* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Scope
Survey
Document related concepts
Medical genetics wikipedia , lookup
Point mutation wikipedia , lookup
Skewed X-inactivation wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
Designer baby wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Neocentromere wikipedia , lookup
X-inactivation wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Genome (book) wikipedia , lookup
Oncogenomics wikipedia , lookup
Transcript
Scope The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences. Editorial correspondance Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected] Staff Sylvie Yau Chun Wan - Senon Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France). The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation. http://AtlasGeneticsOncology.org © ATLAS - ISSN 1768-3262 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Scope The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles (“cards”) on genes, leukaemias, solid tumours, cancer-prone diseases, and also more traditional review articles (“deep insights”) on the above subjects and on surrounding topics. It also present case reports in hematology and educational items in the various related topics for students in Medicine and in Sciences. Editorial correspondance Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected] Staff Sylvie Yau Chun Wan - Senon Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France). The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation. http://AtlasGeneticsOncology.org © ATLAS - ISSN 1768-3262 The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Editor-in-Chief Jean-Loup Huret (Poitiers, France) Editorial Board Alessandro Beghini Anne von Bergh Vasantha Brito-Babapulle Charles Buys Anne Marie Capodano Fei Chen Antonio Cuneo Paola Dal Cin Louis Dallaire François Desangles Gordon Dewald Richard Gatti Oskar Haas Anne Hagemeijer Nyla Heerema Jim Heighway Sakari Knuutila Lidia Larizza Lisa Lee-Jones Edmond Ma Cristina Mecucci Yasmin Mehraein Fredrik Mertens Konstantin Miller Felix Mitelman Hossain Mossafa Florence Pedeutour Susana Raimondi Mariano Rocchi Alain Sarasin Albert Schinzel Clelia Storlazzi Sabine Strehl Nancy Uhrhammer Dan Van Dyke Roberta Vanni Franck Viguié Thomas Wan Bernhard Weber (Milan, Italy) (Rotterdam, The Netherlands) (London, UK) (Groningen, The Netherlands) (Marseille, France) (Morgantown, West Virginia) (Ferrara, Italy) (Boston, Massachussetts) (Montreal, Canada) (Paris, France) (Rochester, Minnesota) (Los Angeles, California) (Vienna, Austria) (Leuven, Belgium) (Colombus, Ohio) (Liverpool, UK) (Helsinki, Finland) (Milano, Italy) (Newcastle, UK) (Hong Kong, China) (Perugia, Italy) (Homburg, Germany) (Lund, Sweden) (Hannover, Germany) (Lund, Sweden) (Cergy Pontoise, France) (Nice, France) (Memphis, Tennesse) (Bari, Italy) (Villejuif, France) (Schwerzenbach, Switzerland) (Bari, Italy) (Vienna, Austria) (Clermont Ferrand, France) (Rochester, Minnesota) (Montserrato, Italy) (Paris, France) (Hong Kong, China) (Würzburg, Germany) Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Genes Section Genes / Leukemia Sections Leukemia Section Deep Insights Section Solid Tumors Section Genes / Deep Insights Sections Leukemia Section Genes / Solid Tumors Sections Education Section Leukemia / Solid Tumors Sections Leukemia / Deep Insights Sections Cancer-Prone Diseases / Deep Insights Sections Genes / Leukemia Sections Deep Insights Section Leukemia Section Genes / Deep Insights Sections Deep Insights Section Solid Tumors Section Solid Tumors Section Leukemia Section Genes / Leukemia Sections Cancer-Prone Diseases Section Solid Tumors Section Education Section Deep Insights Section Leukemia Section Genes / Solid Tumors Sections Genes / Leukemia Section Genes Section Cancer-Prone Diseases Section Education Section Genes Section Genes / Leukemia Sections Genes / Cancer-Prone Diseases Sections Education Section Solid Tumors Section Leukemia Section Genes / Leukemia Sections Education Section Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Volume 8, Number 1, January - March 2004 Table of contents Gene Section DIRC2 (disrupted in renal carcinoma 2) Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel 1 DIRC3 (disrupted in renal carcinoma 3) Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel. 3 RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1) Franck Viguié 5 RET (REarranged during Transfection) Patricia Niccoli-Sire 7 ZFHX3 (zinc finger homeobox 3) Nadine Van Roy, Frank Speleman 9 LPHN2 (latrophilin 2) Jim Heighway 11 MNX1 (motor neuron and pancreas homeobox 1) Anne RM von Bergh, H