000; 19(5): 265-273. Medline 20312483

Cloning and characterization of a novel RNA-binding protein SRL300 with RS domains Sawada Y, Miura Y, Umeki K, Tamaoki T, Fujinaga K, Ohtaki S. Biochim Biophys Acta 2000; 1492(1): 191-195. Medline 20461775

Positive and negative regulation of myogenic differentiation of C2C12 cells by isoforms of the multiple homeodomain zinc finger transcription factor ATBF1. Berry FB, Miura Y, Mihara K, Kaspar P, Sakata N, Hashimoto-Tamaoki T, Tamaoki T. J Biol Chem. 2001; 276(27): 25057-25065. Epub 2001. Medline 21326069

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -5- Alpha-fetoprotein producing gastric cancer lacks transcription factor ATBF1 Kataoka H, Miura Y, Joh T, Seno K, Tada T, Tamaoki T, Nakabayashi H, Kawaguchi M, Asai K, Kato T, Itoh M. Oncogene 2001; 20(7): 869-873. Medline 21214482

DNA/RNA-dependent ATPase activity is associated with ATBF1, a multiple homeodomain-zinc finger protein. Kawaguchi M, Miura Y, Ido A, Morinaga T, Sakata N, Oya T, Hashimoto-Tamaoki T, Sasahara M, Koizumi F, Tamaoki T. Biochim Biophys Acta 2001; 1550(2): 164-174. Medline 21628693

Combined M-FISH and CGH analysis allows comprehensive description of genetic alterations in neuroblastoma cell lines. Van Roy N, Van Limbergen H, Vandesompele J, Van Gele M, Poppe B, Salwen H, Laureys G, Manoel N, De Paepe A, Speleman F. Genes Chromosomes Cancer 2001; 32(2): 126-135. Medline 21433806

Expression of homeobox genes in cervical cancer. Li H, Huang CJ, Choo KB. Gynecol Oncol 2002; 84(2): 216-221. Medline 21671191

Regulation of the alpha-fetoprotein gene by the isoforms of ATBF1 transcription factor in human hepatoma. Ninomiya T, Mihara K, Fushimi K, Hayashi Y, Hashimoto-Tamaoki T, Tamaoki T. Hepatology 2002; 35(1): 82-87. Medline 21646261

ATBF1-A protein, but not ATBF1-B, is preferentially expressed in developing rat brain. Ishii Y, Kawaguchi M, Takagawa K, Oya T, Nogami S, Tamura A, Miura Y, Ido A, Sakata N, Hashimoto-Tamaoki T, Kimura T, Saito T, Tamaoki T, Sasahara M. J Comp Neurol 2003; 465(1): 57-71. Medline 22806781

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BiblioGene - INIST

Contributor(s) Written 10- Nadine Van Roy, Frank Speleman

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -6- 2003

Citation This paper should be referenced as such : Van Roy N, Speleman F . ATBF1 (AT-binding transcription factor 1). Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ATBF1ID357.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -7- Atlas of Genetics and Cytogenetics in Oncology and Haematology

DIRC2

Identity Location 3q21 DNA/RNA Description The gene spans 73 kb, 9 exons. The first exon and 5-prime UTR contain a CpG island. The gene contains 12 transmembrane segments. It contains a conserved motif, shared with the major facilitator superfamily of transporters, between membrane-spanning domains 2 and 3, and a proline-rich region between membrane-spanning domains 6 and 7. It also contains a putative N-glycosylation site and several putative phosphorylation sites. Protein

Description 478 amino acids Expression Expression in pancreas, kidney (proximal tubular cells of the kidney), skeletal muscle, liver, lung, placenta, brain and heart. Function see below, may be a transporter Homology Computer predictions of the putative DIRC2 protein showed significant homology to different members of the major facilitator superfamily of transporters. DIRC2 shares 43% similarity with the human homolog of feline leukemia virus type C receptor (FLVXR), which has been classified as a major facilitator superfamily transporter, and over 85% homology with Dirc2 from monkey, pig, dog, and mouse. Implicated in Entity t(2;3)(q35;q21) and hereditary renal cell cancer. Disease Familial renal cell cancer. Cytogenetics Disruption of the gene because of the t(2;3) translocation.

External links Nomenclature GDB DIRC2 Entrez_Gene DIRC2 84925 disrupted in renal carcinoma 2 Cards Atlas DIRC2ID497 GeneCards DIRC2

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -8- Ensembl DIRC2 CancerGene DIRC2 Genatlas DIRC2 GeneLynx DIRC2 eGenome DIRC2 euGene 84925 Genomic and cartography DIRC2 - 3q21 chr3:123996597-124081451 + 3q21.1 (hg17- GoldenPath May_2004) Ensembl DIRC2 - 3q21.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene DIRC2 Gene and transcription

Genbank AK027690 [ SRS ] AK027690 [ ENTREZ ]

Genbank AK075158 [ SRS ] AK075158 [ ENTREZ ]

Genbank BC022204 [ SRS ] BC022204 [ ENTREZ ]

Genbank BC033738 [ SRS ] BC033738 [ ENTREZ ]

Genbank BC039821 [ SRS ] BC039821 [ ENTREZ ]

RefSeq NM_032839 [ SRS ] NM_032839 [ ENTREZ ]

RefSeq NT_086640 [ SRS ] NT_086640 [ ENTREZ ] AceView DIRC2 AceView - NCBI TRASER DIRC2 Traser - Stanford

Unigene Hs.477346 [ SRS ] Hs.477346 [ NCBI ] HS477346 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q96SL1 [ SRS] Q96SL1 [ EXPASY ] Q96SL1 [ INTERPRO ] CluSTr Q96SL1 Blocks Q96SL1 Polymorphism : SNP, mutations, diseases OMIM 602773 [ map ] GENECLINICS 602773

SNP DIRC2 [dbSNP-NCBI]

SNP NM_032839 [SNP-NCI]

SNP DIRC2 [GeneSNPs - Utah] DIRC2 [SNP - CSHL] DIRC2] [HGBASE - SRS] General knowledge Family DIRC2 [UCSC Family Browser] Browser

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -9- SOURCE NM_032839 SMD Hs.477346 SAGE Hs.477346 PubGene DIRC2 Other databases Probes PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation. Bodmer D, Eleveld MJ, Ligtenberg MJL, Weterman MAJ, Janssen BAP, Smeets DFCM, de Wit PEJ, van den Berg A, van den Berg E, Koolen MI, Geurts van Kessel A. Am J Hum Genet 1998; 62: 1475-1483. Medline 9585616

A familial case of renal cell carcinoma and a t(2;3) chromosome translocation. Koolen MI, van der Meyden APM, Bodmer D, Eleveld M, Van der Looij E, Brunner H, Smits A, Van den Berg E, Smeets D, Geurts van Kessel A. Kidney Int 1998; 53: 273-275. Medline 9461085

Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB,.Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J, Huebner K. J Hum Genet 2001; 46: 685-693. Medline 11776380

Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21). Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B, Wetermann M, Schoenmakers E, Nickerson M, Linehan M, Zbar B, Geurts van Kessel A. Hum Molec Genet 2002; 11: 641-649. Medline 11912179

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 10- Anita Bonné, Daniëlle Bodmer, Marc Eleveld, Eric 2003 Schoenmakers, Ad Geurts van Kessel.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -10- Citation This paper should be referenced as such : Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPM, Geurts van Kessel A. . DIRC2. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/DIRC2ID497.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -11- Atlas of Genetics and Cytogenetics in Oncology and Haematology

DIRC3

Identity Location 2q35

DNA/RNA Description The gene spans 3071 bp and contains 12 exons. The last exon contains a consensus polyadenylation site sequence (AGTAA) at 20 nt upstream op the poly(a) addition site. DIRC3 expression could be detected in the placenta, but low expression was found in most tissues and the gene may act as a non-coding RNA. Implicated in Entity t(2;3)(q35;q21) and hereditary renal cell cancer. Disease Familial renal cell cancer. Cytogenetics Disruption of the gene because of the t(2;3) translocation. A schematic overview of the breakpoint regions on chromosome 2 and 3 in a family with a t(2;3) translocation with the breakpoint genes DIRC2 and DIRC3, the fusion protein DIRC3-HSPBAP1 and their neighbouring genes. (TNS: tensin; SEMA5B: sema domain 5B)

Abnormal DIRC3-HSPBAP1 is formed by replacing the first coding exon of Protein HSPBAP1 by the first two exons of DIRC3. The fusion transcript most likely encodes a truncated HSPBAP1 protein starting from a internal

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -12- initiation side embedded in a strong Kozak consensus sequence.

External links Nomenclature GDB DIRC3 Entrez_Gene DIRC3 378482 disrupted in renal carcinoma 3 Cards Atlas DIRC3ID498 GeneCards DIRC3 Ensembl DIRC3 Genatlas DIRC3 GeneLynx DIRC3 eGenome DIRC3 euGene 378482 Genomic and cartography GoldenPath DIRC3 - 2q35 Ensembl DIRC3 - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene DIRC3 Gene and transcription

Genbank - [ SRS ] - [ ENTREZ ] AceView DIRC3 AceView - NCBI TRASER DIRC3 Traser - Stanford Protein : pattern, domain, 3D structure Polymorphism : SNP, mutations, diseases OMIM 608262 [ map ] GENECLINICS 608262

SNP DIRC3 [dbSNP-NCBI]

SNP DIRC3 [GeneSNPs - Utah] DIRC3 [SNP - CSHL] DIRC3] [HGBASE - SRS] General knowledge Family DIRC3 [UCSC Family Browser] Browser PubGene DIRC3 Other databases Probes PubMed PubMed 1 Pubmed reference(s) in LocusLink

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -13- Bibliography Disruption of a novel gene, DIRC3, and expression of DIRC3-HSPBAP1 fusion transcripts in a case of familial renal cell cancer and t(2;3)(q35;q21). Bodmer D, Schepens M, Eleveld M, Schoenmakers EFPM, Geurts van Kessel A. Genes Chromosomes Cancer 2003; 38(2): 107-116. Medline 12939738

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 10- Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric 2003 Schoenmakers, Ad Geurts van Kessel. Citation This paper should be referenced as such : Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPM, Geurts van Kessel A. . DIRC3. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/DIRC3ID498.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -14- Atlas of Genetics and Cytogenetics in Oncology and Haematology

RAP1GDS1

Identity Other RAP1 names GTP-GDP dissociation stimulator 1 Hugo RAP1GDS1 Location 4q22.3 DNA/RNA Description 181.2 kb - 15 exons Transcription mRNA 2487 bases Protein

Description rap1gds, also refered as smgGDS - 61.1 kDa, 558 aa. Contains in major part an armadillo motif, which is composed of tandemly repeated sequences of 43 amino acid residues. Expression Ubiquitary, high level of expression in central nervous system. Function Acts as guanine nucleotide exchange factor (GEF). Activates GDP/GTP exchange reaction on numerous small proteins with GTPase activity (G proteins) containing a C-terminal polybasic region (PBR), including Ras and Rho family GTPases such as rap1a, rap1b, K-ras, rac1, rac2, rhoA, ralB. These proteins play a pivotal role in cell proliferation, differentiation and oncogenic transformation. Homology With other mammalian rap1gds1 proteins. Implicated in Entity t(4;11)(q21;p15). Disease T cell acute lymphocytic leukemia. Cytogenetics Additional anomalies in 2/3 cases. Hybrid/Mutated Quasi totality of RAP1GDS1 fused with 5' part of NUP98. Gene Abnormal Chimeric protein 5' -NUP98 - RAP1GDS1 - 3'. Protein

External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -15- Hugo RAP1GDS1 GDB RAP1GDS1 Entrez_Gene RAP1GDS1 5910 RAP1, GTP-GDP dissociation stimulator 1 Cards GeneCards RAP1GDS1 Ensembl RAP1GDS1 CancerGene RAP1GDS1 Genatlas RAP1GDS1 GeneLynx RAP1GDS1 eGenome RAP1GDS1 euGene 5910 Genomic and cartography RAP1GDS1 - 4q22.3 chr4:99539798-99720993 + 4q23 (hg17- GoldenPath May_2004) Ensembl RAP1GDS1 - 4q23 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RAP1GDS1 Gene and transcription

Genbank AF215923 [ SRS ] AF215923 [ ENTREZ ]

Genbank AF237413 [ SRS ] AF237413 [ ENTREZ ]

Genbank AK055032 [ SRS ] AK055032 [ ENTREZ ]

Genbank AY376900 [ SRS ] AY376900 [ ENTREZ ]

Genbank BC001816 [ SRS ] BC001816 [ ENTREZ ]

RefSeq NM_021159 [ SRS ] NM_021159 [ ENTREZ ]

RefSeq NT_086651 [ SRS ] NT_086651 [ ENTREZ ] AceView RAP1GDS1 AceView - NCBI TRASER RAP1GDS1 Traser - Stanford

Unigene Hs.132858 [ SRS ] Hs.132858 [ NCBI ] HS132858 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P52306 [ SRS] P52306 [ EXPASY ] P52306 [ INTERPRO ]

Prosite PS50176 ARM_REPEAT [ SRS ] PS50176 ARM_REPEAT [ Expasy ]

Interpro IPR008938 ARM [ SRS ] IPR008938 ARM [ EBI ]

Interpro IPR000225 Armadillo [ SRS ] IPR000225 Armadillo [ EBI ] CluSTr P52306

Pfam PF00514 Arm [ SRS ] PF00514 Arm [ Sanger ] pfam00514 [ NCBI-CDD ] Blocks P52306 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -16- OMIM 179502 [ map ] GENECLINICS 179502

SNP RAP1GDS1 [dbSNP-NCBI]

SNP NM_021159 [SNP-NCI]

RAP1GDS1 [GeneSNPs - Utah] RAP1GDS1 [SNP - CSHL] RAP1GDS1] [HGBASE - SNP SRS] General knowledge Family RAP1GDS1 [UCSC Family Browser] Browser SOURCE NM_021159 SMD Hs.132858 SAGE Hs.132858 Amigo function|GTPase activator activity Amigo function|binding Amigo process|biological_process unknown Amigo component|cellular_component unknown PubGene RAP1GDS1 Other databases Probes Probe RAP1GDS1 Related clones (RZPD - Berlin) PubMed PubMed 6 Pubmed reference(s) in LocusLink Bibliography SmgGDS stabilizes nucleotide-bound and -free forms of the Rac1 GTP-binding protein and stimulates GTP/GDP exchange through a substituted enzyme mechanism. Chuang TH, Xu X, Quilliam LA, Bokoch GM. Biochem J 1994; 303 ( Pt 3): 761-767. Medline 7980444

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

Mecucci C, La Starza R, Negrini M, Sabbioni S, Crescenzi B, Leoni P, Di Raimondo F, Krampera M, Cimino G, Tafuri A, Cuneo A, Vitale A, Foa R. t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia. Br J Haematol 2000; 109(4): 788-793. Medline 10929031

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -17-

SmgGDS displays differential binding and exchange activity towards different Ras isoforms. Vikis HG, Stewart S, Guan KL. Oncogene 2002; 21(15): 2425-2432. Medline 11948427

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 10- Franck Viguié 2003 Citation This paper should be referenced as such : Viguié F . RAP1GDS1. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/RAP1GDS1ID400.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -18- Atlas of Genetics and Cytogenetics in Oncology and Haematology

RET (REarranged during Transfection)

Identity Note proto-oncogene Location 10q11.2 DNA/RNA Description 21 exons, 3415 pb Transcription 3 mains alternative spliced mRNA in the 3' region Protein

Description Several isoforms; 3 main isoforms detected in human : long isoform (RET51): 1114 amino acids ; middle isoform (RET 43): 1106 amino acids ; short isoform (RET 9) : 1072 amino acids. Expression RET is mainly expressed in tumors of neural crest origin : medullary thyroid carcinoma, pheochromocytoma, neuroblastoma. In human embryos, RET is expressed in a cranial population of neural crest cells, and in the developing nervous and urogenital systems. RET expression is found in several crest-derived cell lines, spleen, thymus, lymph nodes, salivary glands, spermatogonia, and recently in normal thyroid tissue, thyroid adenoma and both papillary and follicular thyroid cell neoplasias. Function RET is a tyrosine kinase receptor whose ligands are neurotrophic factors of the glial-cell line derived neurotrophic factor (GDNF) family, including GDNF, neurturin, artemin and persefin. RET activation is mediated via different glycosyl phosphatidylinositol-linked GRF_ receptors. Homology General structure is similar to other tyrosine kinase receptors but RET differs by the presence of a cadherin domain in its extracellular region. Mutations Germinal Germline RET mutations causes autosomal dominant inherited multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma only (FMTC). All these mutations are missense activating mutations. There are widely dispersed in 7/21 exons of RET with phenotype-genotype relationships : mutations in exon 11 is strongly associated with MEN2A phenotype, mutations in exon 16 or exons 8, 10, 13, 14, 15, with NEM2B and FMTC (rarely NEM2A) phenotypes respectively. Germline RET mutations are associated to the autosomal inherited

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -19- Hirschprung's disease or colonic aganglionosis (HSCR) which represents 15-20% of HSCR cases. RET mutations are loss-of-function mutations dispersed throughout the RET coding sequence and include deletions, insertions, frameshift missense and nonsense mutations. Somatic Somatic RET mutations have been identified in sporadic medullary thyroid carcinoma (MTC) and pheochromocytoma, mostly located in exon 16 at codon 918 (30-70% of sporadic MTC). Somatic mutations in exons 15, codon 883 and in exon 13, codon 768 have been also detected in rare cases of sporadic MTC. Somatic rearranged forms of RET (RET/PTC) are detected in human papillary thyroid carcinoma (PTC) : several activating genes rearrange with RET to form RET/PTC by juxtaposing the genomic region coding for the tyrosine kinase domain with the 5'-terminal regions of several unrelated genes : H4: PTC1; RIa: PTC2 ; ELE1: PTC3/4 ; RFG5: PTCT5 ; hTIF1: PTC6 ; RFG7: PTC7, and ELKS. RET rearrangement as RET/PTC1 is mostly detected in typical sporadic papillary thyroid carcinoma, RET/PTC3 occured at high frequency in chilhood papillary thyroid carcinoma from areas contaminated by the Chernobyl nuclear reactor accident. Implicated in Entity Multiple Endocrine Neoplasia type 2 (MEN2), Hirschprung's disease (HSCR). Somatic rearranged forms of RET (RET/PTC) are detected in human papillary thyroid carcinoma. Disease MEN 2A (60% of MEN2) associates medullary thyroid carcinoma (MTC) (100% of the cases) with pheochromocytoma in 50% of cases and with primary hyperparathyroidism (pHPT) in 5 to 20% of cases. MEN 2B (5% of MEN2) is characterized by the association of MTC (100% of the cases) with pheochromocytoma (about 50% of the cases) as well as a phenotype including skeletal abnormalities suggestive of Marfan syndrome and the presence of multiple mucosal neuroma ; no pHPT is found in MEN 2B. DISEASE Familial MTC only (FMTC) represents 35% of MEN 2 and is characterized by the absence of other associations throughout the entire follow up. Hirschprung's disease or aganglionosis (HSCR) is a frequent congenital intestinal malformation (1/5000 live births) characterized by the absence of neural crest-derived parasympathetic neurons of the hindgut. Typical sporadic papillary thyroid carcinoma and chilhood papillary thyroid carcinoma linked to radiation exposure are associated with somatic RET/PTC rearrangements. Prognosis The prognosis of MEN2 and FMTC is related to MTC: its depends mainly on the histopathological stage of the MTC disease.