Berna Beverloo 14 SYNPO2 (synaptopodin 2) Jian-Hua Luo 16 Leukaemia Section 11p15 rearrangements in treatment related leukemia Jean-Loup Huret 18 12p13 rearrangements in treatment related leukemia Jean-Loup Huret 19 21q22 rearrangements in treatment related leukemia Jean-Loup Huret 20 inv(16)(p13q22) in treatment related leukemia Jean-Loup Huret 22 t(15;17)(q22;q21) in treatment related leukemia Jean-Loup Huret 24 t(3;21)(q26;q22) in treatment related leukemia Jean-Loup Huret 26 t(8;16)(p11;p13) in treatment related leukemia Jean-Loup Huret 28 t(8;21)(q22;q22) in treatment related leukemia Jean-Loup Huret 30 t(9;22)(q34;q11) in treatment related leukemia Jean-Loup Huret 31 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Acute megakaryoblastic leukemia (AMegL), M7 acute non lymphocytic leukemia (M7-ANLL) Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi 32 Refractory anemia (RA) Antonio Cuneo, Gianluigi Castoldi 35 Refractory anemia with excess blasts (RAEB) Antonio Cuneo, Gianluigi Castoldi 37 Refractory anemia with ringed sideroblasts (RARS) Antonio Cuneo, Gianluigi Castoldi 39 Solid Tumour Section Bladder: Urothelial carcinomas Angela van Tilborg, Bas van Rhijn 41 Ovary: Sex cord-stromal tumors Lisa Lee-Jones 48 Soft tissue tumors: Elastofibroma Roberta Vanni 54 Testis: Spermatocytic seminoma Ewa Rajpert-De Meyts 57 Cancer Prone Disease Section 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) 61 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication DIRC2 (disrupted in renal carcinoma 2) Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, the Netherlands (AB, DB, ME, ES, AGVK) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRC2ID497.html DOI: 10.4267/2042/38036 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity cells of the kidney), skeletal muscle, liver, lung, placenta, brain and heart. HGNC (Hugo): DIRC2 Location: 3q21 Function DNA/RNA Homology See below, may be a transporter. 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. Description The gene spans 73 kb, 9 exons. The first exon and 5prime 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 membranespanning domains 6 and 7. It also contains a putative N-glycosylation site and several putative phosphorylation sites. Implicated in t(2;3)(q35;q21) and hereditary renal cell cancer Protein Disease Familial renal cell cancer. Cytogenetics Disruption of the gene because of the t(2;3) translocation. Description 478 amino acids. Expression Expression in pancreas, kidney (proximal tubular Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 1 DIRC2 Bonné A et al. Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J, Huebner K. Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. J Hum Genet. 2001;46(12):685-93 References Bodmer D, Eleveld MJ, Ligtenberg MJ, Weterman MA, Janssen BA, Smeets DF, de Wit PE, van den Berg A, van den Berg E, Koolen MI, Geurts van Kessel A. An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation. Am J Hum Genet. 1998 Jun;62(6):1475-83 Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B, Weterman M, Schoenmakers E, Nickerson M, Linehan M, Zbar B, van Kessel AG. Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21). Hum Mol Genet. 2002 Mar 15;11(6):641-9 Koolen MI, van der Meyden AP, Bodmer D, Eleveld M, van der Looij E, Brunner H, Smits A, van den Berg E, Smeets D, Geurts van Kessel A. A familial case of renal cell carcinoma and a t(2;3) chromosome translocation. Kidney Int. 1998 Feb;53(2):273-5 This article should be referenced as such: Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPMG, Geurts van Kessel A. DIRC2 (disrupted in renal carcinoma 2). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):1-2. Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB, Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 2 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication DIRC3 (disrupted in renal carcinoma 3) Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel. Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, the Netherlands (AB, DB, ME, ES, AGVK) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRC3ID498.html DOI: 10.4267/2042/38037 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Implicated in HGNC (Hugo): DIRC3 Location: 2q35 t(2;3)(q35;q21) and hereditary renal cell cancer DNA/RNA Disease Familial renal cell cancer. Cytogenetics Disruption of the gene because of the t(2;3) translocation. Abnormal protein DIRC3-HSPBAP1 is formed by replacing the first coding exon of HSPBAP1 by the first two exons of DIRC3. The fusion transcript most likely encodes a truncated HSPBAP1 protein starting from a internal initiation side embedded in a strong Kozak consensus sequence. Description The gene spans 3071 bp and contains 12 exons. The last exon contains a consensus polyadenylation site sequence (AGTAA) at 20 nt upstream up 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. 