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -20-

External links Nomenclature GDB RET RET 5979 ret proto-oncogene (multiple endocrine neoplasia and Entrez_Gene medullary thyroid carcinoma 1, Hirschsprung disease) Cards Atlas RETID76 GeneCards RET Ensembl RET CancerGene MTC1 Genatlas RET GeneLynx RET eGenome RET euGene 5979 Genomic and cartography RET - 10q11.2 chr10:42892533-42942960 + 10q11.21 (hg17- GoldenPath May_2004) Ensembl RET - 10q11.21 [CytoView]

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

Genbank AF032124 [ SRS ] AF032124 [ ENTREZ ]

Genbank AF520975 [ SRS ] AF520975 [ ENTREZ ]

Genbank AF520979 [ SRS ] AF520979 [ ENTREZ ]

Genbank AF520983 [ SRS ] AF520983 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -21- Genbank AJ243297 [ SRS ] AJ243297 [ ENTREZ ]

RefSeq NM_020630 [ SRS ] NM_020630 [ ENTREZ ]

RefSeq NM_020975 [ SRS ] NM_020975 [ ENTREZ ]

RefSeq NT_086766 [ SRS ] NT_086766 [ ENTREZ ] AceView RET AceView - NCBI TRASER RET Traser - Stanford

Unigene Hs.350321 [ SRS ] Hs.350321 [ NCBI ] HS350321 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P07949 [ SRS] P07949 [ EXPASY ] P07949 [ INTERPRO ]

Prosite PS50268 CADHERIN_2 [ SRS ] PS50268 CADHERIN_2 [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 Prosite PROTEIN_KINASE_TYR [ Expasy ]

Interpro IPR002126 Cadherin [ SRS ] IPR002126 Cadherin [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ]

Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]

Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ] CluSTr P07949 Pfam PF00028 Cadherin [ SRS ] PF00028 Cadherin [ Sanger ] pfam00028 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00112 CA [EMBL]

Smart SM00219 TyrKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom P07949 RET_HUMAN [ Domain structure ] P07949 RET_HUMAN [ sequences sharing at least 1 domain ] Blocks P07949 Polymorphism : SNP, mutations, diseases OMIM 164761 [ map ] GENECLINICS 164761

SNP RET [dbSNP-NCBI]

SNP NM_020630 [SNP-NCI]

SNP NM_020975 [SNP-NCI]

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

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -22- Family RET [UCSC Family Browser] Browser SOURCE NM_020630 SOURCE NM_020975 SMD Hs.350321 SAGE Hs.350321

2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG Enzyme ] 2.7.1.112 [ WIT ] Amigo function|ATP binding Amigo function|ATP binding Amigo function|cAMP-dependent protein kinase activity Amigo component|cAMP-dependent protein kinase complex Amigo function|cAMP-dependent protein kinase regulator activity Amigo function|calcium ion binding Amigo process|cell surface receptor linked signal transduction Amigo process|homophilic cell adhesion Amigo component|integral to membrane Amigo component|integral to membrane Amigo process|posterior midgut development Amigo process|protein amino acid phosphorylation Amigo process|protein amino acid phosphorylation Amigo function|protein-tyrosine kinase activity Amigo function|protein-tyrosine kinase activity Amigo function|receptor activity Amigo process|signal transduction Amigo process|signal transduction Amigo function|transferase activity Amigo function|transmembrane receptor protein tyrosine kinase activity PubGene RET Other databases Other Somatic mutation (COSMIC-CGP-Sanger) database Probes PubMed PubMed 88 Pubmed reference(s) in LocusLink Bibliography Cloning and expression of the RET proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -23- Oncogene 1988; 3: 571-578. Medline 3078962

Human RET proto-oncogene mapped to chromosome 10q11.2. Ishizaka Y, Itoh F, Tahira T, Ikeda I, Sugimura T, Tucker J. Oncogene 1989; 4: 1519-1521. Medline 2687772

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Mulligan LM, Kwok JBJ, Healey C, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Ppai L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BA. Nature 1993; 363: 458-460. Medline 8099202

Mutations of the RET proto-oncogene in Hirschsprung's disease. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fekete C, Ponder BA, Munnich A. Nature 1994; 367: 378-379. Medline 8114939

A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Hofstra RMW, Landswater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JWM, van Amstel HKP, Romeo G, Lips CJM, Buys CHCM. Nature 1994; 367: 375-376. Medline 7906866

Somatic mtations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Marsh DJ, Learoyd DL, Andrew SD, Kridhnan L, Pojer R, Richarson AL, Delbridge L, Eng C, Robinson BG. Clin Endocrinol 1996; 44: 24-257. Medline 8729519

RET receptor expression in thyroid follicular epithelial cell-derived tumors. Bunone G, Uggeri M, Mondellini P, Pierotti M, Bongarzone I. Cancer res 2000; 60: 2845-2849. Medline 10850426

The RET proto-oncogene in human cancers. Jhiang SM oncogene 2000; 19: 5590-5597. Medline 11114739

The RET receptor : function in development and dysfunction in congenital

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -24- malformation. Manie S, Santoro S, Fusco A, Billaud M. Trends in genetics 2001; 17: 580-589. Medline 11585664

The GDNF/RET signaling pathway and human disease. Takahashi M. Cytokine and Growth Factor Reviews 2001; 12: 361-373. Medline 11544105

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 10- Patricia Niccoli-Sire 2003 Citation This paper should be referenced as such : Niccoli-Sire P . RET (REarranged during Transfection). Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/RETID76.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -25- Atlas of Genetics and Cytogenetics in Oncology and Haematology

LHCGR (luteinizing hormone/choriogonadotropin receptor)

Identity Note The LHR belongs to the glycoprotein hormone receptor subfamily, with leucine rich repeat motifs, of the G protein-coupled receptor family (GPCR). Other LHR (Luteinizing hormone receptor). names LCGR LGR2 LHCGR (luteinizing hormone/choriogonadotropin receptor) LH/CG-R, LSH-R (lutropin-choriogonadotropic hormone receptor) Hugo LHCGR Location 2p21

Human LHR gene organization (Upper panel), 5' flanking regulatory domains and 176 bp promoter with its functional domains, associated transcription factors and silencing regulatory complex (HDAC/mSin3A) (lower panel). Triangle: multiple transcriptional start sites. PA: poly adenylation sites. Open arrow, up: activation, down: inhibition. ERE: estrogen responsive element. DR: direct repeat. OR: orphan receptor. Sp1 I, Sp1 II: Sp1 sites. PIC: preinitiation complex.

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -26-

Schematic representation of human LHR variants, as deduced from the alternative splicing of the transcripts.

Description The genomic size of human LHR gene is about 80 Kb and consists of 11 coding exons separated by 10 introns. At least three alternatively spliced variants of the hLHR (deletion of exon 8 or 9 or 10) were reported. Transcription Multiple LHR mRNA transcriptional start sites are located within the -176 bp TATA-less 5' flanking promoter domain. Additional upstream transcriptional start sites (> -176 bp) were identified in human testicular mRNA and human choriocarcinoma JAR cell. EREhs (-161 to -171 bp) and upstream sequences (-177 to -2056 bp) are inhibitory. Activation of the human LHR promoter through Sp1/3 factors at Sp1 sites is negatively regulated by cross talk among the transcription factors EAR3/COUP-TFI, Sp1, TFIIB, and independently by histone deacetylase-mSin3A complex at the Sp1 I site. Pseudogene No known pseudogenes Protein

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -27-

Legend diagram: EC: Extracellular domain. TM: Transmembrane domain. IC: Intracellular domain. Triangle box: the putative signal peptide. Vertical lines indicate exons. Normal amino acid residue (white circle). X: Stop. Activating mutations noted as green in familial male precocious puberty (FMPP)-autosomal dominant and/or sporadic male-limited precocious puberty (SMPP) or other; inactivating mutations in Leydig cells hypoplasia (LCH) noted in yellow. Polymorphism noted in blue. Underlined: N-glycosylation sites.

Description The cDNA for the human LHR encodes 699 amino acids. The receptor is composed of two functional units: the extracellular hormone-binding domain and the seven-membrane transmembrane/cytoplasmic module, which is the anchoring unit that transduces the signal initiated in the extracellular domain and couples to G proteins. The large extracellular domain binds LH and hCG with high affinity. Expression LHR is predominantly expressed in gonads. The LHR has also been

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -28- identified in several non-gonadal tissues, including human nonpregnant uterus, placenta, fallopian tubes, uterine vessels, umbilical cord, brain, and lymphocyte. Localisation Predominantly localized in the cell membrane. Function The LHR mediates gonadotropin signaling and triggers intracellular responses that participate in gonadal maturation and function, as well as in the regulation of steroidogenesis and gametogenesis. Luteinizing hormone through its surface receptors on the Leydig cell maintains general metabolic processes and steroidogenic enzymes to regulate the production of androgens. In the ovary, LH promotes follicular development, at stages beyond early antral follicles including the formation of preovulatory follicles and corpora lutea. Homology The percent identity below represents identity using Global pairwise alignment function (GAP): M. musculus: 83.2; R. Norvegicus: 85.2; D. Melanogaster: 40.1; A. gambiae: 39.7; C. elegans: 30.7 Mutations Note Polymorphism detected in exon 1, 8, 10 and 11. Nucleotides insertion/deletion, single nucleotide mutation detected in exon 1, 5, 7, 8, 10 and 11. Deletions of exon 8 or 9 or 10 (splice variants).

Polymorphism: N291S, N312S. Deletion - L204, D355. Insertion at aa 18 - IQ

Activating mutation: A373V, M398T, L457R, I542L, D564G, A568V, M571I, A572V, I575L, T577I, D578G/Y/H/E, C581R

Inhibiting mutation: C131R, F194V, C343S, E354K, W491X, C543R, C545X, R554X, A593P, S616Y and I625K. Deletion - L608, V609, aa 203-227 (exon 8), aa 228-289 (exon 9), and aa 290-316 (exon 10). Insertion: aa18 - LLKLLLLLQLQ. Implicated in Note Activating mutations: Human familial male precocious puberty (FMPP) and sporadic male-limited precocious puberty (SMPP)- gonadotropin independent precocious puberty with Leydig cell hyperplasia. Inactivating mutations: Male: Leydig cell hypoplasia (LCH) with various degree of hypogonadism severity, pseudohermaphroditism. Female: Infertility hypergonadotropic hypogonadism and primary amenorrhea. Association of FMPP and testicular seminoma (D578G) - 1 patient or nodular Leydig cell hyperplasia (D578G) - 1 patient. Somatic mutation of the LHR (D578H) with Leydig cell adenoma and no history of FMPP (3 patients). Mutations may be linked to breast cancer prognosis (18LQ insert)

External links

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -29- Nomenclature Hugo LHCGR GDB LHCGR Entrez_Gene LHCGR 3973 luteinizing hormone/choriogonadotropin receptor Cards Atlas LHRID288 GeneCards LHCGR Ensembl LHCGR CancerGene LHCGR Genatlas LHCGR GeneLynx LHCGR eGenome LHCGR euGene 3973 Genomic and cartography LHCGR - 2p21 chr2:48825620-48894468 - 2p16.3 (hg17- GoldenPath May_2004) Ensembl LHCGR - 2p16.3 [CytoView]

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

Genbank AF024642 [ SRS ] AF024642 [ ENTREZ ]

Genbank AF082076 [ SRS ] AF082076 [ ENTREZ ]

Genbank X84753 [ SRS ] X84753 [ ENTREZ ]

Genbank M63108 [ SRS ] M63108 [ ENTREZ ]

Genbank M73746 [ SRS ] M73746 [ ENTREZ ]

RefSeq NM_000233 [ SRS ] NM_000233 [ ENTREZ ]

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

Unigene Hs.468490 [ SRS ] Hs.468490 [ NCBI ] HS468490 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P22888 [ SRS] P22888 [ EXPASY ] P22888 [ INTERPRO ]

PS00237 G_PROTEIN_RECEP_F1_1 [ SRS ] PS00237 Prosite G_PROTEIN_RECEP_F1_1 [ Expasy ]

PS50262 G_PROTEIN_RECEP_F1_2 [ SRS ] PS50262 Prosite G_PROTEIN_RECEP_F1_2 [ Expasy ] Interpro IPR000276 GPCR_Rhodpsn [ SRS ] IPR000276 GPCR_Rhodpsn [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -30- Interpro IPR002131 Gphrmn_receptor [ SRS ] IPR002131 Gphrmn_receptor [ EBI ]

Interpro IPR001611 LRR [ SRS ] IPR001611 LRR [ EBI ]

Interpro IPR002273 LSH_receptor [ SRS ] IPR002273 LSH_receptor [ EBI ] CluSTr P22888 Pfam PF00001 7tm_1 [ SRS ] PF00001 7tm_1 [ Sanger ] pfam00001 [ NCBI-CDD ]

Pfam PF00560 LRR [ SRS ] PF00560 LRR [ Sanger ] pfam00560 [ NCBI-CDD ] Blocks P22888

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

PDB 1XUL [ SRS ] 1XUL [ PdbSum ], 1XUL [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 152790 [ map ] GENECLINICS 152790

SNP LHCGR [dbSNP-NCBI]

SNP NM_000233 [SNP-NCI]

SNP LHCGR [GeneSNPs - Utah] LHCGR [SNP - CSHL] LHCGR] [HGBASE - SRS] General knowledge Family LHCGR [UCSC Family Browser] Browser SOURCE NM_000233 SMD Hs.468490 SAGE Hs.468490 process|G-protein signaling, coupled to cyclic nucleotide second Amigo messenger Amigo component|endosome Amigo component|integral to plasma membrane Amigo function|lutropin-choriogonadotropic hormone receptor activity Amigo process|male genitalia morphogenesis Amigo process|male gonad development PubGene LHCGR Other databases Probes Probe LHCGR Related clones (RZPD - Berlin) PubMed PubMed 39 Pubmed reference(s) in LocusLink Bibliography Cloning and sequencing of porcine LH-hCG receptor cDNA: variants lacking transmembrane domain. Loosfelt H, Misrahi M, Atger M, Salesse R, Vu Hai-Luu Thi MT, Jolivet A, Guiochon-

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -31- Mantel A, Sar S, Jallal B, Garnier J, et al Science 1989; ;245(4917): 525-528. Medline 2502844

Lutropin-choriogonadotropin receptor: an unusual member of the G protein- coupled receptor family. McFarland KC, Sprengel R, Phillips HS, Kohler M, Rosemblit N, Nikolics K, Segaloff DL, Seeburg PH. Science 1989; 45(4917): 494-499. Medline 2502842

Cloning and sequencing of human LH/hCG receptor cDNA. Minegishi T, Nakamura K, Takakura Y, Miyamoto K, Hasegawa Y, Ibuki Y, Igarashi M. Biochem Biophys Res Commun 1990; 172(3):1049-1054. Medline 2244890

Intronic nature of the rat luteinizing hormone receptor gene defines a soluble receptor subspecies with hormone binding activity. Tsai-Morris CH, Buczko E, Wang W, Dufau ML. J Biol Chem 1990; 265(32): 19385-19388. Medline 2174034

Expression of human luteinizing hormone (LH) receptor: interaction with LH and chorionic gonadotropin from human but not equine, rat, and ovine species. Jia XC, Oikawa M, Bo M, Tanaka T, Ny T, Boime I, Hsueh AJ. Mol Endocrinol 1991; 5(6): 759-768. Medline 1922095

Structure of the luteinizing hormone receptor gene and multiple exons of the coding sequence. Koo YB, Ji I, Slaughter RG, Ji TH. Endocrinology 1991; 128(5): 2297-2308. Medline 2019252

Structural organization of the rat luteinizing hormone (LH) receptor gene. Tsai-Morris CH, Buczko E, Wang W, Xie XZ, Dufau ML. J Biol Chem 1991; 266(17): 11355-11359. Medline 2040640

Changes in binding activity of luteinizing hormone receptors by site directed mutagenesis of potential glycosylation sites. Zhang R, Tsai-Morris CH, Kitamura M, Buczko E, Dufau ML. Biochem Biophys Res Commun 1991; 181(2): 804-808. Medline 1755859

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -32- Promoter and regulatory regions of the rat luteinizing hormone receptor gene. Tsai-Morris CH, Xie X, Wang W, Buczko E, Dufau ML. J Biol Chem 1993; 268(6): 4447-4452. Medline 8440726

Transcriptional protein binding domains governing basal expression of the rat luteinizing hormone receptor gene. Tsai-Morris CH, Geng Y, Xie XZ, Buczko E, Dufau ML. J Biol Chem 1994; 269(22): 15868-15875. Medline 8195242

Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5' non-coding regions. Atger M, Misrahi M, Sar S, Le Flem L, Dessen P, Milgrom E. Mol Cell Endocrinol 1995; 111(2): 113-123 Medline 7556872

Identification of constitutively activating mutation of the luteinising hormone receptor in a family with male limited gonadotrophin independent precocious puberty (testotoxicosis). Kawate N, Kletter GB, Wilson BE, Netzloff ML, Menon KM. J Med Genet 1995; 32(7): 553-554. Medline 7562970

Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. Kremer H, Kraaij R, Toledo SP, Post M, Fridman JB, Hayashida CY, van Reen M, Milgrom E, Ropers HH, Mariman E, et al. Nat Genet 1995; 9(2): 160-164. Medline 7719343

Characterization of diverse functional elements in the upstream Sp1 domain of the rat luteinizing hormone receptor gene promoter. Tsai-Morris CH, Geng Y, Buczko E, Dufau ML. J Biol Chem 1995; 270(13): 7487-7494. Medline 7706295

Functional glycosylation sites of the rat luteinizing hormone receptor required for ligand binding. Zhang R, Cai H, Fatima N, Buczko E, Dufau ML. J Biol Chem 1995; 270(37): 21722-21728. Medline 7665591

Compound heterozygous mutations of the luteinizing hormone receptor gene in Leydig cell hypoplasia. Laue LL, Wu SM, Kudo M, Bourdony CJ, Cutler GB Jr, Hsueh AJ, Chan WY.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -33- Mol Endocrinol 1996; 10(8): 987-997. Medline 8843415

Requirement of cysteine residues in exons 1-6 of the extracellular domain of the luteinizing hormone receptor for gonadotropin binding. Zhang R, Buczko E, Dufau ML. J Biol Chem 1996; 271(10): 5755-5760. Medline 8621442

The luteinizing hormone receptor. Dufau ML. Annu Rev Physiol 1998; 60: 461-496. Review. Medline 9558473

The human luteinizing hormone receptor gene promoter: activation by Sp1 and Sp3 and inhibitory regulation. Geng Y, Tsai-Morris CH, Zhang Y, Dufau ML. Biochem Biophys Res Commun 1999; 263(2): 366-371. Medline 10491299

Genomic distribution and gonadal mRNA expression of two human luteinizing hormone receptor exon 1 sequences in random populations. Tsai-Morris CH, Geng Y, Buczko E, Dehejia A, Dufau ML. Hered 1999; 49(1): 48-51. Medline 9858858.

Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH. Gromoll J, Eiholzer U, Nieschlag E, Simoni M. J Clin Endocrinol Metab 2000 Jun; 85(6): 2281-2286. Medline 10852464

Naturally occurring mutations of the luteinizing hormone receptor gene affecting reproduction. Latronico AC. Semin Reprod Med 2000; 18(1): 17-20. Review. Medline 11299516

Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Themmen AP, Huhtaniemi IT. Endocr Rev 2000; 21(5): 551-583. Review. Medline 11041448

Luteinizing hormone receptor mutations in disorders of sexual development

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -34- and cancer. Wu SM, Leschek EW, Rennert OM, Chan WY. Front Biosci 2000; 5: D343-352. Review. Medline 10704433

Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. Zhang Y, Dufau ML. J Biol Chem 2000; 275(4): 2763-2770. Medline 10644740

An overview of the past, present, and future of nongonadal LH/hCG actions in reproductive biology and medicine. Rao CV. Semin Reprod Med 2001; 19(1):7-17 Review. Medline 11394207

EAR2 and EAR3/COUP-TFI regulate transcription of the rat LH receptor. Zhang Y, Dufau ML. Mol Endocrinol 2001; 15(11): 1891-1905. Medline 11682620

The lutropin/choriogonadotropin receptor, a 2002 perspective. Ascoli M, Fanelli F, Segaloff DL. Endocr Rev 2002; 23(2): 141-174. Review. Medline 11943741

Structural aspects of luteinizing hormone receptor: information from molecular modeling and mutagenesis. Fanelli F, Puett D. Endocrine 2002; 18(3): 285-293. Review. Medline 12450321

Activating mutations of the lutropin choriogonadotropin receptor in precocious puberty. Shanker A. Receptors Channels 2002; 8(1): 3-18. Review. Medline 12408104

Silencing of transcription of the human luteinizing hormone receptor gene by histone deacetylase-mSin3A complex. Zhang Y, Dufau ML. J Biol Chem 2002; 277(36): 33431-33438. Epub 2002; Jun. Medline 12091390

Luteinizing hormone signaling and breast cancer: polymorphisms and age of

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -35- onset. Powell BL, Piersma D, Kevenaar ME, van Staveren IL, Themmen AP, Iacopetta BJ, Berns EM. J Clin Endocrinol Metab 2003; 88(4): 1653-1657. Medline 12679452

Dual mechanisms of regulation of transcription of luteinizing hormone receptor gene by nuclear orphan receptors and histone deacetylase complexes. Zhang Y, Dufau ML. J Steroid Biochem Mol Biol 2003; 85(2-5): 401-414. Medline 12943729

A splice variant of the human luteinizing hormone (LH) receptor modulates the expression of wild-type human LH receptor. Nakamura K, Yamashita S, Omori Y, Minegishi T. Mol Endocrinol 2004; 18(6): 1461-1470. Epub 2004; Mar Medline 15031322

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 08- Chon-Hwa Tsai-Morris, Maria L Dufau 2004 Citation This paper should be referenced as such : Tsai-Morris CH, Dufau ML . LHCGR (luteinizing hormone/choriogonadotropin receptor). Atlas Genet Cytogenet Oncol Haematol. August 2004 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/LHRID288.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -36- Atlas of Genetics and Cytogenetics in Oncology and Haematology

LPHN2 (latrophilin 2)

Identity Other LPHH1 names LEC1 KIAA0786 Hugo LPHN2 Location 1p31.1 --ELTD1---LPHH1----FLJ23033----PRKACB-- DNA/RNA

Representation of the genomic structure of LPHH1. Black blocks represent core exons which are present in the majority of gene transcripts. The yellow blocks represent alternatively spliced coding exons which may be incorporated variably in transcripts derived from different cell types/tissues or as a consequence of differing cellular states. The red boxes represent the presence of multiple, in some cases tissue-specific, leader exons that have been identified for this gene, an observation consistent with the existence of multiple dispersed promoter elements. The most variably spliced region of the coding sequence was the carboxy-terminal domain D.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -37- Description LPHH1 consists of 19 commonly used coding exons. A further seven exons have been identified which may be alternatively spliced into the core backbone with variable frequencies and tissue specificities. At least a number of these additional exons are highly conserved in mammalian species. The core exons (ATG, exon 1 to stop, exon 19) span a region of about 154kb. However, the 5'end of the gene is not precisely defined with transcripts in different tissues apparently initiating from specific locations over an extensive region. The most distant leader exon identified (foetal lung) lies approximately 390kb from exon 1 which makes the total size of the gene at least 550kb. Transcription Expression has been observed by RT-PCR in all normal tissues and lines tested with the clear exception of lymphocytes and lymphoblastoid cells. Strongest expression was observed in foetal lung, normal adult lung and thyroid. Alternative splicing to some degree in at least one domain (minimally the carboxy-terminal domain D) was seen in each tissue and line examined with human brain showing a characteristic pattern and additional variability in the other three coding sequence domains. Pseudogene No known pseudogene. Protein

Alternative splicing in domain D dramatically alters the structure of the carboxy- terminus of the encoded protein, latrophilin 2. Variable splicing in this region occurs in all tissues and cell lines tested.

Description LPHH1 encodes a putative seven-span transmembrane receptor with atypically large extra membrane N (predicted to be extra-cellular) and C termini. In addition to the seven hydrophobic membrane spanning domains, a putative lectin-like region is present near the N-terminus. Expression Protein likely to be ubiquitously expressed in adherent cells but that has not so far been confirmed. Human brain-specific alternative splices alter the structure of the extra-membrane, intra-cellular loop between TM domains 5 and 6, a region thought to be critical for G-protein/receptor interactions.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -38- Localisation Likely to be plasma membrane. Function Likely role in coupling cell adhesion to cell signalling. Homology Latrophilin 2 is part of a small sub-family of 7TMs which includes latrophilins 1 and 3. Latrophilin 1 is the receptor for Black Widow spider toxin: -latrotoxin. Mutations Note None reported. Implicated in Entity Breast carcinoma Note Analysis of breast cancer cell lines has demonstrated dramatic differences in transcript levels between certain lines. In one case, strong expression was allelically imbalanced.

Entity Lung carcinoma Note strong expression in normal lung was reduced in 55% (35/64) of matched primary non-small cell lung carcinomas (NSCLC). Over- representation was not scored in any tumour, nor in any lung cancer cell line tested and transcript was undetectable by RT-PCR in one line (1/15) and very low in a further two. Loss of heterozygosity was scored in 8/16 informative NSCLC lesions. Primary and SCLC lines showed a characteristic pattern of alternative splicing.

External links Nomenclature Hugo LPHN2 GDB LPHN2 Entrez_Gene LPHN2 23266 latrophilin 2 Cards Atlas LPHH1ID313 GeneCards LPHN2 Ensembl LPHN2 Genatlas LPHN2 GeneLynx LPHN2 eGenome LPHN2 euGene 23266 Genomic and cartography LPHN2 - 1p31.1 chr1:82038670-82230694 + 1p31.1 (hg18- GoldenPath Mar_2006) Ensembl LPHN2 - 1p31.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -39- OMIM Disease map [OMIM] HomoloGene LPHN2 Gene and transcription

Genbank AB018329 [ ENTREZ ]

Genbank AF104266 [ ENTREZ ]

Genbank AF104938 [ ENTREZ ]

Genbank AF104939 [ ENTREZ ]

Genbank AJ131581 [ ENTREZ ]

RefSeq NM_012302 [ SRS ] NM_012302 [ ENTREZ ] AceView LPHN2 AceView - NCBI TRASER LPHN2 Traser - Stanford

Unigene Hs.24212 [ SRS ] Hs.24212 [ NCBI ] HS24212 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O95490 [ SRS] O95490 [ EXPASY ] O95490 [ INTERPRO ]

PS00649 G_PROTEIN_RECEP_F2_1 [ SRS ] PS00649 Prosite G_PROTEIN_RECEP_F2_1 [ Expasy ]

PS00650 G_PROTEIN_RECEP_F2_2 [ SRS ] PS00650 Prosite G_PROTEIN_RECEP_F2_2 [ Expasy ]

PS50227 G_PROTEIN_RECEP_F2_3 [ SRS ] PS50227 Prosite G_PROTEIN_RECEP_F2_3 [ Expasy ]

PS50261 G_PROTEIN_RECEP_F2_4 [ SRS ] PS50261 Prosite G_PROTEIN_RECEP_F2_4 [ Expasy ]

Prosite PS50221 GPS [ SRS ] PS50221 GPS [ Expasy ]

Prosite PS51132 OLF [ SRS ] PS51132 OLF [ Expasy ]

Prosite PS50228 SUEL_LECTIN [ SRS ] PS50228 SUEL_LECTIN [ Expasy ]

Interpro IPR000832 GPCR_secretin [ SRS ] IPR000832 GPCR_secretin [ EBI ]

Interpro IPR001879 hormone_rcpt [ SRS ] IPR001879 hormone_rcpt [ EBI ]

Interpro IPR003334 Latrophilin_C [ SRS ] IPR003334 Latrophilin_C [ EBI ]

Interpro IPR003924 Latrophl_rcpt [ SRS ] IPR003924 Latrophl_rcpt [ EBI ]

Interpro IPR000922 Lectin_gal_bd [ SRS ] IPR000922 Lectin_gal_bd [ EBI ]

Interpro IPR003112 Olfac_like [ SRS ] IPR003112 Olfac_like [ EBI ]

Interpro IPR000203 PKD_cys_rich [ SRS ] IPR000203 PKD_cys_rich [ EBI ] CluSTr O95490 Pfam PF00002 7tm_2 [ SRS ] PF00002 7tm_2 [ Sanger ] pfam00002 [ NCBI-CDD ]

PF02140 Gal_Lectin [ SRS ] PF02140 Gal_Lectin [ Sanger Pfam ] pfam02140 [ NCBI-CDD ]

Pfam PF01825 GPS [ SRS ] PF01825 GPS [ Sanger ] pfam01825 [ NCBI-CDD ]

Pfam PF02793 HRM [ SRS ] PF02793 HRM [ Sanger ] pfam02793 [ NCBI-CDD ]

Pfam PF02354 Latrophilin [ SRS ] PF02354 Latrophilin [ Sanger ] pfam02354

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -40- [ NCBI-CDD ]

Pfam PF02191 OLF [ SRS ] PF02191 OLF [ Sanger ] pfam02191 [ NCBI-CDD ]

Smart SM00303 GPS [EMBL]

Smart SM00008 HormR [EMBL]

Smart SM00284 OLF [EMBL]

Prodom PD005612 Gal_lectin[INRA-Toulouse] Prodom O95490 LPHN2_HUMAN [ Domain structure ] O95490 LPHN2_HUMAN [ sequences sharing at least 1 domain ] Blocks O95490 HPRD O95490 Protein Interaction databases DIP O95490 IntAct O95490 Polymorphism : SNP, mutations, diseases OMIM 607018 [ map ] GENECLINICS 607018

SNP LPHN2 [dbSNP-NCBI]

SNP NM_012302 [SNP-NCI]

SNP LPHN2 [GeneSNPs - Utah] LPHN2] [HGBASE - SRS]

HAPMAP LPHN2 [HAPMAP] General knowledge Family LPHN2 [UCSC Family Browser] Browser SOURCE NM_012302 SMD Hs.24212 SAGE Hs.24212 Amigo biological process unknown Amigo receptor activity Amigo G-protein coupled receptor activity Amigo G-protein coupled receptor activity Amigo sugar binding Amigo molecular function unknown Amigo signal transduction Amigo G-protein coupled receptor protein signaling pathway Amigo neuropeptide signaling pathway Amigo cellular component unknown Amigo membrane Amigo integral to membrane Amigo integral to membrane

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -41- Amigo latrotoxin receptor activity Amigo latrotoxin receptor activity PubGene LPHN2 Other databases Probes Probe LPHN2 Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography Genomic structure and expression profile of LPHH1, a 7TM gene variably expressed in breast cancer cell lines. White GRM, Varley JM, Heighway J. Biochimica et Biophysica Acta 2000; Gene structure and expression 1491: 75-92. Medline 20225451

A family of heptahelical receptors with adhesion-like domains: A marriage between two super families. Hayflick JS. Journal of Receptor and Signal Transduction Research 2003; 20: 119-131 (REVIEW) Medline 20448105

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 11- Jim Heighway 2003 Citation This paper should be referenced as such : Heighway J . LPHN2 (latrophilin 2). Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://AtlasGeneticsOncology.org/Genes/LPHH1ID313.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -42- Atlas of Genetics and Cytogenetics in Oncology and Haematology

HLXB9 (homeo box HB9)

Identity Note telomeric to c7orf3 and SHH Other HB9 names HOXHB9 SCRA1 Mnr1 Hugo HLXB9 Location 7q36.3 Note telomeric to c7orf3 and SHH DNA/RNA Description 3 exons stretched over an area of 5-6 kb. Transcription In a telomere to centromere direction; 2061 bp mRNA, 1206 bp open reading frame. Protein

Description The homeobox gene HLXB9 encodes the nuclear protein HB9. The protein contains a polyalanine repeat region and a homeobox domain. Expression Expressed in lymphoid and pancreatic tissues. Highly expressed in CD34+ bone marrow cells, down regulated upon differentiation. Localisation Nuclear Function Putative transcription factor. Homology Related to Mnr2. Mutations Note Mutations in HLXB9 cause an autosomal dominant form of sacral agenesis, known as Currarino syndrome. Implicated in Entity t(7;12)(q36;p13) - associated infant acute myeloid leukemia (AML) Prognosis Prognosis probably poor: median survival is 13 months. Cytogenetics t(7;12)(q36;p13), but not always visible by chromosome banding; may also be misdiagnosed as del(12)(p13).

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -43-

Fig. 3. Schematic representation of the HLXB9 and ETV6 proteins and the putative HLXB9-ETV6 chimeric protein resulting from the t(7;12)(q36;p13). Arrow, the observed breakpoints. nt numbers (cDNA level) are given above each protein, and amino acid numbers are given in bold type below each protein.

Hybrid/Mutated 5' HLXB9 _ 3' ETV6 Gene Abnormal N-term HLXB9, including its polyalanine repeat, is fused to a large C- Protein term part of the ETV6 protein including its HLH domain and ETS domain; the homeobox domain of HLXB9 is not retained in the fusion protein; the reciprocal transcript is not expressed.

To be noted The t(7;12) is heterogeneous at the molecular level. The formation of a fusion gene has only been described in 2 cases and may not be the only mechanism by which HLXB9 is involved in t(7;12)-associated leukaemias. Additional 7q36 genes may also be involved. External links Nomenclature Hugo HLXB9 GDB HLXB9 Entrez_Gene HLXB9 3110 homeobox HB9 Cards Atlas HLXB9ID393 GeneCards HLXB9 Ensembl HLXB9 Genatlas HLXB9 GeneLynx HLXB9 eGenome HLXB9 euGene 3110 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -44- HLXB9 - 7q36.3 chr7:156490308-156496108 - 7q36.3 (hg18- GoldenPath Mar_2006) Ensembl HLXB9 - 7q36.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene HLXB9 Gene and transcription

Genbank AF107457 [ ENTREZ ]

Genbank CR623223 [ ENTREZ ]

Genbank X56537 [ ENTREZ ]

RefSeq NM_005515 [ SRS ] NM_005515 [ ENTREZ ] AceView HLXB9 AceView - NCBI TRASER HLXB9 Traser - Stanford

Unigene Hs.37035 [ SRS ] Hs.37035 [ NCBI ] HS37035 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P50219 [ SRS] P50219 [ EXPASY ] P50219 [ INTERPRO ]

Prosite PS00027 HOMEOBOX_1 [ SRS ] PS00027 HOMEOBOX_1 [ Expasy ]

Prosite PS50071 HOMEOBOX_2 [ SRS ] PS50071 HOMEOBOX_2 [ Expasy ]

Interpro IPR001356 Homeobox [ SRS ] IPR001356 Homeobox [ EBI ] Interpro IPR012287 Homeodomain-rel [ SRS ] IPR012287 Homeodomain-rel [ EBI ]

IPR009057 Homeodomain_like [ SRS ] IPR009057 Interpro Homeodomain_like [ EBI ] CluSTr P50219

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

Smart SM00389 HOX [EMBL]

Prodom PD000010 Homeobox[INRA-Toulouse] Prodom P50219 HLXB9_HUMAN [ Domain structure ] P50219 HLXB9_HUMAN [ sequences sharing at least 1 domain ] Blocks P50219 HPRD P50219 Protein Interaction databases DIP P50219 IntAct P50219 Polymorphism : SNP, mutations, diseases OMIM 142994;176450 [ map ] GENECLINICS 142994;176450

SNP HLXB9 [dbSNP-NCBI]

SNP NM_005515 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -45- SNP HLXB9 [GeneSNPs - Utah] HLXB9] [HGBASE - SRS]

HAPMAP HLXB9 [HAPMAP] General knowledge Family HLXB9 [UCSC Family Browser] Browser SOURCE NM_005515 SMD Hs.37035 SAGE Hs.37035 Amigo transcription factor activity Amigo RNA polymerase II transcription factor activity Amigo nucleus Amigo regulation of transcription from RNA polymerase II promoter Amigo humoral immune response Amigo morphogenesis Amigo sequence-specific DNA binding PubGene HLXB9 Other databases Probes Probe HLXB9 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography A novel human homeobox gene distantly related to proboscipedia is expressed in lymphoid and pancreatic tissues. Harrison KA, Druey KM, Deguchi Y, Tuscano JM, Kehrl JH. J Biol Chem 1994; 269(31): 19968-19975. Medline 94327547

A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Ross AJ, Ruiz-Perez V, Wang Y, Hagan DM, Scherer S, Lynch SA, Lindsay S, Custard E, Belloni E, Wilson DI, Wadey R, Goodman F, Orstavik KH, Monclair T, Robson S, Reardon W, Burn J, Scambler P, Strachan T. Nat Genet 1998; 20(4): 358-361. Medline 99057341

Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Beverloo HB, Panagopoulos I, Isaksson M, van Wering E, van Drunen E, de Klein A, Johansson B, Slater R. Cancer Res 2001; 61(14): 5374-5377 Medline 21347207

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -46-

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- Anne RM von Bergh, H Berna Beverloo 2003 Citation This paper should be referenced as such : von Bergh ARM, Beverloo HB . HLXB9 (homeo box HB9). Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://AtlasGeneticsOncology.org/Genes/HLXB9ID393.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -47- Atlas of Genetics and Cytogenetics in Oncology and Haematology

SYNPO2

Identity Note Myopodin probably represents an alternative splicing variant of synaptopodin 2. The predicted synaptopodin 2 contains 1021 amino acid and myopodin 698. The extra 323 amino acid in synaptopodin 2 is located at the N-terminus. Other Myopodin names synaptopodin 2 Hugo SYNPO2 Location 4q27 DNA/RNA

Genome structure of myopodin and synaptopodin 2. Green represents exons of myopodin, and orange synaptopodin 2. Introns are indicated with lines.

Description The genome sequence of myopodin contains 6.8 Kb, while synaptopodin 2 38 kb. Transcription A typical messenger RNA of myopodin is 4.2-4.4 kb, and synaptopodin 2 6.7 kb. Pseudogene Unknown Protein

Protein structure of myopodin and synaptopodin 2. Orange represents sequence unique to synaptopodin 2, Green myopodin. Black stripe represents sequence homologous to synaptopodin 1.

Description A nuclear localization signal is identified in N-terminus region of myopodin. Myopodin also contains six stretches of homologous

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -48- sequences with synaptopodin 1. Expression Skeletal muscle, prostate, large and small intestine. Localisation Nucleus, cytoplasm. Function Actin bundling. Homology Synaptopodin Mutations Germinal Not known Somatic Deletion Implicated in Disease Prostate cancer and urothelial cell carcinoma. Prognosis Deletion preferentially occurs in aggressive type of prostate cancer. Loss of expression in nucleus in urothelial cell carcinoma is predictive of poor clinical outcome. Cytogenetics Not known

External links Nomenclature Hugo SYNPO2 GDB SYNPO2 Entrez_Gene SYNPO2 171024 synaptopodin 2 Cards GeneCards SYNPO2 Ensembl SYNPO2 CancerGene SYNPO2 Genatlas SYNPO2 GeneLynx SYNPO2 eGenome SYNPO2 euGene 171024 Genomic and cartography SYNPO2 - 4q27 chr4:120167599-120340005 + 4q26 (hg17- GoldenPath May_2004) Ensembl SYNPO2 - 4q26 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] HomoloGene SYNPO2 Gene and transcription

Genbank AF177291 [ SRS ] AF177291 [ ENTREZ ]

Genbank AJ010482 [ SRS ] AJ010482 [ ENTREZ ]

Genbank AL832031 [ SRS ] AL832031 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -49- Genbank AL832363 [ SRS ] AL832363 [ ENTREZ ]

Genbank AL833294 [ SRS ] AL833294 [ ENTREZ ]

RefSeq NM_133477 [ SRS ] NM_133477 [ ENTREZ ]

RefSeq NT_016354 [ SRS ] NT_016354 [ ENTREZ ] AceView SYNPO2 AceView - NCBI TRASER SYNPO2 Traser - Stanford

Unigene Hs.480615 [ SRS ] Hs.480615 [ NCBI ] HS480615 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9UMS6 [ SRS] Q9UMS6 [ EXPASY ] Q9UMS6 [ INTERPRO ]

Prosite PS50106 PDZ [ SRS ] PS50106 PDZ [ Expasy ] CluSTr Q9UMS6 Blocks Q9UMS6 Polymorphism : SNP, mutations, diseases

SNP SYNPO2 [dbSNP-NCBI]

SNP NM_133477 [SNP-NCI]

SNP SYNPO2 [GeneSNPs - Utah] SYNPO2 [SNP - CSHL] SYNPO2] [HGBASE - SRS] General knowledge Family SYNPO2 [UCSC Family Browser] Browser SOURCE NM_133477 SMD Hs.480615 SAGE Hs.480615 PubGene SYNPO2 Other databases Probes Probe SYNPO2 Related clones (RZPD - Berlin) PubMed PubMed 3 Pubmed reference(s) in LocusLink Bibliography Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers. Lin F, Yu YP, Woods J, Cieply K, Gooding B, Finkelstein P, Dhir R, Krill D, Becich MJ, Michalopoulos G, Finkelstein S, Luo JH. Am J Pathol. 2001; 159(5): 1603-1612. Medline 11696420

Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P. J Cell Biol 2001; 155(3): 393-404.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -50- Medline 11673475

Tumor suppressor role for myopodin in bladder cancer: loss of nuclear expression of myopodin is cell-cycle dependent and predicts clinical outcome. Sanchez-Carbayo M, Schwarz K, Charytonowicz E, Cordon-Cardo C, Mundel P. Oncogene 2003; 22(34): 5298-5305. Medline 12917631

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- Jian-Hua Luo 2003 Citation This paper should be referenced as such : Luo JH . SYNPO2. Atlas Genet Cytogenet Oncol Haematol. December 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SYNPO2ID488.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -51- Atlas of Genetics and Cytogenetics in Oncology and Haematology

11p15 rearrangements in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes,Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL) Note The study included 17 cases; t-MDS without progression to ANLL accounted for 35%, t-MDS with progression to ANLL for 18% and t- ANLL for the remaining 47% (M2 or M4 mainly); no case of acute lymphoblastic leukaemia Epidemiology 11p15 rearrangements were found in 3% of t-MDS/t-ANLL and have been reported to be found in 5% of childhood t-MDS/t-ANLL; sex ratio: 4M/13F Clinics Age at diagnosis of the primary disease 45 yrs (range 2-70); age at diagnosis of the t-MDS/t-ANLL: 50 yrs (range 4-75). Median interval was short: 54 mths (range: 11-189). Primary disease was a solid tumor in 47% of cases (in particular breast cancer) and a hematologic malignancy in 53%, treatment was chemotherapy (42%), or both chemotherapy and radiotherapy (58%). Treatment included topoisomerase II inhibitors in 71% of cases and alkylating agents in 76%. Prognosis Median survival was 13 mths, with 56% of patients surviving at 1 yr, and 33% at 2 yrs., a similar survival to what is found in treatment related leukemias with a 21q22 rearrangement Cytogenetics Additional 11p15 rearrangements included inv(11)(p15q23) in 35% of cases, anomalies t(7;11)(p15;p15)in 18%, or, more rarely: t(1;11)(p32;p15), t(2;11)(q31;p15), t(4;11)(q22;p15), t(10;11)(q22-23;p15), t(11;17)(p15;q21), or t(11;20)(p15;q11); additional anomalies were: - 7/del(7q) in 24%, and -5/del(5q) in 12 %. Complex karyotypes were found in 18%. Result of the chromosomal

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -52- anomaly Hybrid gene 5' NUP98 -3¹ partner Description

Bibliography Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K, Olney HJ, Baer MR. Genes Chromosomes Cancer 2002; 33: 401-412. Medline 11921274

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . 11p15 rearrangements in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11p15TreatRelLeukID1299.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -53- Atlas of Genetics and Cytogenetics in Oncology and Haematology

12p13 rearrangements in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes,Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL) Note The study included 9 cases; t-MDS without progression to ANLL accounted for 2 of 9 cases, t-MDS with progression to ANLL for 1 case and t-ANLL for the remaining 6 cases; no case of acute lymphoblastic leukaemia Epidemiology 12p13 rearrangements were found in 2% of t-MDS/t-ANLL; sex ratio: 5M/4F Clinics Age at diagnosis of the primary disease 40 yrs (range 11-64); age at diagnosis of the t-MDS/t-ANLL: 48 yrs (range 25-69). Median interval was relatively long: 81 mths (range: 18-223). Primary disease was a solid tumor in only 2 of 9 cases, and a hematologic malignancy in 7/9; treatment was chemotherapy (3/9), or both (6/9). Treatment included topoisomerase II inhibitors in 5 of 9 cases and alkylating agents in 8/9. Prognosis Median survival was very poor: 4 mths, with 15% of patients surviving at 1 yr, and none at 2 yrs. Cytogenetics Additional 12p13 rearrangements included: t(1;12)(q21;p13), t(4;12)(q12;p13), anomalies t(7;12)(p15;p13), t(8;12)(p12;p13), t(12;20)p13;q11),and t(12;22)(p13;q11) ID: t(12;22)(p13;q11)> and other rearrangements. Complex karyotypes were found in 7 of 9 cases; -7/del(7q) and/or were found in 6 of 9 cases. Result of the chromosomal anomaly Hybrid gene 5' ETV6 -3¹ partner where ETV6 is known to be involved Description

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -54-

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . 12p13 rearrangements in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/12p13TreatRelLeukID1301.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -55- Atlas of Genetics and Cytogenetics in Oncology and Haematology

21q22 rearrangements in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes, Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL) Note The study included 79 cases; t-MDS without progression to ANLL accounted for 15%, t-MDS progressing to ANLL for 18%, t-ANLL for the remaining 67%; there was no case of acute lymphoblastic leukaemia Phenotype / MDS cases were frequently refractory anemia with excess of blasts cell stem cases; 58% of ANLL cases were M2 ANLL origin Etiology Frequent antracyclin exposure Epidemiology 21q22 rearrangements were found in 15% of t-MDS/t-ANLL; 1M to 1F sex ratio Clinics Age at diagnosis of the primary disease was 47 yrs (range 2-75); age at diagnosis of the t-MDS/t-ANLL was 51 yrs (11-77) and median interval was 39 mths (6-306). Primary disease was a solid tumor in 56% of cases (mainly: breast, lung, sarcoma/ PNET, colon cancer) and an hematologic malignancy in 43%. Treatment of the primary disease included radiotherapy (in 6%), chemotherapy (46%) or both (48%). 75% of patients with a 21q22 rearrangement had previously received topoisomerase II inhibitors, a higher proportion than other subgroups of treatment related leukemia, except 11q23 patients, who were 84% to have been exposed to topoisomerase II inhibitors; alkylating agents exposure was higher than in patients with t(15;17) or inv(16) Treatment Patients who received bone marrow transplantation had a higher median survival (31 mths). Prognosis Median survival was 14 mths, there was 58% of patients surviving 1 yr, 33% 2 yrs, and 18% 5 yrs., a better outcome than patients with 11q23 rearrangement, 3q21q26 rearrangement, 12p13 rearrangement, t(9;22), or t(8;16) and a worse outcome than those with t(15;17) or

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -56- inv(16) treatment related leukemias.By th 21q22 group, patients with a t(8;21) had a better outcome, and those with a t(3;21) had a worse outcome. Cytogenetics Cytogenetics t(8;21)(q22;q22) ( ETO / AML1) was found in 56% of cases, Morphological t(3;21)(q26;q22) ( MDS-EVI1 / AML1 in 20 %, t(16;21)(q24;q22) ( CBFA2T3 / AML1) in 5%. Rare recurrent anomalies were: t(1;21)(p36;q22), t(9;21)(p22;q22), t(10;21)(p12;q22), t(15;21)(q21- 22;q22), t(17;21)(q12;q22), and t(20;21)(q11;q22) Additional -7/del(7q) in 23% of cases (espacially in cases with alkylating agents anomalies exposure), +8 in 11%, -5/del(5q) rarely found; complex karyotypes in 28% of cases (more frequently than in treatment related leukemias with a 11q23 rearrangement or a t(15.17)) Genes involved and Proteins

Result of the chromosomal anomaly Hybrid gene 5' AML1 - 3' partner Description

Bibliography 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. Genes Chromosomes Cancer 2002; 33: 379-394. Medline 11921272

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . 21q22 rearrangements in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/21q22TreatRelLeukID1296.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -57- Atlas of Genetics and Cytogenetics in Oncology and Haematology

inv(16)(p13q22) in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes,Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL) Note The study included 48 cases; t-MDS without progression to ANLL accounted for 8%, t-MDS with progression to ANLL for 13% and t- ANLL for the remaining 79% the ANLL subtype was M4eo in 83%, M2 in 14%; no case of acute lymphoblastic leukaemia Epidemiology inv(16)(p13q22) was found in 9% of t-MDS/t-ANLL; sex ratio: 18M/30F Clinics Age at diagnosis of the primary disease 43 yrs (range 6-75); age at diagnosis of the t-MDS/t-ANLL: 48 yrs (range 13-77). Median interval was short: 22 mths (range: 8-533). Primary disease was a solid tumor in 71% of cases (in particular breast cancer, sarcoma, cancer of the ovary) and a hematologic malignancy in 27%, treatment was radiotherapy (21%, a relatively high proportion compared to other groups), chemotherapy (29%), or both (50%). Treatment included topoisomerase II inhibitors in 60% of cases and alkylating agents in 63%. Prognosis Patients under 55 yrs of age had better outcome. Median survival was 29 mths, with 45% of patients surviving at 5 yrs, the best survival among subgroups of treatment related leukemias with a balanced chromosome aberration (patients with 11q23 rearrangement, 3q21q26 rearrangement, 12p13 rearrangement, t(9;22), t(8;16), or a 21q22 rearangement)). Patients with t(15;17) had similar median survival, but less long term survivors. Cytogenetics Additional The inv(16) was found solely in 46% of cases; additional anomalies anomalies were: +8 in 17% , +21 in 13%, +22 in 8%, -7/del(7q) in 8%, +13 in 6%, or -5/del(5q). Result of the chromosomal anomaly

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -58- Hybrid gene 5'CBFB -3¹ MYH11 Description

External links Other inv(16)(p13q22) in treatment related Mitelman database (CGAP - database leukemia NCBI) Bibliography Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Andersen MK, Larson RA, Mauritzson N, Schnittger S, Jhanwar SC, Pedersen- Bjergaard J. Genes Chromosomes Cancer 2002; 33: 395-400. Medline 11921273

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . inv(16)(p13q22) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/inv16p13q22TreatRelID1297.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -59- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(3;21)(q26;q22) in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes,Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL) Note The study included 16 cases; t-MDS without progression to ANLL accounted for 38%, t-MDS progressing to ANLL for 25%, t-ANLL for the remaining 38% (to be compared with the 80% of t-ANLL in cases with t(8;21)); no case of acute lymphoblastic leukaemia Epidemiology t(3;21)(q26;q22) was found in 3% of t-MDS/t-ANLL; sex ratio: 5M/11F Clinics Age at diagnosis of the primary disease 49 yrs (range 14-72); age at diagnosis of the t-MDS/t-ANLL: 53 yrs range 19-73). Median interval was 36 mths, range: 17-139). Primary disease was a solid tumor in 56% of cases and a hematologic malignancy in 44%. Treatment included topoisomerase II inhibitors in 81% of cases). Prognosis Median survival was 8 mths. Outcome was worse than the outcome of patients with t(8;21)(q22;q22), t(15;17) or inv(16) treatment related leukemias, and similar to the outcome of patients with 11q23 rearrangement Cytogenetics Additional The t(3;21) was found solely in 31% of cases; additional anomaly was: - anomalies 7/del(7q) in 31% of cases, +8 was not observed . A complex karyotype was found in 25% of cases Result of the chromosomal anomaly Hybrid gene 5' AML1 - 3' MDS1-EVI1; breakpoint is most often in the AML1 intron 6. Description

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -60- External links Other t(3;21)(q26;q22) in treatment related Mitelman database (CGAP - database leukemia NCBI) Other t(3;21)(q26;q22) in treatment related CancerChromosomes (NCBI) database leukemia Bibliography 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. Genes Chromosomes Cancer 2002; 33: 379-394. Medline 11921272

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(3;21)(q26;q22) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0321q26q22TreatRelID1294.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -61- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(8;16)(p11;p13) in treatment related leukemia

External links Other t(8;16)(p11;p13) in treatment related Mitelman database (CGAP - database leukemia NCBI)

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -62- Other t(8;16)(p11;p13) in treatment related CancerChromosomes (NCBI) database leukemia Bibliography Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K, Olney HJ, Baer MR. Genes Chromosomes Cancer 2002; 33: 401-412. Medline 11921274

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(8;16)(p11;p13) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0816p11p13TreatRelID1302.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -63- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(8;21)(q22;q22) in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes,Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL) Note The study included 44 cases; t-MDS with or without progression to ANLL accounted for 20% and t-ANLL for the remaining 80%; no case of acute lymphoblastic leukaemia Epidemiology t(8;21)(q22;q22) was found in 9% of t-MDS/t-ANLL; 1M to 1F sex ratio Clinics Age at diagnosis of the primary disease 45 yrs (range 2-75); age at diagnosis of the t-MDS/t-ANLL: 47 yrs for patients with the t(8;21) solely and 50 yrs for patients with an additional anomaly; range was(15-77). Median interval was 39 mths for cases with t(8;21) solely, and 33 mths in other cases; (range: 6-306). Primary disease was a solid tumor in 70% of cases ( breast cancer in particular) and a hematologic malignancy in 30%, treated with radiotherapy (12%), chemotherapy (42%), or both (46%). Cytology Cell morphology was similar to those of de novo t(8;21) Prognosis Median survival was 17mths and 31 mths respectively for patients without and with additionnal anomalies, but the difference was not significant. Outcome was better than the outcome of patients with 11q23 rearrangement, 3q21q26 rearrangement, 12p13 rearrangement, t(9;22), t(8;16), or a t(3;21) and worse than the outcome of patients with with t(15;17) or inv(16) treatment related leukemias. Cytogenetics Additional The t(8;21) was found solely in 25% of cases; additional anomalies anomalies were: -Y or -X in 25% of cases, del(9q) in 18 %, +8 in 9%, -7/del(7q) in 7%. A complex karyotype was found in 32% of cases Result of the chromosomal anomaly

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -64- Hybrid gene 5' AML1 - 3' ETO; breakpoint is most often in the AML1 intron 5. Description

External links Other t(8;21)(q22;q22) in treatment related Mitelman database (CGAP - database leukemia NCBI) Other t(8;21)(q22;q22) in treatment related CancerChromosomes (NCBI) database leukemia Bibliography 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. Genes Chromosomes Cancer 2002; 33: 379-394. Medline 11921272

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(8;21)(q22;q22) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0821q22q22TreatRelID1293.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -65- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(9;22)(q34;q11) in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes,Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related acute non lymphocytic leukaemias (t-ANLL) and lymphocytic leukemias (t-ALL) Note The study included 10 cases; t-ANLL and t-ALL accounted for half cases each. Treatment related acute lymphocytic leukemias (t-ALL) are extremely rare, found in only 20 of 511 cases (4%) in this workshop: 5 cases of t(9;22), 12 cases of t(4;11)(q22;q23), 2 cases of t(8;14)(q24;q32), and 1 case of t(11;19)(q23;p13.3) Epidemiology t(9;22)(q34;q11) was found in 2% of treatment related acute leukaemias; sex ratio: 2M/8F Clinics Age at diagnosis of the primary disease 45 yrs (range 3-76); age at diagnosis of the t-MDS/t-ANLL: 64 yrs (range 12-78). Median interval was long: 110 mths (range: 25-310). Primary disease was a solid tumor in 70% of cases (in particular breast cancer) and a hematologic malignancy in 20%; treatment was radiotherapy in 1/10, chemotherapy (6/10), or both (3/10). Treatment included topoisomerase II inhibitors in 4 of 9 cases and alkylating agents in 5/9. Prognosis Median survival was very poor: 5 mths, with 14% of patients surviving at 1 yr, and none at 2 yrs. Cytogenetics Additional Complex karyotypes were found in 6 of 10 cass. anomalies Result of the chromosomal anomaly Hybrid gene Description 5' BCR -3¹ ABL

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -66- External links Other t(9;22)(q34;q11) in treatment related Mitelman database (CGAP - database leukemia NCBI) Other t(9;22)(q34;q11) in treatment related CancerChromosomes (NCBI) database leukemia Bibliography Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K, Olney HJ, Baer MR. Genes Chromosomes Cancer 2002; 33: 401-412. Medline 11921274

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(9;22)(q34;q11) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0922q34q11TreatRelID1300.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -67- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(15;17)(q22;q21) in treatment related leukemia

Identity Note This data is extracted from a very large study from an International Workshop on treatment related leukemias - restricted to balanced chromosome aberrations (i.e.: -5/del(5q)and -7/del(7q) not taken into account per see), published in Genes,Chromosomes and Cancer in 2002. Clinics and Pathology Disease Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL) Note The study included 41 cases; t-MDS with progression to ANLL accounted for 7% and t-ANLL for the remaining 93% the ANLL subtype was M3 in all but one case; no case of acute lymphoblastic leukaemia Epidemiology t(15;17)(q22;q21) was found in 8% of t-MDS/t-ANLL; sex ratio: 15M/26F Clinics Age at diagnosis of the primary disease 46 yrs (range 18-79); age at diagnosis of the t-MDS/t-ANLL: 49 yrs (range 19-81). Median interval was 29 mths (range: 9-175). Primary disease was a solid tumor in 71% of cases ( breast cancer in particular) and a hematologic malignancy in 27%, treatment was radiotherapy (29%, a high proportion compared to other groups), chemotherapy (17%), or both (54%). Treatment included topoisomerase II inhibitors in 49% of cases and alkylating agents in 59%. Prognosis Median survival was 29 mths. Outcome was better than the outcome of patients with 11q23 rearrangement, 3q21q26 rearrangement, 12p13 rearrangement, t(9;22), t(8;16), or a 21q22 rearangement) and similar, during the first 2 yrs to that of the inv(16) treatment related leukemias. Cytogenetics Additional The t(15;17) was found solely in 59% of cases; additional anomalies anomalies were: +8 in 12% , -5/del(5q) in 5%, or -7/del(7q). Result of the chromosomal anomaly Hybrid gene 5¹ PML -3¹ RARA Description

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -68-

External links Other t(15;17)(q22;q21) in treatment related Mitelman database (CGAP - database leukemia NCBI) Other t(15;17)(q22;q21) in treatment related CancerChromosomes (NCBI) database leukemia Bibliography Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Andersen MK, Larson RA, Mauritzson N, Schnittger S, Jhanwar SC, Pedersen- Bjergaard J. Genes Chromosomes Cancer 2002; 33: 395-400. Medline 11921273

Contributor(s) Written 10- Jean-Loup Huret 2003 Citation This paper should be referenced as such : Huret JL . t(15;17)(q22;q21) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1517q22q21TreatRelID1298.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -69- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Acute megakaryoblastic leukemia (AMegL) M7 acute non lymphocytic leukemia (M7-ANLL)

Identity Note Sometimes presenting as "acute myelofibrosis" Other AML-M7 names Clinics and Pathology Phenotype / This leukemia is thought to derive from the transformation of a cell stem multipotent myeloid progenitor cell. In the adult patient multilineage origin dysplasia is a common finding and in some cases a minority of myeloid blast cells is present. The blast cells show one or more megakaryocytic markers (i.e. Factor VIII, CD61, CD41, or CD42), they test negative when using the anti- myeloperoxidase monoclonal antibody and never show coordinated expression of lymphoid markers, though isolated CD2 or CD7 positivity can be found on some occasions. The CD34, CD13 and CD33 markers are positive in a substantial fraction of cases, as is the case with the CD36/thrombospondin receptor. The myeloperoxidase stain is negative by light microscopy, but ultrastructural peroxidase activity with a specific peri-nuclear staining pattern can be detected at the electron microscopy level. Epidemiology The disease is rare and, due to difficulty in diagnosis, its exact incidence is not known. Reasonably, it may account for approximately 1-2% of all de novo acute myeloid leukemias (AML) in the adult population, but the incidence in the pediatric age group is higher, partly due to an association with Down syndrome. Clinics The presentation is usually acute, though AMegL may develop after myelodysplastic syndrome or chronic myelogenous leukemia (CML). In some cases acute myelofibrosis is the presentation picture. AMegL should be distinguished from AML with megakaryoblastic involvement showing a minority of megakaryoblasts. In children there is an association with Down syndrome. Cytology The blast cell morphology varies from case to case. In some patients the blasts are undifferentiated and the diagnosis requires immunophenotyping or electron microscopy studies. Dysmegakaryocytopoiesis is rather frequent. Other patients may show bleb-forming blasts, but this feature is nor specific for

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -70- megakaryoblasts. Micromegakaryocytes can be frequently seen. Pathology The bone biopsy almost invariably shows fibrosis, which can be extensive in up to 75% of the cases. Spleen enlargement is frequently seen in children, less frequently in adults. Treatment Myeloablative treatment followed, whenever possible, by allogeneic or autologous bone marrow transplant is the treatment of choice Prognosis In general, the prognosis is severe. 30-to-50 % of the adult patients achieve a complete morphologic remission, but the majority relapse within a few months. Median duration of CR and survival in a study was 10.6 months and 10.4 months, respectively. Some children may fare better, with a 50% 3-year event free survival in AML-M7 post Down Syndrome or with the t(1;22) (see below). Prognosis is dismal in children with other cytogenetic abnormalities. Cytogenetics Cytogenetics a) Adults Morphological There is no cytogenetic anomaly that is specific for AML-M7. The karyotype is abnormal in the vast majority of cases with complex aberrations (i.e. 3 or more clonal aberrations) occurring more frequently than in other AMLs. -5/5q- and/or -7/7q+ are found, as a rule, in virtually all cases with complex karyotype, which globally account for 70-80% of abnormal cases. 3q21 or q26 aberrations are found in 20-30% of the cases; the t(9;22) is another recurrent chromosome aberrations in de novo AML-M7. Trisomy 19 and 21 may occur in de novo as well as in secondary AML-M7. They are the most frequently occurring chromosome gains and they may be associated with any of the cytogenetic group listed above.

b) Children The t(1;22)(p13;q13) is specifically associated with children AML-M7, being found in approximately half of the cases. The remaining patients may show +21 (irrespective of the association with Down syndrome), +19, +8. The karyotype may be normal in approximately 10% of the cases. Cytogenetics Partial trisomy 19, involving the q13 band, can be shown to occur at a Molecular 20-30% incidence by comparative genomic hybridization The t(1;22)(p13;q13) fuses the OTT(RBM15) gene on 1p13 to the MAL(MLK1) gene on chromosome 22, leading to the OTT-MAL fusion gene on the derivative 22 Genes involved and Proteins Gene OTT (one twenty-two) or RBM15(Rna-binding motif protein 15) Name Location 1p13 Gene MAL (Megakaryocytic acute leukemia) or MLK1 (megakaryoblastic

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -71- Name leukemia-1) Location 22q13 Result of the chromosomal anomaly Hybrid The fusion gene OTT-MAL is on the der(22) chromosome and contains gene Note almost all of the sequences of each gene. Bibliography Megakaryoblastic acute leukemia: identification by the ultrastructural demonstration of platelet peroxidase. Breton-Gorius J, Reyes F, Duhamel G, Najman A, Gorin NC. Blood 1978; 51: 45-60. Medline 201318

Megakaryoblastic leukemia and Down's syndrome: a review. Zipursky A, Peeters M, Poon A. Pediatr Hematol Oncol 1987; 4(3): 211-230. Medline 2978961

Leukemias with megakaryoblastic involvement: clinical, hematologic, and immunologic characteristics. San Miguel JF, Gonzalez M, Canizo MC, Ojeda E, Orfao A, Caballero MD, Moro MJ, Fisac P, Lopez Borrasca A. Blood 1988; 72: 402-407. Medline 3165292

Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients. Cuneo A, Mecucci C, Kerim S, Vandenberghe E, Dal Cin P, Van Orshoven A, Rodhain J, Bosly A, Michaux JL, Martiat P, Castroldi G, Van Den Berghe H. Blood 1989; 74: 1781-1790. Medline 2790202

Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Tallman MS, Neuberg D, Bennett JM, Francois CJ, Paietta E, Wiernik PH, Dewald G, Cassileth PA, Oken MM, Rowe JM. Blood 2000; 96: 2405-2411. Medline 11001891

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

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Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X, Bouman D, Li Y, Mehta PK, Nizetic D, Kaneko Y, Chan GC, Chan LC, Squire J, Scherer SW, Hitzler JK. Nat Genet 2001; 28: 220-221. Medline 11431691

Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Mercher T, Coniat MB, Monni R, Mauchauffe M, Khac FN, Gressin L, Mugneret F, Leblanc T, Dastugue N, Berger R, Bernard OA. Proc Natl Acad Sci U S A 2001; 98: 5776-5579.

Common trisomies in M7. Dastugue N, Berger R on behalf of the Groupe Francais de Cytogenetique Hematologique. Blood 2002; 100: 3838-3839.

Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH). Dastugue N, Lafage-Pochitaloff M, Pages MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Leonard C, Bilhou-Nabera C, Cabrol C, Capodano AM, Cornillet- Lefebvre P, Lessard M, Mugneret F, Perot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R; Groupe Francais d'Hematologie Cellulaire. Blood 2002; 100: 618-626. Medline 12091356

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

Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Francais d'Hematologie Cellulaire (GFHC). Duchayne E, Fenneteau O, Pages MP, Sainty D, Arnoulet C, Dastugue N, Garand R, Flandrin G; Groupe Francais d'Hematologie Cellulaire; Groupe Francais de Cytogenetique Hematologique Leuk Lymphoma 2003; 44: 49-58. Medline 12691142 Contributor(s) Written 11- Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi 2003 Citation

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -73- This paper should be referenced as such : Cuneo A, Cavazzini F, Castoldi G . Acute megakaryoblastic leukemia (AMegL),M7 acute non lymphocytic leukemia (M7-ANLL). Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/M7ANLLID1100.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -74- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Refractory anemia with excess blasts (RAEB)

Identity Note This disorder is part of the heterogeneous category of myelodysplastic syndrome (MDS). According to the FAB classification of MDS, RAEB includes those patients with 5-20% blasts in the bone marrow (BM). Because the severity of the disease largely depends on the percentage of blasts in the BM, two categories of RAEB were recognised by the WHO classification, i.e. RAEB-1 and RAEB-2, with 5-9% and 10-19% blasts, respectively. In this card, the FAB classification will be used, because the majority of available data on cytogenetic anomalies was derived from studies published before WHO classification. Other RAEB-1 and RAEB-2 names Clinics and Pathology Phenotype / RAEB is a clonal disorder originating from a totipotent stem cell or from cell stem a multipotent myeloid progenitor cell, characterized by ineffective origin hemopoiesis and diserythropoiesis. The blast cell present in the BM are usually CD34+ and express myeloid markers (i.e. CD33 and/or CD13). Epidemiology There are few data on the epidemiology of RAEB, which may account for 20-30% of all MDS cases. MDS is predominantly diagnosed in the elderly population. The global incidence of all MDS was comprised between 3,5 and 12,6 new cases / year / per 100,000 in some studies. The incidence may rise from 0,5 MDS cases per year in the 40 years age-group to 89 cases per year in the >80 age-group. Clinics RAEB usually presents with hypercellular bone marrow (BM) with 5- 20% blasts (5-9% in RAEB-1 and 10-19% in RAEB-2) and cytopenias of various degree. Blast cells (<20%) can be present in the peripheral blood. The patient may be asymptomatic or, alternatively he/she may suffer from BM failure-related symptoms. Cytology Criteria for the recognition of dysplastic features of BM cells were published by the FAB group. Dyserythropoiesis includes megaloblastoid changes of erythroid precursors, multinuclearity, nuclear fragmentation, unstained area in the cytoplasm (dysemoglobinization). Dysgranulocytopoiesis include hypogranular neutrophils, the pseudo-Pelger anomaly of neutrophils.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -75- Micromegakaryocytes, large mononuclear forms and multiple separated nuclei are major signs of dysmegakaryocytopoiesis. Pathology The bone biopsy may be useful in some cases of MDS with BM fibrosis and allows for the demonstration of the so called "abnormal localization of immature precursors" (ALIP) which may represent a prognostic factor. Treatment Treatment of this condition in the elderly patient is largely supportive, including blood transfusion in patients with symptomatic anemia. Anemic patients with low serum erythropoietin (EPO) levels may benefit of the administration of rHu-EPO. Low dose cytarabine can be used to reduce the burden of blasts. Myeloablative regimens including anthracyclines and cytarabine in conventional or high doses can be used in high-risk patients under 60 years. Allogeneic bone marrow transplantation may offer a chance of cure in young patients. Evolution This is an oligoblastic leukemia, carrying a 20-40% probability of evolving into leukemia. In a study approximately 25% of the patient developed acute myeloid leukemia (AML) within 18 months. The probability of RAEB to transform into AML is lower in the RAEB-1 group (approximately 50% of the patients develop acute leukemia within 6 years) than in the RAEB-2 group (approximately 50% at 18 months with overt leukemia). Prognosis Median survival of RAEB falls in the 1-2 year range. The best outcome is usually observed in RAEB-1. Chromosomal abnormalities have independent prognostic significance and are to be included in risk assessment at diagnosis. Favourable cytogenetic features are normal karyotype, 5q- or 20q- isolated; unfavourable features are complex karyotype (i.e. 3 or more clonal anomalies) and abnormalities of chromosome 7q; other abnormalities identify patients in the intermediate cytogenetic-risk group. Cytogenetics Cytogenetics There is no specific chromosome marker for patients with RAEB, up to Morphological 60% of whom may show an abnormal karyotype. More sensitive techniques such as fluorescence in situ hybridization (FISH) found that a minority of patients with apparently normal karyotype can be shown to carry an occult chromosome defect The 5q- chromosome may be found in up to 40% of the cases, usually in association with additional chromosome aberrations. Approximately 20% of the cases may carry a -7/7q- or trisomy 8. A chromosome 12p deletion or 11q deletion can be found in 5% of cytogenetically abnormal cases. Those patients with a 17p deletion may display distinctive hematologic features, including dysgranulopoiesis with the pseudo-Pelger anomaly and small vacuoles in the cytoplasm of the neutrophils, p53 mutation and poor outcome. A number of very rare chromosome aberrations were described in some reports. Recurrent deletions are represented by del(3)(p14p21), del(6)(p21), del(9)(q13q22), del(12)(p13), del(18)(p11). Monosomy Y may occur more frequently in eledrly males. Rare recurrent structural anomalies which can also be found in acute myeloid leukemia include:

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -76- t(6;9)(p23;q34); t(3;5)(q25;q35); t(1;3)(p36;q21); t(3;21)(q26;q22); inv(3)(q21q26); t(7;11)(p15;p15). Trisomies are represented in <1% of the cases by +4; +11; +13; +21. Bibliography Proposals for the classification of the myelodysplastic syndromes. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Br J Haematol 1982; 51: 189-199. Medline 6952920

Prognostic factors of myelodysplastic syndromes-a simplified 3-D scoring system. Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J, Callat MP, Accard F, Chaperon J. Leuk Res 1990; 14: 255-262. Medline 2319806

Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H, Hirashima K, Hotta T, Kuramoto A, Kuriya S, et al. Leukemia 1993; 7: 499-508. Medline 8464227

Life expectancy in primary myelodysplastic syndromes: a prognostic score based upon histopathology from bone marrow biopsies of 569 patients. Maschek H, Gutzmer R, Choritz H, Georgii A. Eur J Haematol 1994; 53: 280-287. Medline 7813708

Myelodysplastic syndrome and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of p53 mutations. Lai JL, Preudhomme C, Zandecki M. Leukemia 1995; 9: 370-381 Medline 7885035

Cytogenetics of Myelodysplastic syndromes. Fenaux P, Morel P, Lai JL. Seminrs Hematol 1996; 33: 127-138. Medline 8722683

International scoring system for evaluating prognosis in myelodysplastic syndromes. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. Blood 1997; 89: 2079-2088.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -77- Medline 9058730

Myelodysplastic syndromes: recent advances. Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci C, Morra E, Saglio G, Visani G, Tura S. Haematologica 2001; 86: 1124-1157. Medline 11694400

Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Rigolin GM, Bigoni R, Milani R, Cavazzini F, Roberti MG, Bardi A, Agostini P, Della Porta M, Tieghi A, Piva N, Cuneo A, Castoldi G. Leukemia 2001; 15: 1841-1847. Medline 11753603

The World Health Organization (WHO) classification of the myeloid neoplasms. Vardiman JW, Harris NL, Brunning RD. Blood 2002; 100: 2292-2302. Medline 12239137

Contributor(s) Written 11- Antonio Cuneo, Gianluigi Castoldi 2003 Citation This paper should be referenced as such : Cuneo A, Castoldi G . Refractory anemia with excess blasts (RAEB). Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/RAEBID1105.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -78- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Refractory anemia (RA)

Identity Note This disorder is part of the heterogeneous category of myelodysplastic syndrome (MDS). According to the FAB classification of MDS, RA includes those patients with refractory cytopenia with multilineage dysplasia (RCMD), the latter category having been recognised as a distinct entity by the WHO classification (vide infra). Also, the 5q- syndrome is part of the RA in the FAB classification. In this card, the FAB classification will be used, because the majority of available data on cytogenetic anomalies was derived from studies published before WHO classification. Clinics and Pathology Phenotype / RA is a clonal disorder originating from a totipotent stem cell or from a cell stem multipotent myeloid progenitor cell, characterized by ineffective origin hemopoiesis and diserythropoiesis. Epidemiology There are few data on the epidemiology of RA, which may account for 30-40% of all MDS cases. MDS is predominantly diagnosed in the elderly population. The global incidence of all MDS was comprised between 3,5 and 12,6 new cases / year / per 100,000 in some studies. The incidence may rise from 0,5 MDS cases per year in the 40 years age-group to 89 cases per year in the >80 age-group. Clinics RA usually presents with hypercellular bone marrow (BM) and anemia. There may be leukopenia and/or and thrombocytopenia, but these features do not represent a diagnostic requirement. In the WHO classification RA shows anemia, no or rare blasts in the peripheral blood, isolated erythoid dysplasia with <5% blasts and <15% ringed sideroblasts in the BM. RCMD shows cytopenias (bicytopenia or pancytopenia) in the peripheral blood plus dysplasia in more than 10% of the cells in 2 or more myeloid lineages. Cytology Criteria for the recognition of dysplastic features of BM cells were published by the FAB group. Dyserythropoiesis includes megaloblastoid changes of erythroid precursors, multinuclearity, nuclear fragmentation, unstained area in the cytoplasm (dysemoglobinization). Pathology The bone biopsy may be useful in some cases of MDS with BM fibrosis and allows for the demonstration of the so called "abnormal localization of immature precursors" (ALIP) which may represent a prognostic factor.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -79- Treatment Treatment of this condition is largely supportive, including blood transfusion in patients with symptomatic anemia. Anemic patients with low serum erythropoietin (EPO) levels may benefit of the administration of rHu-EPO. Evolution This is a preleukemic condition, carrying a 10-20% probability of evolving into leukemia. The probability of RA to transform into AML may be lower when including the 5q- syndrome and excluding RCMD, but prospective studies are lacking. In a study 25% of the patient developed acute myeloid leukemia (AML) within 5 years. Prognosis Median survival of RA may fall in the 27-50 month range. As noted above, heterogeneity of patient population may account for inter-study variability in median survival. The best outcome is usually observed in RA with isolated 5q- (5q- syndrome of the WHO classification) and in those patients without multilineage dysplasia, corresponding to the RA category in the WHO classification. Chromosomal abnormalities have independent prognostic significance and are to be included in risk assessment at diagnosis. Favourable cytogenetic features are normal karyotype, 5q- or 20q- isolated; unfavourable features are complex karyotype (i.e. 3 or more clonal anomalies) and abnormalities of chromosome 7q; other abnormalities identify patients in the intermediate cytogenetic-risk group. Cytogenetics Cytogenetics There is no specific chromosome marker for patients with RA, 70 to Morphological 80% of whom may show a normal karyotype. More sensitive techniques such as fluorescence in situ hybridization (FISH) failed to increase the percentage of abnormal cases in this category of MDS. The 5q- chromosome may be found in as many as 70% of RA with a clonal aberrations. Usually, but not invariably, the breakpoints involve the bands q13 and q33. When the 5q- is the sole change and it is associated with hypolobated megakaryocytes in the BM, with macrocytic anemia, with normal or increased platelet count then the patient should be diagnosed as having the "5q- syndrome". The 5q- can be present in other subsets of MDS. A chromosome 20q deletion if found in 5% of all MDS and in 10-15% of RA with abnormal karyotype. Other chromosome aberrations in RA include trisomy 8 in 10% of cytogenetically abnormal cases -7/7q- or 11q- in < 5% of the abnormal cases. A number of very rare chromosome aberrations were described in single reports. Bibliography Myelodysplastic syndromes: recent advances. Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci C, Morra E, Saglio G, Visani G, Tura S. Haematologica 2001; 86: 1124-1157. Medline 11694400

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -80- Proposals for the classification of the myelodysplastic syndromes. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Br J Haematol 1982; 51: 189-199. Medline 6952920

Two types of acquired idiopathic sideroblastic anaemia (AISA). Gattermann N, Aul C, Schneider W. Br J Haematol 1990; 74: 45-52. Medline 2310696

Prognostic factors of myelodysplastic syndromes--a simplified 3-D scoring system. Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J, Callat MP, Accard F, Chaperon J. Leuk Res 1990; 14: 255-262. Medline 2319806

The World Health Organization (WHO) classification of the myeloid neoplasms. Vardiman JW, Harris NL, Brunning RD.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -81- Blood 2002; 100: 2292-2302. Medline 12239137

Contributor(s) Written 11- Antonio Cuneo, Gianluigi Castoldi 2003

Citation This paper should be referenced as such : Cuneo A, Castoldi G . Refractory anemia (RA). Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/RAID1104.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -82- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Refractory anemia with ringed sideroblasts (RARS)

Identity Note This disorder is part of the heterogeneous category of myelodysplastic syndrome (MDS). According to the FAB classification of MDS, RARS includes those patients with refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS), the latter category having been recognised as a distinct entity by the WHO classification (vide infra). In this card, the FAB classification will be used, because the majority of available data on cytogenetic anomalies was derived from studies published before WHO classification. Clinics and Pathology Phenotype / RARS is a clonal disorder originating from a totipotent stem cell or cell stem from a multipotent myeloid progenitor cell, characterized by ineffective origin hemopoiesis and diserythropoiesis. Epidemiology There are few data on the epidemiology of RARS, which may account for 5-15% of all MDS cases. MDS is predominantly diagnosed in the elderly population. The global incidence of all MDS was comprised between 3,5 and 12,6 new cases / year / per 100,000 in some studies. The incidence may rise from 0,5 MDS cases per year in the 40 years age-group to 89 cases per year in the >80 age-group. Clinics RARS usually presents with hypercellular bone marrow (BM) and anemia. There may be leukopenia and/or and thrombocytopenia, but these features do not represent a diagnostic requirement. According to the WHO classification RARS shows anemia, no blasts in the peripheral blood, isolated erythroid dysplasia with <5% blasts and >15% ringed sideroblasts in the BM. RCMD-RS shows cytopenias (bicytopenia or pancytopenia) in the peripheral blood plus dysplasia in more than 10% of the cells in 2 or more myeloid lineages and no Auer rods. Cytology Criteria for the recognition of dysplastic features of BM cells were published by the FAB group. Typically, more than 15% of the erythroid cells are ringed sideroblasts showing iron laden mitochondria around the nucleus. These cells appear as erythroblast with Prussian Blue- positive granules which form an arc extending around at least 30% of the nucleus. There is evidence that mutations occurring in the mitochondrial DNA may have a role in generating deranged mitochondrial iron metabolism with consequent accumulation of the of the ferric form (Fe3+) in the matrix.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -83- Pathology The bone biopsy may be useful in some cases of MDS with BM fibrosis and allows for the demonstration of the so called "abnormal localization of immature precursors" (ALIP) which may represent a prognostic factor. Treatment Treatment of this condition is largely supportive, including blood transfusion in patients with symptomatic anemia. Anemic patients with low serum erythropoietin (EPO) levels may benefit of the administration of rHu-EPO. Evolution This is a preleukemic condition, carrying a 10-20% probability of evolving into leukemia. The probability of RARS to transform into AML may be lower when excluding RCMD, but prospective studies are lacking. In a study 25% of the patient developed acute myeloid leukemia (AML) in approximately 10 years. Prognosis Median survival of RARS may fall in the 40-50 month range. Chromosomal abnormalities have independent prognostic significance and are to be included in risk assessment at diagnosis. Favourable cytogenetic features are normal karyotype, 5q- syndrome or 20q- isolated; unfavourable features are complex karyotype (i.e. 3 or more clonal anomalies) and abnormalities of chromosome 7q; other abnormalities identify patients in the intermediate cytogenetic-risk group. Cytogenetics Cytogenetics There is no specific chromosome marker for patients with RARS, 70 to Morphological 80% of whom may show a normal karyotype. More sensitive techniques such as fluorescence in situ hybridization (FISH) failed to increase the percentage of abnormal cases in this category of MDS. The 5q- chromosome may be found in 20% of RARS with a clonal aberrations. A chromosome11q deletion may be found in as many as 20% of the cases. A chromosome 20q deletion can be found in 5% of all MDS and in 10-15% of RARS with abnormal karyotype. Other chromosome aberrations in RARS include trisomy 8 in 20% of cytogenetically abnormal cases -7/7q- or 11q- in < 5% of the abnormal cases. A number of rare chromosome aberrations were described in single reports. Bibliography Proposals for the classification of the myelodysplastic syndromes. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Br J Haematol 1982; 51: 189-199. Medline 6952920

Two types of acquired idiopathic sideroblastic anaemia (AISA). Gattermann N, Aul C, Schneider W. Br J Haematol 1990; 74: 45-52. Medline 2310696

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -84- Prognostic factors of myelodysplastic syndromes--a simplified 3-D scoring system. Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J, Callat MP, Accard F, Chaperon J. Leuk Res 1990; 14: 255-262. Medline 2319806

De novo myelodysplastic syndrome with deletion of the long arm of chromosome 20: a subtype of MDS with distinct hematologic and clinical features? Wattel E, Lai JL,Hebbar M, Preudhomme C, Grahek D, Morel P, Bauters F, Fenaux P. Leuk Res 1993; 17: 921-926 Medline 8231232

Cytogenetics of Myelodysplastic syndromes. Fenaux P, Morel P, Lai JL. Seminrs Hematol 1996; 33: 127-138. Medline 8722683

Myelodysplastic syndromes: recent advances. Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci C, Morra E, Saglio G, Visani G, Tura S. Haematologica 2001; 86: 1124-1157. Medline 11694400

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -85- Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Rigolin GM, Bigoni R, Milani R, Cavazzini F, Roberti MG, Bardi A, Agostini P, Della Porta M, Tieghi A, Piva N, Cuneo A, Castoldi G. Leukemia 2001; 15: 1841-1847. Medline 11753603

Myelodysplastic syndromes. Greenberg P, Young N, Gattermann N. Merican Society of Hematology Education Program Book. Philadelphia, Pennsylvania. December 6-10, 2002

The World Health Organization (WHO) classification of the myeloid neoplasms. Vardiman JW, Harris NL, Brunning RD. Blood 2002; 100: 2292-2302. Medline 12239137

Contributor(s) Written 11- Antonio Cuneo, Gianluigi Castoldi 2003 Citation This paper should be referenced as such : Cuneo A, Castoldi G . Refractory anemia with ringed sideroblasts (RARS). Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/RARSID1106.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -86- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Bladder: Urothelial carcinomas

Identity

Bladder cancer : gross pathology : the bladder wall is massively infiltered by an ulcerated and hemorragic tumor. Courtesy Pierre Bedossa Classification Histologic types: urothelial carcinoma of the bladder, herein described squamous cell carcinoma adenocarcinoma (2%), rare poorly differenciated carcinoma/small cell carcinoma, exceptional. Clinics and Pathology Disease cancer of the urothelium Epidemiology urothelial carcinoma of the transitional epithelium is the most frequent bladder cancer in Europe and in the USA, representing 90-95 % of cases, while sqamous cell carcinoma represents only 5% in these countries, but up to 70-80% of cases in the Middle East; annual incidence: 250/106, 2% of cancers, the fourth cancer in males, the seventh in females, 3M/1F; occurs mainly in the 6th-8th decades of life; risk factors: cigarette smoking and occupational exposure (aniline, benzidine, naphtylamine); 20 to 30 yrs latency after exposure. Clinics Hematuria, irritation.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -87-

staging - Editor

Pathology grading and staging: tumours are: graded by the degree of cellular atypia (G1->G3), and staged: - papilloma - papillary tumor of low malignant potential (PTLMP) - papillary urothelial carcinomas low grade - papillary urothelial carcinomas high grade. Treatment Resection (more or less extensive: electrofulguration --> cystectomy); chemo and/or radiotherapy, BCG-therapy. Evolution Recurrence is highly frequent. Prognosis According to the stage and the grade; pTa is of good prognosis (> 90% are cured); prognosis is uncertain in pT1 and G2 tumours. 20% survival at 1 yr (stable at 3yrs) is found in T4 cases; however, identification of individual patient's prognosis is often difficult, although of major concern for treatment decision and for follow up. Multiple endpoints may be identified in bladder cancer. Recurrence (does it come back), recurrence rate (how soon/often does it come back), progression and (disease specific) survival are of importance. Patients with superficial bladder cancer (pTa and pTis) are frequently evaluated by cystoscopy to allow early detection of a possible recurrence and to prevent disease progression to invasive, potentially lethal, bladder cancer. According to mutational status of FGFR3 and TP53; tumors with an FGFR3 mutation have a lower recurrence rate, tumors with elevated immunohistochemical expression of p53 and MIB-1 have the highest recurrence rate: and the highest propensity for progression and death of disease (see figure below). Cytogenetics Cytogenetics Karyotype

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -88- Morphological Urothelial carcinomas exhibit pseudo diploid karyotypes with only a few anomalies in early stages, evolving towards pseudo-tetraploides complexes karyotypes. Partial or complete monosomy 9 (-9) is an early event, found in half cases. Deletion (11p) or -11 is found in 20- 50% of cases, more often in high grade and invasive tumours. Del(13q) is found in 25% of cases and correlated with high grade/stage; tumours with Rb alterations are invasive. Del(17p) is a late event, found in 40% of cases; TP53 alterations are correlated with grade and stage, tumour progression, and a worse prognosis. Del(1p), i(5q), +7, and many other rearrangements - more often deletions than duplications - are frequently found. These losses of heterozygocity point to a multistep complex process involving tumor suppressor genes.

Amplifications

Chromosome 1: P73 (1p36) is often over-expressed. Chromosome 8: C-MYC (8q24) is rarely amplified. Chromosome 11: cyclin D1 is often over-expressed. Amplifications 10q13-14, 13q21-31 and 17q22-23 have been noted.

Losses

Chromosome 8: loss of 8p12-22. The potential target is the FEZ1/LZTS1 gene, which is downregulated in high-grade carcinomas. Chromosome 9: Allelic loss on chromosome 9q is a very frequent event in bladder carcinogenesis. Monosomy 9 or deletions of chromosome 9 are found in about 50% of cases; at times found as the sole anomaly, demonstrating that it is an early event, found equally in pTa stage and in more advanced stages; not associated with a given grade, and not correlated with p53 expression. Efforts have been directed towards identifying the postulated tumour suppressor genes on this chromosome arm by deletion mapping and mutation analysis. However, no convincing candidate genes have been identified. Homozygous deletions of CDKN2A/MTS1/P16 (9p21) have been documented; LOH + mutation on the second allele of CDKN2A are rare, but of significance; CDKN2A is implicated in pTa stage but not in pTIS, where p53 is found mutated; CDKN2B/INK4B/P15 (9p21) is also implicated in a small subset of cases. LOH + mutation on the second allele of TSC1 (9q33-34) has been described. Homozygous deletion and methylational silencing of a candidate gene DBCCR1 (9q32-33) has been reported. Chromosome 10: PTEN (10q23), appears to be implicated in a very few percentage of cases (homozygote deletion has been found); Fas/APO1/CD95 (10q24): loss of one allele and mutation in the second allele has been reported; a hot-spot of mutations has been determined. Chromosome 11: HRAS1 (11p15.5) is mutated in 15% of cases. Chromosome 13: an altered Rb (13q14) is expressed in 30 to 40%

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -89- of tumours; these are high stage, invasive, and indicate a short survival; 90% of tumours expressing Rb are invasives; disregulation of the normal P16-Rb interactions have been documented, with hyper expression of Rb and loss of function of P16. Chromosome 17: P53 (17p13) alterations are correlated with grade and stage (often PT3), and tumour progression; P53 is mutated in more than 50% of high grade/stage tumours, and in most PTIS; P53 is a prognostic factor: by high grade/stage tumours, those expressing P53 are of a worse prognosis; by low grade/stage, those not expressing P53 are of better outcome; there is usually LOH + mutation on the second allele of P53; ERBB2 (HER2/Neu) (17q21) is expressed in high grade/stages tumours, in metastases, and is associated with relapses; NF1 (17q11) expression may be very low in tumours

LOH LOH analysis in bladder cancer has so far not led to the identification of tumor suppressor genes. LOH appears to be numerous within a given chromosome (e.g. on chromosome 9 five regions, 9p21, 9q22, 9q31-32, 9q33 and 9q34, and on chromosome 5 four regions, 5q13.3- q22, 5q22-q31.1, 5q31.1-q32, and 5q34, and on chromosome 3 frequent LOH has been found in three regions, 3p12-14, 3p21.3-22 and 3p24.2-25), but loci remain to be precised, as reports are controversial. Due to the unique possibility to study multiple recurrent tumors from the same patient, it is now becoming apparent that loss of heterozygosity (LOH) on chromosome 9 is almost never the characteristic first step in tumor development. LOH can be detected in up to 67% of markers tested. The regions of loss are multiple and variable in different tumours from the same patient and expand in subsequent tumours. Moreover, the regions of loss on chromosome 9 vary from patient to patient. To explain the type and extent of genetic damage in combination with the low stage and grade of these tumors, it was hypothesized that in bladder cancer pathogenesis an increased rate of mitotic recombination is acquired early in the tumorigenic process. Cytogenetics (Matrix) CGH Molecular Array-based comparative genomic hybridization detected high-level amplification of 6p22.3 (E2F3), 8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1, EMS1, INT2), and 19q13.1 (CCNE) and homozygous deletion of 6p22 (TRAF6), 9p21.3 (CDKN2A/p16) and 8p23.1. Genes involved and Proteins Gene FGFR3 Name Note The expression of a constitutively activated FGFR3 in a large proportion of bladder cancers is the first evidence of an oncogenic role for FGFR3 in these carcinomas. FGFR3 currently appears to be the most frequently mutated oncogene in bladder cancer: it is mutated in more

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -90- than 30% of cases. FGFR3 seems to mediate opposite signals, acting as a negative regulator of growth in bone and as an oncogene in several tumour types. Complete elucidation of the role of FGFR3 in normal and malignant tissues requires further investigation. Missense mutations were observed identical to those in thanatophoric dysplasia (R248C, S249C, G372C, and K652E), achondroplasia and SADDAN (G380/382R and K650/652M, respectively) and Crouzon Syndrome with Acanthosis Nigricans (A393E). Furthermore, a K650/652T mutation was found not previously identified in carcinomas or thanatophoric dysplasia. In urothelial papilloma, generally considered a benign lesion, 9/12 (75%) mutations were found. Another novel finding was the occurrence of two simultaneous FGFR3 mutations in four tumours.

Gene TP53 Name Note The TP53 gene in bladder cancer is mainly an indicator of progression and recurrence rate. Interestingly, mutations in FGFR3 and TP53 are mutually exclusive in bladder cancer.

Gene HRAS Name Note HRAS mutations are found in approximately 15% of cases.

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Gelsolin: a candidate for suppressor of human bladder cancer. Tanaka M, Mullauer L, Ogiso Y, Fujita H, Moriya S, Furuuchi K, Harabayashi T, Shinohara N, Koyanagi T, Kuzumaki N. Cancer Res 1995; 55: 3228-3232. Medline 95339298

Detection of chromosomal imbalances in transitional cell carcinoma of the bladder by comparative genomic hybridization. Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P, Schalken J, du Manoir S, Ramaekers F, Lichter P, Hopman A. Am J Pathol 1995; 146: 1341-1354. Medline 95297584

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Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations. Simoneau AR, Spruck CH 3rd, Gonzalez-Zulueta M, Gonzalgo ML, Chan MF, Tsai YC, Dean M, Steven K, Horn T, Jones PA. Cancer Res 1996; 56: 5039-5043. Medline 97051022

The 9p21 region in bladder cancer cell lines: large homozygous deletion inactivate the CDKN2, CDKN2B and MTAP genes. Stadler WM, Olopade OI. Urol Res 1996; 24: 239-244. Medline 97027219

Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer. Takle LA, Knowles MA. Oncogene 1996; 12: 1083-1087. Medline 96243053

Loss of chromosome 11 and 11 p/q imbalances in bladder cancer detected by fluorescence in situ hybridization. Voorter CE, Ummelen MI, Ramaekers FS, Hopman AH. Int J Cancer 1996; 65: 301-307. Medline 96163513

Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Cappellen D, Gil Diez de Medina S, Chopin D, Thiery JP, Radvanyi F. Oncogene 1997; 14(25): 3059-3066. Medline 9223669

Superimposed histologic and genetic mapping of chromosome 17 alterations in human urinary bladder neoplasia. Chaturvedi V, Li L, Hodges S, Johnston D, Ro JY, Logothetis C, von Eschenbach AC, Batsakis JG, Czerniak B. Oncogene 1997; 14: 2059-2070. Medline 97304523

Cytogenetics of bladder cancer. Gibas Z, Gibas L. Cancer Genet Cytogenet 1997; 95: 108-115. Medline 97285187

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Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Richter J, Jiang F, Gšršg JP, Sartorius G, Egenter C, Gasser TC, Moch H, Mihatsch MJ, Sauter G. Cancer Res 1997; 57: 2860-2864. Medline 9230190

Chromosome 8p deletions are associated with invasive tumor growth in urinary bladder cancer. Wagner U, Bubendorf L, Gasser TC, Moch H, Gorog JP, Richter J, Mihatsch MJ, Waldman FM, Sauter G. Am J Pathol 1997; 151: 753-759. Medline 97430717

Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder? Bartlett JM, Watters AD, Ballantyne SA, Going JJ, Grigor KM, Cooke TG. Br J Cancer 1998; 77: 2193-2198. Medline 98311466

Human bladder cancers and normal bladder mucosa present the same hot spot of heterozygous chromosome-9 deletion. Baud E, Catilina P, Boiteux JP, Bignon YJ. Int J Cancer 1998; 77: 821-824. Medline 98377849

Chromosomal changes during progression of transitionnal cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q. Bruch J, Wšhr G, Hautmann R, Mattfeldt T, BrŸderlein S, Mšller P, Sauter S, Hameister H, Vogel W, Paiss T. Genes Chromosomes Cancer 1998; 23: 167-174. Medline 9739020

Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman JG, Bose S, Wang SI, Parsons R, Sidransky D. Oncogene 1998;16: 3215-3218. Medline 98334477

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Genetic alterations in primary bladder cancers and their metastases. Hovey RM, Chu L, Balazs M, De Vries S, Moore D, Sauter G, Caroll.PR, Waldman FM Cancer Res 1998; 58: 3555-3560. Medline 9721860

Detecting human bladder carcinoma cells in voided urine samples by assaying for the presence of telomerase activity. Kavaler E, Landman J, Chang Y, Droller MJ, Liu BCS. Cancer 1998; 82: 708-714. Medline 9477104

Polysomies but not Y chromosome losses have prognostic significance in pTa/pT1 urinary bladder cancer. Neuhaus M, Wagner U, Schmid U, Ackermann D, Zellweger T, Maurer R, Alund G, Knongel H, Rist M, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Hum Pathol 1999; 30: 81-86.

Chromosomal aberrations associated with invasion in papillary superficial bladder cancer. Simon R, BŸrger H, Brinkschmidt C, Bšcher W, Hertle L, Terpe HJ. J Pathol 1998; 185: 345-351. Medline 9828832

Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer. Tsutsumi M, Tsai YC, Gonzalgo ML, Nichols PW, Jones PA. Oncogene 1998; 17: 3021-3027. Medline 99096031

Loss of heterozygosity on chromosome 9 and loss of chromosome 9 copy number are separate events in the pathogenesis of transitional cell carcinoma of the bladder. van Tilborg AA, Hekman AC, Vissers KJ, van der Kwast TH, Zwarthoff EC. Int J Cancer 1998; 75(1): 9-14. Medline 9426683

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Urinary bladder transitional cell carcinogenesis is associated with down- regulation of NF1 tumor suppressor gene in vivo and in vitro. Aaltonen V, Bostrom PJ, Soderstrom KO, Hirvonen O, Tuukkanen J, Nurmi M, Laato M, Peltonen J. Am J Pathol 1999; 154: 755-765. Medline 99180762

The expression of PAX5 in human transitional cell carcinoma of the bladder: relationship with de-differentiation. Adshead JM, Ogden CW, Penny MA, Stuart ET, Kessling AM. BJU Int 1999; 83: 1039-1044. Medline 99296801

Somatic mutation of PTEN in bladder carcinoma. Aveyard JS, Skilleter A, Habuchi T, Knowles MA. Br J Cancer l999; 80: 904-908. Medline 99287418

Pl6 involvement in primary bladder tumors: analysis of deletions and mutations. Baud E, Catilina P, Bignon YJ. Int J Oncol 1999; 14: 441-445. Medline 99150453

Level of retinoblastoma protein expression correlates with pl6 (MTS- 1/INK4A/CDKN2) status in bladder cancer. Benedict WF, Lerner SP, Zhou J, Shen X, Tokunaga H, Czerniak B. Oncogene 1999;18: 1197-1203. Medline 99144723

Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F. Nat Genet 1999; 23(1): 18-20. Medline 10471491

Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer. Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH. Cancer Res 1999; 59: 2791-2793. Medline 99310505

Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic

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Can p53 help select patients with invasive bladder cancer for bladder preservation? Herr HW, Bajorin DF, Scher HI, Cordon-Cardo C, Reuter VE. J Urol 1999;161: 20-22. Medline 10037358

Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T, Knowles MA. Oncogene 1999; 18: 2657-2661. Medline 99280077

Interphase cytogenetic diagnosis of bladder cancer on cells from urine and bladder washing. Junker K, Werner W, Mueller C, Ebert W, Schubert J, Claussen U. Int J Oncol 1999; 14: 309-313. Medline 9917507

Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK. Cancer Genet Cytogenet 1999; 110: 87-93. Medline 99230970

Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder. Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, Lee HK, Kim HS, Jang JJ, Kim CS, Kim SH, Lee JY, Yoo NJ. Cancer Res 1999; 59: 3068-3072. Medline 10397246

Comparison of comparative genomic hybridization, fluorescence in situ hybridization and flow cytometry in urinary bladder cancer. Mahdy E, Yoshihiro S, Zech L, Wester K, Pan Y, Busch C, Dohner H, Kallioniemi O, Bergerheim U, Malmstrom PU. Anticancer Res 1999; 19: 7-12. Medline 99243105

Localization of tumor suppressor gene associated with distant metastasis of urinary bladder cancer to a 1-Mb interval on 8p22.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -98- Ohgaki K, Iida A, Ogawa O, Kubota Y, Akimoto M, Emi M. Genes Chromosomes Cancer 1999; 25: 1-5. Medline 99236522

Multifocality of transitional cell carcinoma results from genetic instability of entire transitional epithelium. Pycha A, Mian C, Hofbauer J, Brossner C, Haitel A, Wiener H, Marberger M. Urology 1999; 53: 92-97. Medline 99101686

Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Richter J, Wagner U, Scharml P, Maurer R, Alund G, Knšnagel H, Moch H, Mihatsch MJ, Gasser TC, Sauter G . Cancer Res 1999; 59: 5687-5691. Medline 10582685

Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31. Simoneau M, Aboulkassim TO, LaRue H, Rousseau F, Fradet Y. Oncogene 1999; 18: 157-163. Medline 99124120

Arylamine N-acetyltransferase type 2 (NAT2), chromosome 8 aneuploidy, and identification of a novel NAT1 cosmid clone: an investigation in bladder cancer by interphase FISH. Stacey M, Matas N, Drake M, Payton M, Fakis G, Greenland J, Sim E. Genes Chromosomes Cancer 1999; 25: 376-383. Medline 99326405

Genes for human arylamine N-acetyltransferases in relation to loss of the short arm of chromosome 8 in bladder cancer. Thygesen P, Risch A, Stacey M, Giannoulis F, Takle L, Knowles M, Sim E. Pharmacogenetics 1999; 9: 1-8. Medline 99223335

Evidence for two candidate tumour suppressor loci on chromosome 9q in transitional cell carcinoma (TCC) of the bladder but no homozygous deletions in bladder tumour cell lines. van Tilborg AA, Groenfeld LE, van der Kwast TH, Zwarthoff EC. Br J Cancer 1999; 80(3-4): 489-494. Medline 10408858

Overexpression of the wild type p73 gene in human bladder cancer. Yokomizo A, Mai M, Tindall DJ, Cheng L, Bostwick DG, Naito S, Smith DI, Liu W. Oncogene 1999; 18: 1629-1633.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -99- Medline 99200778

Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Cancer Res 1999; 59: 4658-4661. Medline 10493521

Aberration of chromosomes 8 and 11 in bladder cancer as detected by fluorescence in situ hybridization. Awata S, Sakagami H, Tozawa K, Sasaki S, Ueda K, Kohri K. Urol Res 2000; 20, 3:185-190. Medline 10929427

Loss of heterozygosity analysis on chromosome 5p defines 5p13-12 as the critical region involved in tumor progression of bladder carcinomas. Bšhm M, Kleine-Besten R, Wieland I. Int J Cancer 2000; 89: 194-197. Medline 10754499

Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case- control studies. Brennan P, Boguillot O, Cordier S, Greiser E, Schill W, Vineis P, Lopez Abente G, Tzonou A, Chang Claude J, Bolm Audorff U, et al. Int J Cancer 2000; 86: 289-294. Medline 10738259

Loss of heterozygosity at chromosome segments 8p22 and 8p11.2-21.1 in transitionnal-cell carcinoma of the urinary bladder. Choi C, Kim MH, Juhng SW, Oh BR. Int J Cancer 2000; 86: 501-505. Medline 10797262

Genetic modeling in human urinary bladder carcinogenesis. Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA, Hodges S, Benedict WF. Genes Chrom Cancer 2000; 27:392-402. Medline 10719370

Allelic losses demonstrate monoclonality of multifocal bladder tumors. Louhelainen J, Wijkstršm H, Hemminki K. Int J Cancer 2000; 87: 522-527. Medline 10918192

Initiation-development modelling of allelic losses on chromosome 9 in multifocal bladder cancer. Louhelainen J, Wijkstršm H, Hemminki K.

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High density deletion mapping of bladder cancer localizes the putative tumor suppressor gene between loci D8S504 and D8S264 at chromosome 8p23.3. Muscheck M, Sukosd F, Pesti T, Kovacs G. Lab Inves 2000; 80(7): 1089-1094. Medline 10908154

Progressive increases in de novo methylation of CpG islands in bladder cancer. Salem C, Liang G, Tsai Y C, Coulter J, Knowles MA, Feng AC, Groshen S, Nichols PW, Jones PA. Cancer Res 2000; 60, 2473-2476. Medline 10811126

Molecular evolution of multiple recurrent cancers of the bladder. van Tilborg AA, de Vries A, de Bont M, Groenfeld LE, van der Kwast TH, Zwarthoff EC. Hum Mol Genet 2000; 9(20): 2973-2980. Medline 11115841

Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Billerey C, Chopin D, Aubriot-Lorton MH, Ricol D, Gil Diez de Medina S, Van Rhijn B, Bralet MP, Lefrere-Belda MA, Lahaye JB, Abbou CC, Bonaventure J, Zafrani ES, van der Kwast T, Thiery JP, Radvanyi F. Am J Pathol 2001; 158(6): 1955-1959. Medline 11395371 p15(INK4b) in bladder carcinomas: decreased expression in superficial tumours. Le Frere-Belda MA, Cappellen D, Daher A, Gil-Diez-de-Medina S, Besse F, Abbou CC, Thiery JP, Zafrani ES, Chopin DK, Radvanyi F. Br J Cancer 2001; 85(10): 1515-1521. Medline 11720438

The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. van Rhijn BW, Lurkin I, Radvanyi F, Kirkels WJ, van der Kwast TH, Zwarthoff EC. Cancer Res 2001; 61(4): 1265-1268. Medline 11245416

The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. van Tilborg AA, de Vries A, Zwarthoff EC. J Pathol 2001; 194(1): 76-80.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -101- Medline 11329144

Genome-wide study of gene copy numbers, transcripts, and protein levels in pairs of non-invasive and invasive human transitional cell carcinomas. Orntoft TF, Thykjaer T, Waldman FM, Wolf H, Celis JE. Mol Cell Proteomics 2002; 1(1): 37-45. Medline 12096139

Frequent FGFR3 mutations in urothelial papilloma. van Rhijn BW, Montironi R, Zwarthoff EC, Jobsis AC, van der Kwast TH. J Pathol 2002; 198(2): 245-251. Medline 12237885

Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Van Rhijn BW, Van Tilborg AA, Lurkin I, Bonaventure J, De Vries A, Thiery JP, Van Der Kwast TH, Zwarthoff EC, Radvanyi F. Eur J Hum Genet 2002; 10(12): 819-824. Medline 12461689

The random development of LOH on chromosome 9q in superficial bladder cancers. van Tilborg AA, de Vries A, de Bont M, Groenfeld LE, Zwarthoff EC. J Pathol 2002; 198(3): 352-358. Medline 12375268

Molecular genetic analysis of chromosome 9 candidate tumor-suppressor loci in bladder cancer cell lines. Williams SV, Sibley KD, Davies AM, Nishiyama H, Hornigold N, Coulter J, Kennedy WJ, Skilleter A, Habuchi T, Knowles MA. Genes Chromosomes Cancer 2002; 34(1): 86-96. Medline 11921286

Identifying distinct classes of bladder carcinoma using microarrays. Dyrskjot L, Thykjaer T, Kruhoffer M, Jensen JL, Marcussen N, Hamilton-Dutoit S, Wolf H, Orntoft TF. Nat Genet 2003; 33(1): 90-96. Medline 12469123

Genome-Wide Genetic Characterization of Bladder Cancer: A Comparison of High-Density Single-Nucleotide Polymorphism Arrays and PCR-based Microsatellite Analysis. Hoque MO, Lee CC, Cairns P, Schoenberg M, Sidransky D. Cancer Res 2003; 63(9): 2216-2222. Medline 12727842

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -102- Fibroblast growth factors and their receptors in transitional cell carcinoma. Munro NP, Knowles MA. J Urol 2003; 169(2): 675-682. Medline 12544341

Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses. Obermann EC, Junker K, Stoehr R, Dietmaier W, Zaak D, Schubert J, Hofstaedter F, Knuechel R, Hartmann A. J Pathol 2003; 199(1): 50-57. Medline 12474226

Gene discovery in bladder cancer progression using cDNA microarrays. Sanchez-Carbayo M, Socci ND, Lozano JJ, Li W, Charytonowicz E, Belbin TJ, Prystowsky MB, Ortiz AR, Childs G, Cordon-Cardo C. Am J Pathol 2003; 163(2): 505-516. Medline 12875971

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

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 08- Jean-Loup Huret, Claude Léonard 1997 Updated 10- Jean-Loup Huret, Claude Léonard 1999 Updated 10- Jean-Loup Huret, Claude Léonard 2000 Updated 10- Angela van Tilborg, Bas van Rhijn 2003 Citation This paper should be referenced as such : Huret JL, Léonard C . Bladder: Urothelial carcinomas. Atlas Genet Cytogenet Oncol Haematol. August 1997 . URL : http://AtlasGeneticsOncology.org/Tumors/blad5001.html Huret JL, Léonard C . Bladder: Urothelial carcinomas. Atlas Genet Cytogenet Oncol Haematol. October 1999 .

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -103- URL : http://AtlasGeneticsOncology.org/Tumors/blad5001.html Huret JL, Léonard C . Bladder: Urothelial carcinomas. Atlas Genet Cytogenet Oncol Haematol. October 2000 . URL : http://AtlasGeneticsOncology.org/Tumors/blad5001.html van Tilborg AA, van Rhijn BW . Bladder: Urothelial carcinomas. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/blad5001.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -104- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Soft tissue tumors: Elastofibroma

Identity Note Elastofibroma is a rare, slow-growing benign lesion of unknown origin, typically arising from the connective tissue between the subscapular area and the chest wall in elderly persons. It was first reported by Jarvi and Saxen in 1959 and published in 1961. Other Elastofibroma dorsi names

CT of the lower thorax: a semilunar-shaped mass (M) of soft tissue density with foci of fatty attenuations abutting two left-side ribs. A smaller heterogeneous mass is seen at the same location on the right. From Rivka Zissin MD and Myra Shapiro-Feinberg MD. IMAJ 2001; 3: 780. Courtesy of the Editor. Clinics and Pathology Etiology The etiology of this lesion remains unclear. It seems likely that the pseudotumor mass is the product of abnormal elastogenesis rather than of degeneration of preformed fibers. It has been suggested that repeated trauma by mechanical friction of the scapula against the ribs may induce the tumorlike process, since there is an increased prevalence in persons having a history of hard manual labor. A family history of the lesion is reported in up to one-third of cases, suggesting that its origin may be influenced genetically. Epidemiology Elastofibroma is a rare condition whose exact incidence is unknown.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -105- Using computerized tomography, an incidence of 2% has been reported in the elderly, but it is found in autopsies, with lesions 3 cm in diameter or smaller, in 11.2% of men and 24.4% of women. It is more common in women (93%, usually older than 55 years) than men, whereas cases in young adults, teenagers and children have not been reported. Clinics In 99% of reported cases, elastofibroma appears in the periscapsular area as a well-circumscribed large mass, most often not adhering to overlying skin. It is usually located in the lower subscapular area, deep in the rhomboid and latissimus dorsi muscles, firmly attached to the chest wall. Other, but very uncommon, locations include the deltoid muscle, ischial tuberosity, greater trochanter, olecranon, thoracic wall, foot, stomach, mediastinum, orbita and cornea. It is slow-growing. 10% of cases show bilateral lesions. Most patients are asymptomatic; hence the lesion can be overlooked. Elastofibroma has a distinctive appearance in ultrasonography, computed tomography and magnetic resonance imaging. Its MR and CT features are different from those of most other soft-tissue tumors, reflecting entrapped fat within a predominantly-fibrous mass. Although not pathognomonic, the presence of these features in a subscapular lesion in an older patient suggests a diagnosis of elastofibroma. Nonetheless, a biopsy is mandatory to confirm clinical diagnosis, since the subscapular site may be the location of neoplasms such as lipomas and sarcoma, as well as of metastases, extra-abdominal fibromatosis and hemangioma.

A. H&E stain: paucicellular, hyalinized stroma containing large, coarse, pale eosinophilic collagen and elastic fibers. B. Vehoeff's elastic stain showing numerous globular and fiber-like elastic materials. Courtesy of Dr. Margaret Grimes, http://www.pathology.vcu.edu/residentcases

Pathology Macroscopically the lesion appears as a grey-white spherical mass 5- 10 cm in diameter.On microscopic examination, it appears as a dermal unencapsulated tumorlike mass composed of eosinophilic collagen and elastic fibers, with scattered aggregates of fat cells. The elastic fibers have a degenerated, beaded appearance or are fragmented into small petaloid or serrated globules arranged in a linear pattern. On ultrastructural examination, the elastic fibers appear as granular or fibrillary aggregations of electron-dense material surrounded by an amorphous matrix with scattered microfibrils.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -106- Treatment Complete surgical excision is the treatment of choice in symptomatic patients. Recurrence after surgery is very rare. Spontaneous regression without treatment has been observed in exceptional cases. Evolution Elastofibroma is a benign condition, and malignant transformation has not been described. Cytogenetics Note Very few lesions have been studied using chromosome banding. Cytogenetics The prominent cytogenetic feature of elastofibroma is remarkably high Morphological karyotypic instability, responsible for structural changes involving virtually all chromosomes. Changes are usually random, and when clonal they have always been observed in no more than two cells. The most frequently nonrandomly affected breakpoint is at the 1p32 band, but breakpoints at 1p36 and 3q21 have been recorded. Cytogenetics One study performed using comparative genomic hybridization Molecular showed the presence of DNA imbalances in 33% of the examined cases, with DNA gains at Xq12-q22 being the most common. Bibliography Elastofibroma dorsi. Jarvi O, Saxen E. Acta Pathol Microbiol Scand 1961; 51(Suppl 144): 83-84. Medline 13789598

Subclinical elastofibromas in the scapular region in an autopsy series. Jarvi OH, Lansimies PH. Cancer 1969; 23(1): 42-63. Medline 1124654

Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Nagamine N, Nohara Y, Ito E. Cancer 1982; 50: 1794-1805. Medline 7116305

Elastofibroma: a familial occurrence. Schepel JA, Wille J, Seldenrijk CA, van Ramshorst B. Eur J Surg 1998; 164: 557-558. Medline 9696981

Chromosome instability in elastofibroma. Vanni R, Marras S, Faa G, Uccheddu A, Dal Cin P, Sciot R, Samson I, Van den Berghe H. Cancer Genet Cytogenet 1999; 111: 182-183. Medline 10347562

Elastrofibroma dorsi of the chest wall.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -107- Bui-Mansfield LT, Chew FS, Stanton CA. AJR Am J Roentgenol 2000; 175: 244. Medline 10882280

Elastofibroma dorsi: elaboration of cytologic features and review of its pathogenesis. Mojica WD, Kuntzman T. Diagn Cytopathol 2000; 23: 393-396. Medline 11074644

Clonal chromosome aberrations secondary to chromosome instability in an elastofibroma. Batstone P,Forsyth L,Goodlad J. Cancer Genet Cytogenet 2001; 128: 46-47. Medline 11458949

Cytogenetic instability, predominantly involving chromosome 1, is characteristic of elastofibroma. McComb EN, Feely MG, Neff JR, Johansson SL, Nelson M, Bridge JA. Cancer Genet Cytogenet 2001; 126: 68-72.

Benign fibrous tissue tumors. Weiss SW,Goldblum JR. In: Soft Tissue Tumors. Enzinger FM and Weiss SW (eds). 4th edition. Mosby Year Book, St. Louis, 2001; pp286-289.

Elastofibroma dorsi: CT appearance. Zissin R, Shapiro-Feinberg M. Isr Med Assoc J 2001; 3: 780. Medline 11692559

Gain of Xq detected by comparative genomic hybridization in elastofibroma. Nishio JN, Iwasaki H, Ohjimi Y, Ishiguro M, Koga T, Isayama T, Naito M, Kikuchi M. Int J Mol Med 2002; 10: 277-280. Medline 12165800

Sonographic detection of elastofibroma dorsi. Dalal A, Miller TT, Kenan S. J Clin Ultrasound 2003; 31(7): 375-378. Medline 12923883

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

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -108- Contributor(s) Written 11- Roberta Vanni 2003

Citation This paper should be referenced as such : Vanni R . Soft tissue tumors: Elastofibroma. Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/ElastofibromaID5173.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -109- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Ovary: Sex cord-stromal tumors

Identity Note Sex cord-stromal tumours develop from the gonadal stroma, and are a type of ovarian tumour. They account for 5-10 % of all ovarian neoplasms. Classification Ovarian sex cord-stromal tumours are subdivided into the following clinicopathological entities: Granulosa cell tumour Theca cell tumour Thecoma Fibroma Sertoli-Leydig cell tumour Sex cord tumour with annular tubules Lipid cell tumour Gynandroblastoma. Clinics and Pathology Etiology There appear to be several established clinical syndromes associated with several subtypes of sex cord-stromal tumours.

30% of patients with sex cord tumours with annular tubules have Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterised by multiple gastrointestinal hamartomatous polyps, increased risk of various neoplasms, and melanocytic macules of the lips, buccal mucosa, and digits. Peutz-Jegher females are also susceptible to granulosa cell tumours. When associated with this syndrome, the tumour is usually small, benign and bilateral. Meanwhile in the absence of this syndrome, it is usually large and unilateral, and malignant in 20% of cases.

There have also been clinical reports of several other types of sex cord-stromal tumours being less frequently associated with PJS including: - oxyphilic Sertoli cell tumour; - Sertoli cell tumour (lipid-rich); - malignant Sertoli-Leydig cell tumour and - ovarian fibroma. 10% of patients with lipid cell tumours have Cushing Syndrome. Fibromas are associated with Meigs Syndrome. The phenotype of

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -110- Meigs syndrome is a benign ovarian tumour (fibroma), with ascites and pleural effusion that resolve within several weeks to months following surgical resection without any recurrence. Thus it imitates a malignant tumour, but has a very good prognosis. Indeed, following resection, life expectancy is similar to the general population. Ovarian fibromas occur in 75% of female patients with Gorlin syndrome (also known as Nevoid basal cell carcinoma syndrome). Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibroma and medulloblastoma. 2 theories account for the aetiology of sex cord-stromal tumours hypothesising that they develop either from: (1) mesenchyme of the developing genital ridge, or (2) precursors of the mesonephric and coelmic epithelium. No definite aetiologies have been established for granulosa cell tumours, although chromosomal abnormalities and abnormal autocrine and endocrine signalling have been suggested. Epidemiology The frequency of sex cord-stromal tumours is similar throughout the world. There does not appear to a racial predisposition, in contrast to epithelial ovarian cancers. Every year, 15-20,000 new cases of sex cord-stromal tumours are diagnosed in the USA. Sex cord-stromal tumours appear in any age group but usually in the 4th and 5th decades. Fibromas are usually detected in the fifth decade of life. The mean age of presentation of Leydig cell tumours is 50. The median age of diagnosis of adult granulosa cell tumours is 52, and is 53-years for theca cell tumours. Theca cell tumours account for 1 % of ovarian neoplasms, and are rarely diagnosed in women under 30-years of age, unless they have luteinized thecoma which is more apparent in younger women. However, Sertoli-Leydig cell tumours tend to present at a younger age, usually in the third decade of life. Clinics Granulosa cell tumours usually follow a nonaggressive clinical course. However, they may become malignant or recur (up to 30 years after the initial diagnosis). 65% of granulosa cell tumours occur in postmenopausal females. Juvenile and adult granulosa cell tumours, fibromas, and Sertoli-Leydig cell tumours are usually unilateral. Granulosa-theca cell tumours are usually large and benign, with cystic degeneration (http://chorus.rad.mcw.edu/doc/00506). Intra-abdominal bleeding following rupture is often the presenting symptom of patients with granulosa cell tumour. Both adult and juvenile granulosa cell tumours are indolent. Approximately 10% of granulosa cell tumours occur in pregnant patients, and should be surgically removed at 16-18 weeks of gestation. The excess oestrogen produced by some stromal tumours, such as adult granulosa cell tumours and thecomas, causes isosexual precocious puberty, postmenopausal bleeding, menorrhagia, menometrorrhagia, amenorrhea, endometrial hyperplasia or cancer or fibrocystic breast disease (http://chorus.rad.mcw.edu/doc/00506). Thecomas usually develop in postmenopausal women, on average grow to 7-8 cm, and >97% of cases are unilateral. Most thecomas are

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -111- hormone producing and cause postmenopausal bleeding in two-thirds of patients. Luteinized thecomas are usually androgenic, and these tend to present in younger women. Approximately 40% of patients with Sertoli-Leydig cell tumours and most patients with Leydig cell tumours show virilization. This is attributable to the Leydig cells which produce androgens. Lipid cell tumours usually cause virilization. A subset of patients with Sertoli-Leydig cell tumours secrete excess oestrogen. Pathology All ovarian sex cord-stromal tumours are derived from the stroma of the developing ovary. The gonadal stoma is primitive, and consequently can develop in a testicular or ovarian differentiation pathway. Adult and Juvenile Granulosa cell tumour Adult granulosa cell tumours contain granulosa cells in the presence or absence of theca cells. Granulosa theca cell tumours are composed of at least 25% theca cells in addition to the granulosa cells. Varying histologies have been reported in adult granulosa cell tumours, including well-differentiated histologies such as microfollicular, macrofollicular, trabecular and insular, and less well diffentiated subtypes including diffuse and watered-silk (gyriform). Call-Exner bodies are pathognomonic of granulosa cell tumour, and are found in the microfollicular pattern, the most common histological subtype. Call- Exner bodies consist of small rings of granulosa cells surrounding eosinophilic fluid and basement membrane material (http://www.emedicine.com/med/topic928.htm#target2 ), and the watered-silk entity contains cells arranged in single file in lines (http://www.emedicine.com/med/topic928.htm#target4). Both the well- differentiated and the less well-differentiated adult granulosa cell tumours contain large, pale, ovoid or angular nuclei with nuclear grooves. Few mitotic figures, mild nuclear atypia and little cytoplasm are usually found, however luteinization can sometimes be evident. The gross appearance of juvenile granulosa cell tumours is similar to the adult counterparts-both comprise a mixture of solid and cystic components with many haemorrhagic areas. However the similarity ceases at the gross level, as morphologically both types differ greatly. Juvenile granulosa cell tumours contain round hyperchromatic nuclei, nuclear grooves are usually absent, severe nuclear atypia, contain more mitotic figures, more cytoplasm (which is dense). Gross image of granulosa cell tumour can be viewed at: http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM057.html Microscopic images at varying magnification powers can be viewed at: http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM058.html http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM063.html http://pathweb.uchc.edu/eAtlas/GYN/1953.htm http://pathweb.uchc.edu/eAtlas/GYN/1954.htm http://pathweb.uchc.edu/eAtlas/GYN/1955.htm Fibromas

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -112- Fibromas are benign and are classified as such if they contain <3 mitoses per high-power field. Malignant fibromas are called fibrosarcomas, and are classified as such if they have >4 mitoses per high-power field. Less than 5% of fibromas are malignant. Gross appearance of an ovarian fibroma can be viewed at: http://www- medlib.med.utah.edu/WebPath/FEMHTML/FEM049.html http://pathweb.uchc.edu/eAtlas/GYN/469.htm http://pathweb.uchc.edu/eAtlas/GYN/470.htm http://pathweb.uchc.edu/eAtlas/GYN/471.htm Histological images of fibromas can be viewed at: http://pathweb.uchc.edu/eAtlas/GYN/1956.htm http://pathweb.uchc.edu/eAtlas/GYN/1957.htm http://pathweb.uchc.edu/eAtlas/GYN/1958.htm Thecomas Thecomas or theca cell tumours contain exclusively theca cells. Thecomas are solid, tan or yellow-orange tumours. They are highly similar to fibromas, except that thecomas secrete excess oestrogen. Thecomas are usually benign, and are characterised by <3 mitoses per high-power field. Malignant thecomas have >3 mitoses per field. Microscopic analysis reveals round or ovoid cells with pale nuclei and a lipid-rich cytoplasm. Hyaline bands frequently intersperse cells (http://www.emedicine.com/med/topic928.htm#target5). Luteinized thecomas contain lipid rich cytoplasmic cells and a more fibromatous stroma (http://www.emedicine.com/med/topic928.htm#target6). Less than 5% of thecomas are malignant. http://pathy.med.nagoya-u.ac.jp/atlas/misc/thecoma.html Sertoli cell tumours Sertoli cell tumours contain Sertoli cells in a tubular arrangement. Sertoli-Leydig cell tumours As the name suggests, Sertoli-Leydig cells contain both Sertoli and Leydig cells. They are subclassified in accordance with the WHO as follows: 1. well-differentiation (predominant tubular pattern) 2. intermediate differentiation (sheets of immature Sertoli cells with some stroma) 3. poor differentiation (immature Sertoli cells with little or no stroma) 4. containing heterologous elements with retiform pattern. Less than 5% of Sertoli-Leydig tumours are malignant. Leydig cell tumours Leydig cell tumours contain Leydig cells, and are usually benign. When located in the hilus they are described as hilus cell tumours. Leydig cell tumours contain Reinke crystals. Lipid cell tumours Lipid cell tumours are characterised by round Leydig-like cells,

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -113- luteinized stroma, adrenocortical cells and the absence of Reinke crystals. 30% of lipid cell tumours are malignant. Gynandroblastoma These are rare ovarian tumours which contain granulosa stromal cells and Sertoli stromal cells. 100% of gynandroblastomas are malignant. Sex cord tumour with annular tubules (SCTAT) Histologically SCTAT is intermediate between granulosa cell tumour and the Sertoli cell tumour. It is characterised by sex cord cells in the form of a ring with nuclei orientated around a central hyalonized body. Treatment Surgery may be the only treatment necessary. Surgical intervention of patients with sex cord-stromal tumours is age dependent. Trans abdominal hysterectomy or bilateral salpingo-oophorectomy is appropriate for women beyond childbearing age, whereas unilateral oophorectomy is appropriate for younger women. There is a paucity of data on treatment of advanced or recurrent stromal tumours due to their rarity, varied histology and indolence. Combination chemotherapies have yielded some responses in each subtype of sex cord-stromal tumour. Pelvic radiation has also been used for localised tumours. No effective treatment is available for metastatic lipid cell tumours. Evolution 20% of lipid cell tumours metastasise. In the low percentage of granulosa cell tumours showing aggressive behaviour, any organ can be affected by metastatic disease, although it is usually confined to the pelvis and abdomen. Prognosis The prognosis of sex-cord-stromal tumours is good, as these tumours usually present when confined to a single ovary, and are responsive to chemotherapy. Patients with juvenile granulosa cell tumours have a good prognosis-mortality is only 1.5% for patients with stage IA. For individuals with granulosa cell tumours, diffuse growth pattern, increased mitotic figures and cellular atypia correlate with poor prognosis. >90% of adult and juvenile granulosa cell tumours are diagnosed at stage I. 5-year survival rates are 90-95 % for stage I tumours, but only 25-50% for those presenting with advanced disease. Adult granulosa cell tumours usually develop in postmenopausal women, recur after longer time intervals, (average of 5-years), and the average survival following recurrence is 5-years. Meanwhile, most juvenile granulosa tumours develop in individuals under 30-years of age, recur within 3-years and then are rapidly fatal. Individuals with completely resected granulosa cell tumours with normal DNA diploid content, have a much better prognosis than when residual tumour remains after laparotomy, and the DNA content is aneuploid. Theca cell tumours have an excellent prognosis, with 5-year survival rates of nearly 100%, as they are usually benign. The prognosis of Sertoli-Leydig cell tumours is governed by the stage and differentiation of the tumour. 97.5% of such tumour entities are stage 1, the remainder being advanced-stage.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -114- Cytogenetics Cytogenetics Trisomy 12 is a recurrent finding, often as the sole anomaly in benign Morphological sex cord-stromal tumours including fibromas, fibrothecomas, thecomas, granulosa cell tumours. The consistent occurrence of trisomy 12 in different subtypes of sex cord-stromal tumours suggests a common mechanism of oncogenesis within this diverse group of neoplasms. Numerical abnormalities of chromosome 12 can readily be demonstrated by interphase cytogenetics.

Trisomy 12 and 14, and monosomy 22 are the characteristic recurrent cytogenetic aberrations in granulosa cell tumours. There has been a single case of a Sertoli cell tumour in which cytogenetics was performed. Supernumerary i(1q) was present as the sole abnormality. Monosomy 22 was identified as the sole anomaly in a mixed germ cell-sex cord-stromal tumour in the ovary, by both karyotyping and CGH, which may suggest a common pathogenetic mechanism for both tumour types. Monosomy 22 was also identified as the sole abnormality in a fibrothecoma. Monosomy 22 and trisomy 14 may be early events in the pathogenesis of adult granulosa cell tumour, and particularly adult granulosa-thecoma cell tumours.

Other abnormalities found include:

44,XX,dup(p13p31),del(3)(p14),add(10p),-16,-22 in one case of fibrothecoma, 57,XX,+4,+5,+6,+10,+12,+12,+14,+17,+18,+19,+20 in another fibrothecoma case, +4,+9,+12 in fibrothecoma, trisomy 12 and 4 as only cytogenetic aberrations in a thecoma. Cytogenetics CGH and FISH analysis of an ovarian metastasising Sertoli-Leydig Molecular cell tumour demonstrated trisomy 8 as the sole anomaly, suggesting that the molecular pathogenesis of Sertoli-Leydig cell tumours differs from the other subtypes of sex cord-stromal tumours. In a study, FISH using DNA-specific probes for chromosome 12, 17, 22 and X on granulosa cell tumours revealed monosomy 22 in 6/20; trisomy 12 in 5/20; monosomy X in 2/20 and monosomy 17 in 1/20. They also analysed this series of tumours by CGH and identified gains of chromosome 12 (6/20) and 14 (6/20) and losses of chromosome 22 (7/20) and X (1/20) as the predominant findings. These findings corroborate previous reports of the prevalence of trisomy 12 and 14 and monosomy 22 in granulosa cell tumours. Genes involved and Proteins Note Involvement of the follicle stimulating hormone receptor, FSHR, gene in granulosa cell tumours has now been excluded. An initial study found mutations in 9 out of 13 sex cord tumours, which were later shown to arise from contamination in the tissue processing procedures. Other studies have confirmed the absence of somatic mutations in the FSHR

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -115- in sex cord-stromal tumours, and in particular granulosa cell tumours.

Activating mutations of the G-protein subunit, G-alpha I-2, have been found in 30% of ovarian sex cord tumours, however none were found in a series of 13 granulosa cell tumours. Data for involvement of the mutations in G-alpha I-2 (Gia2) gene, in ovarian granulosa cell tumours is contradictory. However, 2 studies have excluded any major involvement of this gene in the genesis of ovarian granulosa cell tumours.

As discussed earlier, sex cord tumours with annular tubules are present at increased frequency in individuals with PJS, which is caused by germline inactivating mutations of the STK11 gene at 19p13.3. A study investigated whether LOH was present in 2 cases of PJS associated sex cord-stromal tumours, and in 5 sex cord-stromal tumours in individuals without PJS. LOH was identified in both tumours associated with PJS. Neither LOH nor somatic mutations of STK11 were present in the sporadic tumours.

Immunohistochemistry has demonstrated that 32/33 granulosa cell tumours, and 10/11 Sertoli-Leydig cell tumours show inhibin alpha (INHA) immunopositivity, and 18/33 granulosa cell tumours and 6/11 Sertoli-Leydig cell tumours MIC2 (CD99 antigen) immunopositivity. Knockout mouse models null for the INHA gene develop granulosa cell tumours suggesting that this gene may act as a tumour suppressor gene. To find supporting evidence that this was the case in human granulosa cell tumours, It has been investigated whether LOH of the INHA locus at 2q33-qter was evident in a series of 17 granulosa cell tumours. However LOH was found in only one case, suggesting that this gene does not function as a tumour suppressor gene in granulosa cell tumours in human, contrary to the findings in the mouse model. However this supports the observation of elevated expression of inhibin which has been reported previously in these tumours. Thus there appears to be an apparent dichotomy between the human granulosa cell tumour and the mouse models.

A study to address whether trisomy 12 was associated with amplification of the KRAS2 oncogene (12p12.1) demonstrated no relationship in 2 fibromas and 1 granulosa cell tumour with trisomy 12 (taking the ploidy level into account). Cyclin D2 (CCND2) has been suggested as the candidate gene on 12p, and has been reported to demonstrate increased expression. Granulosa cell tumours demonstrated increased expression of FSHR, CCND2, RII-beta and COX-2 (PTGS2), whereas they showed decreased expression of SGK and LHCGR (luteinizing hormone/choriogonadotropin receptor) compared to normal ovarian tissue by RT-PCR. Altered expression levels of the following genes have also been found in granulosa cell tumours: Mullerian inhibiting substance; inhibin; p53; ERBB2; and MYC. A role for the INK4 family of cyclin-dependent kinase inhibitors has also

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -116- been suggested in granulosa cell tumours.

The role of mutations of WT1 in sex cord-stromal tumours was investigated. Of 11 granulosa cell tumours, 3 Leydig cell tumours and 1 Sertoli-Leydig cell tumour, none harboured a mutation in the zinc finger domain where >90% of WT1 mutations are found in sporadic Wilms' tumours, despite most of the tumours expressing WT1 mRNA. However loss of the normal wild type allele of WT1 was observed in a granulosa cell tumour present in a patient with Denys-Drashattributable to a germline mutation of WT1.

Studies on the role of TP53 mutations in granulosa cell tumours have been contradictory. It was found that over-expression of TP53 was not characteristic of 19 ovarian granulosa cell tumours; whereas other workers found a correlation between expression of mutated TP53 with poor prognosis, which was supported by other findings. Neither point mutations (exons 5-8 analysed only), nor LOH of TP53 were evident in a series of 17 granulosa cell tumours, suggesting that they have a distinct molecular pathogenesis to that of epithelial ovarian tumours. Mutations outside the hotspot exon 5-8 were not excluded by their study, but are unlikely to be significant since an association between TP53 and granulosa cell tumour by immunohistochemistry was not demonstrated in th efirst study.

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Absence of mutations in the FSH receptor in ovarian granulosa cell tumors. Kotlar T, Young RH, Albanese C, Crowley WF, Jr., Scully RE, Jameson JL. J Clin Endocrinol Metab 1998; 83: 3001. Medline 9709983

Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas. Riopel MA, Perlman EJ, Seidman JD, Kurman RJ, Sherman ME. Int J Gynecol Pathol 1998; 17: 46-53. Medline 9475192

Sertoli cell tumor causing precocious puberty in a girl with Peutz-Jeghers syndrome. Zung A, Shoham Z, Open M, Altman Y, Dgani R, Zadik Z. Gynecol Oncol 1998; 70: 421-424. Medline 9790799

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

Diagnostic utility of Mullerian inhibiting substance determination in patients with primary and recurrent granulosa cell tumors. Lane AH, Lee MM, Fuller AF, Jr., Kehas DJ, Donahoe PK, MacLaughlin DT. Gynecol Oncol 1999; 73: 51-55.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -121- Medline 10094880

Analysis of mutations in genes of the follicle-stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors. Ligtenberg MJ, Siers M, Themmen AP, Hanselaar TG, Willemsen W, Brunner HG. J Clin Endocrinol Metab 1999; 84: 2233-2234. Medline 10372736

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

Inhibin forms in serum from postmenopausal women with ovarian cancers. Robertson DM, Cahir N, Burger HG, Mamers P, Groome N. Clin Endocrinol (Oxf) 1999; 50: 381-386. Medline 10435065

Monosomy 22 and trisomy 14 may be early events in the tumorigenesis of adult granulosa cell tumor. Van den Berghe I, Dal Cin P, De Groef K, Michielssen P, Van den BH. Cancer Genet Cytogenet 1999; 112: 46-48. Medline 10432935

Somatic mutations in the STK11/LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz-Jegher's syndrome. Connolly DC, Katabuchi H, Cliby WA, Cho KR. Am J Pathol 2000; 156: 339-345. Medline 10623683

Assessment of inhibin and p53 in granulosa cell tumors of the ovary. Gebhart JB, Roche PC, Keeney GL, Lesnick TG, Podratz KC. Gynecol Oncol 2000; 77: 232-236. Medline 10785470

No evidence of somatic activating mutations on gonadotropin receptor genes in sex cord stromal tumors. Giacaglia LR, Kohek MB dF, Carvalho FM, Fragoso MC, Mendonca B, Latronico AC. Fertil Steril 2000; 74: 992-995. Medline 11056247

Goldman L Cecil Textbook of Medicine 2000. Saunders

Trisomy 8 as sole karyotypic aberration in an ovarian metastasizing Sertoli- Leydig cell tumor. Manegold E, Tietze L, Gunther K, Fleischer A, Amo-Takyi BK, Schroder W, Handt S.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -122- Hum Pathol 2001; 32: 559-562. Medline 11381376

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

Conservative treatment of recurrent ovarian fibromas in a young patient affected by Gorlin syndrome. Seracchioli R, Bag ;noli A, Colombo FM, Missiroli S, Venturoli S. Hum Reprod 2001; 16: 1261-1263. Medline 11387302

Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors. Arcellana-Panlilio MY, Egeler RM, Ujack E, Magliocco A, Stuart GC, Robbins SM, Coppes MJ Genes Chromosomes Cancer 2002; 35: 176-181. Medline 12203782

FSH-regulated gene expression profiles in ovarian tumours and normal ovaries. Chu S, Rushdi S, Zumpe ET, Mamers P, Healy DL, Jobling T, Burger HG, Fuller PJ. Mol Hum Reprod 2002; 8: 426-433. Medline 11994539

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

Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz-Jeghers syndrome, von Hippel-Lindau disease, Cowden's disease). Papageorgiou T, Stratakis CA. Int J Gynecol Cancer 2002; 12: 337-347. Medline 12144681

Meigs Syndrome. Chavda R, Akhter A, Lessnau KD. http://www.emedicine.com/med/topic1422.htm 2003.

Granulosa-Theca Cell Tumors. Michener CM, Wu AY, Barnes A. www.emedicine.com/med/topic928.htm 2003.

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Atlas Genet Cytogenet Oncol Haematol 2004; 1 -123- Last year automatic search in PubMed publications Contributor(s) Written 11- Lisa Lee-Jones 2003 Citation This paper should be referenced as such : Lee-Jones L . Ovary: Sex cord-stromal tumors. Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/OvarSexCordStromID5223.html

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -124- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Testis: Spermatocytic seminoma

Identity Note Spermatocytic seminoma is a rare testicular neoplasm derived from germ cells. It was first described by Masson in 1946. This tumour occurs exclusively in the testes, in relatively older men. There is no female (ovarian) equivalent. Other Spermatocytoma names

En example of spermatocytic seminoma, HE-stained. Classification Note Classification of germ cell tumours has not been adapted uniformly in the world. Two classifications most commonly used are the modified WHO classification and the British Testicular Panel (BTTP) classification. In addition Grigor proposed in 1993 a new classification based on biological features, and it was suggested in the AFIP Atlas of Tumor Pathology a modified classification of testicular and paratesticular tumours and tumour-like lesions. Spermatocytic seminoma is classified in these four systems as follows:

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Clinics and Pathology Disease Spermatocytic seminoma has a relatively mild clinical course. Most patients present with a painless swelling of one testis, but in some cases tenderness was reported. Metastases are very rare and have been basically reported only in cases with sarcomatous transformation. Phenotype / The origin of spermatocytic seminoma from the germ cell lineage has cell stem been clearly demonstrated by a number of studies, however the cell of origin origin have been a matter of debate. The initial hypothesis suggested that the spermatocyte was the progenitor cell and the tumour might contain post-meiotic haploid cells. Subsequent studies failed to find haploid DNA values, thus arguing against a true meiotic-phase tumour. Other hypotheses stipulated that spermatocytic seminoma might be a better differentiated variant of classical seminoma (composed of cells differentiating in the direction of spermatocytes but which have not yet reached this stage) or may originate from type B (dark) spermatogonia, which are committed to enter meiosis. Finally, some researchers suggested that spermatocytic seminoma might be derived from primordial germ cells or gonocytes. The current consensus, based on comparative studies of the phenotypes of spermatocytic seminoma, normal germ cells and other germ cell derived tumours, is that spermatocytic seminoma is derived from spermatogonia that are committed to enter meiosis but have not yet done so. Importantly, spermatocytic seminoma is not derived from carcinoma in situ (CIS), the gonocytes-like intratubular precursor lesion for germ cell tumours of adolescents and young adults (classical seminoma and non-seminoma). Etiology Aetiology of spermatocytic seminoma is unknown. Epidemiology Spermatocytic seminoma is rare and represents around 2-5% of seminomas. It occurs in patients at 45-80 years of age, and is extremely rare in young men under than 35. This is in contrast to the classical seminoma, which demonstrates the peak of age-specific incidence around 35 years of age. Cytology A characteristic feature of spermatocytic seminoma is the presence of three types of cells with different nuclear size: large, small and intermediate. Some nuclei may exhibit a presence of nuclear thread- like chromatin.

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A high power image showing characteristic polymorphism of the cell nucleus size of spermatocytic seminoma.

Pathology There is no specific marker for spermatocytic seminoma. Proteins/antigens that are highly expressed in spermatogonia (most of them of them also present in gonocytes and primary spermatocytes), such as SSX (synovial sarcoma on X chromosome), NSE (neuron- specific enolase), CHK2, MAGE-A4, NY-ESO-1, VASA are present in spermatocytic seminoma. Antigens expressed in embryonic germ cells but not in the normal adult testis, e.g. PLAP (placental-like alkaline phosphatase), TRA-1-60, or KIT are usually undetectable in spermatocytic seminoma. High expression of p53 protein in a subset of cells was demonstrated in approximately 80% of cases. Proteins highly abundant in post-meiotic spermatids, e.g. p19INK4d, are usually not present in spermatocytic seminoma. The expression of telomerase (the RNA component) in spermatocytic seminoma was found to be moderate: lower than in classical seminomas but higher than in mature teratomas.

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MAGE-A4 antigen is abundant is spermatocytic seminoma (visible in a lower part of the picture). Note that MAGE-A4 is also present in spermatogonia (visible in the upper part) (from Rajpert-De Meyts et al. Histopathology 2003).

Treatment Spermatocytic seminoma is treated by surgery (orchiectomy). Evolution Some cases of spermatocytic seminoma may undergo sarcomatous transformation and spread outside the testis. An anaplastic variant was also described. Genetics Note No specific germ-line chromosomal aberration or gene mutations were reported in patients with spermatocytic seminoma. Cytogenetics Note Cytogenetic studies demonstrated variable ploidy of the different cell populations in spermatocytic seminoma, with prevalence of diploid and polyploid cells. No haploid values were found. Cytogenetics Only one molecular study of 4 spermatocytic seminomas was Molecular performed to date. A uniform gain of chromosome 9, and less consistent gains of chromosomes 1 and 20, and loss of chromosome 22 material were found by comparative genomic hybridisation. Bibliography Spermatocytic seminoma. I. Clinicopathologic study of six cases and review of literature. II. Ultrastructural study. Rosai J, Khodadoust K, Silber I. Cancer 1969; 24: 92-116.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -128- Medline 5790281

Testicular tumours _ Introduction. Pugh RC. In: Pugh RC (ed.) Pathology of the testis. Blackwell Scientific, Oxford 1976, 139-159 (REVIEW).

Comparison of various clinical and pathological classifications of tumors of testes. Mostofi FK. Semin Oncol 1979; 6: 26-30 (REVIEW) Medline 572090

The spermatocytic seminoma: views on pathogenesis. Müller J, Skakkebaek NE, Parkinson MC. Int J Androl 1987; 10:147-156. Medline 3583416

Placental-like alkaline phosphatase and DNA flow cytometry in spermatocytic seminoma. Dekker I, Rozeboom T, Delemarre J, Dam ABS, Oosterhuis JW. Cancer 1992; 69: 993-996. Medline 1310437

A new classification of germ cell tumours of the testis. Grigor KM. Eur Urol 1993; 23: 93-103. Medline 8386662

Ultrastructure and histogenesis of spermatocytic seminoma. Romanenko AM, Persidsky YV, Mostofi FK. J Urol Pathol 1993; 1: 387-395. Medline 6880135

Spermatocytic seminoma. Eble JN. Hum Pathol 1994; 25: 1035-1042. Medline 7927308

Anaplastic variant of spermatocytic seminomas. Albores-Saavedra J, Huffman H, Alvarado-Cabrero I, Ayala AG. Hum Pathol 1996; 27: 650-655.

Chromosomal constitution of human spermatocytic seminomas: comparative genomic hybridization supported by conventional and interphase cytogenetics. Rosenberg C, Mostert MC, Schut TB, van de Pol M, van Echten J, de Jong B, Raap

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -129- AK, Tanke H, Oosterhuis JW, Looijenga LHJ. Genes Chromosomes Cancer 1998; 23: 286-291.

Expression of the RNA component of human telomerase in adult testicular germ cell neoplasia. Delgado R, Rahti A, Albores-Saavedra J, Gazdar AF. Cancer 1999; 86: 1802-1811.

Spermatocytic seminoma as compared to classical seminoma: An immunohistochemical and DNA flow cytometric study. Kraggerud SM, Berner A, Bryne M, Petersen EO, Fossa SD. APMIS 1999; 107: 297-302. Medline 10223302

Tumors of the testis, adnexa, spermatic cord, and scrotum. Ulbright TM, Amin MB, Young RH. In: Atlas of Tumor Pathology. Third Series, Fascicle 25. Armed Forces Institute of Pathology, Washington DC, 1999, 1-375 (REVIEW).

Reactivity of germ cell maturation stage-specific markers in spermatocytic seminoma: diagnostic and etiological implications. Stoop H, van Gurp R, de Krijger R, Geurts van Kessel A, K_berle B, Oosterhuis JW, Looijenga LHJ. Lab Invest 2001; 81: 919-928.

The cancer-testis gene, NY-ESO-1 is expressed in normal foetal and adult testes, in spermatocytic seminoma and testicular carcinoma in situ. Satie A-P, Rajpert-De Meyts E, Spagnoli GC, Henno S, Olivo L, Jacobsen GK, Rioux-Leclercq N, J_gou B, Samson M. Lab Invest 2002; 82: 775-780.

The imunohistochemical expression pattern of Chk2, p53, p19-INK4d, MAGE- A4 and other selected antigens provides new evidence for the pre-meiotic origin of spermatocytic seminoma. Rajpert-De Meyts E, Jacobsen GK, Bartkova J, Aubry F, Samson M, Bartek J, Skakkeb_k NE. Histopathology 2003; 42: 217-226.

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Contributor(s) Written 11- Ewa Rajpert-De Meyts 2003

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -130- Citation This paper should be referenced as such : Rajpert-De Meyts E . Testis: Spermatocytic seminoma. Atlas Genet Cytogenet Oncol Haematol. November 2003 . URL : http://AtlasGeneticsOncology.org/Tumors/SpermatSeminID5119.html

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Familial clear cell renal cancer Identity Note Renal cell carcinomas (RCC) represent 85% of all primary renal tumors. In general, RCCs are sporadic tumors but cases of familial RCC have also been reported. If detected early and without metastases, the disease can be cured surgically with conservation of renal function. Both familial and sporadic cases have in common the presence of abnormalities involving chromosome 3, suggesting a primary role for this chromosome in RCC causation, particularly the clear cell type. An early gene rearrangement due to translocation may be a primary event. Loss of 3p and somatic mutation(s) in a tumor-surpressor-gene(s) on 3p (e.g.VHL) may be recurring events related to tumor progression Inheritance The inherited form of renal cancer is characterized by : - the tumor is found at an early age compared to sporadic tumors (see below) - the tumors are found frequently bilateral - multiple occurrence. Other (well known) classes of inherited renal cell carcinomas are: the Von Hippel-Lindau syndrome, and the Lynch syndrome II. Also chromosome abnormalities may be related to inherited renal cancer. Clinics Note No phenotypic sign. Neoplastic Multiple and/or bilateral nonpapillary renal cell carcinomas, with median risk age 45 yrs at diagnosis (range 18-79 yrs, most cases being between 35 and 55 yrs old). Treatment If the tumor is detected at an early stage the tumor can be surgical removed, without the lost of the renal function. Prognosis Depends on the stage of the tumor at the time of detection. Cytogenetics Note Clear-cell renal cell carcinomas are associated with chromosome 3 translocations and deletions of 3p. Genes involved and Proteins

Gene FHIT Name

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -132- Location 3p14.2 Note FHIT is a breakpoint spanning gene on chromosome 3 in a constitutional familial case of a t(3;8)(p14;q24) translocation. DNA/RNA Description 10 exons Protein Description 147 amino acids

Gene TRC8 Name Location 8q24 Note TRC8 is a breakpoint spanning gene on chromosome 8 in a constitutional familial case of a t(3;8)(p14;q24) translocation.

Gene DIRC2 Name Location 3q21 Note Dirc2 is a breakpointspanning gene on chromosome 3 in a constitutional familial case of a t(2;3)(q35;q21) translocation. DNA/RNA Description The gene spans 73 kb, 9 exons. Protein Description 478 amino acids Expression Expression in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain and heart. Localisation Proximal tubular cells of the kidney. Function May be a transporter.

Gene DIRC3 Name Location 2q35 Note Dirc3 is a breakpointspanning gene on chromosome 2 in a constitutional familial case of a t(2;3)(q35;q21) translocation. DNA/RNA Description The gene spans 3071 bp and contains 12 exons.

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -133- Gene DIRC1 Name Location 2q33 Note Dirc1 is a breakpointspanning gene on chromosome 2 in a constitutional familial case of a t(2;3)(q33;q22) translocation. DNA/RNA Description DIRC1 gene contains 2 exons and spans approximately 57 kb of genomic DNA

Bibliography A new inducible fragile site on chromosome 3 (p14.2) in human lymphocytes. Wegner RD. Hum. Genet 1983; 63: 297-298. Medline 6852828

Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Wang N, Perkins KL. Cancer Genet Cytogenet 1984; 11: 479-481. Medline 6704944

An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation. Bodmer D, Eleveld MJ, Ligtenberg MJL, Weterman MAJ, Janssen BAP, Smeets DFCM, de Wit PEJ, van den Berg A, van den Berg E, Koolen MI, Geurts van Kessel A. Am J Hum Genet 1998; 62: 1475-1483. Medline 9585616

The DIRC1 gene at chromosome 2q33 spans a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. Druck T, Podolski J, Byrski T, Wyrwicz L, Zajaczek S, Kata G, Borowka A, Lubinski J, Huebner K. J Hum Genet 2001; 46: 583-589. Medline 11587072

Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB, Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J, Huebner K. J Hum Genet 2001; 46: 685-693. Medline 11776380

Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21). Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B, Wetermann M,

Atlas Genet Cytogenet Oncol Haematol 2004; 1 -134- Schoenmakers E, Nickerson M, Linehan M, Zbar B, van Kessel AG. Hum Molec Genet 2002; 11: 641-649. Medline 11912179

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. Gemmill RM, Bemis LT, Lee JP, Sozen MA, Baron A, Zeng C, Erickson PF, Hooper JE, Drabkin HA. Oncogene 2002; 21: 3507-3516. Medline 12032852

Disruption of a novel gene, DIRC3, and expression of DIRC3-HSPBAP1 fusion transcripts in a case of familial renal cell cancer and t(2;3)(q35;q21). Bodmer D, Schepens M, Eleveld MJ, Schoenmakers EF, Geurts van Kessel A. Genes Chromosomes Cancer 2003; 38(2): 107-116. Medline 12939738

Molecular study of a new family with hereditary renal cell carcinoma and a translocation t(3;8)(p13;q24.1). Melendez B, Rodriguez-Perales S, Martinez-Delgado B, Otero I, Robledo M, Martinez-Ramirez A, Ruiz-Llorente S, Urioste M, Cigudosa JC, Benitez J. Hum Genet 2003; 112: 178-185. Medline 12522559

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 10- Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric 2003 Schoenmakers, Ad Geurts van Kessel. Citation This paper should be referenced as such : Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPM, Geurts van Kessel A. . Familial clear cell renal cancer. Atlas Genet Cytogenet Oncol Haematol. October 2003 . URL : http://AtlasGeneticsOncology.org/Kprones/FamClearCellRenalID10081.html

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