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). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 3 DIRC3 disrupted in renal carcinoma 3 Bonné A et al. References This article should be referenced as such: Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPMG, Geurts van Kessel A. DIRC3 (disrupted in renal carcinoma 3). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):3-4. Bodmer D, Schepens M, Eleveld MJ, Schoenmakers EF, Geurts van Kessel A. 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). Genes Chromosomes Cancer. 2003 Oct;38(2):107-16 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 4 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1) Franck Viguié Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex 04, France (FV) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/RAP1GDS1ID400.html DOI: 10.4267/2042/38038 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology proliferation, transformation. Identity Other names: RAP1; GTP-GDP stimulator 1 HGNC (Hugo): RAP1GDS1 Location: 4q22.3 dissociation and oncogenic Homology With other mammalian rap1gds1 proteins. Implicated in DNA/RNA t(4;11)(q21;p15) Disease T cell acute lymphocytic leukemia Cytogenetics Additional anomalies in 2/3 cases. Hybrid/Mutated gene Quasi totality of RAP1GDS1 fused with 5' part of NUP98. Abnormal protein Chimeric protein 5' -NUP98 - RAP1GDS1 - 3'. 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. References de Mazancourt P, Goldsmith PK, Weinstein LS. Inhibition of adenylate cyclase activity by galanin in rat insulinoma cells is mediated by the G-protein Gi3. Biochem J. 1994 Oct 15;303 ( Pt 2):369-75 Expression Ubiquitary, high level of expression in central nervous system. Hussey DJ, Nicola M, Moore S, Peters GB, Dobrovic A. The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood. 1999 Sep 15;94(6):2072-9 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 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) differentiation 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, Foà 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 Jun;109(4):788-93 5 RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1) Viguié F Vikis HG, Stewart S, Guan KL. SmgGDS displays differential binding and exchange activity towards different Ras isoforms. Oncogene. 2002 Apr 4;21(15):2425-32 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) This article should be referenced as such: Viguié F. RAP1GDS1 (RAP1, GTP-GDP dissociation stimulator 1). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):5-6. 6 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review RET (REarranged during Transfection) Patricia Niccoli-Sire Service d'Endocrinologie, Diabète et Maladies Métaboliques, Hôpital de la Timone, 254, rue St Pierre, 13385 Marseille cedex 05, France (PNS) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/RETID76.html DOI: 10.4267/2042/38039 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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 phosphatidylinositollinked GRF_ receptors. Identity HGNC (Hugo): RET Location: 10q11.2 Note: proto-oncogene. Homology DNA/RNA General structure is similar to other tyrosine kinase receptors but RET differs by the presence of a cadherin domain in its extracellular region. Description 21 exons, 3415 pb. Transcription Mutations 3 mains alternative spliced mRNA in the 3' region. Germinal Protein 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. They are widely dispersed in 7/21 exons of RET with phenotype-genotype relationships: mutations in exon 11 are 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 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. 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. 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, Function RET is a tyrosine kinase receptor whose ligands are Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 7 RET (REarranged during Transfection) Niccoli-Sire P 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. Prognosis The prognosis of MEN2 and FMTC is related to MTC: it depends mainly on the histopathological stage of the MTC disease. References Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene. 1988 Nov;3(5):571-8 Ishizaka Y, Itoh F, Tahira T, Ikeda I, Sugimura T, Tucker J, Fertitta A, Carrano AV, Nagao M. Human ret proto-oncogene mapped to chromosome 10q11.2. Oncogene. 1989 Dec;4(12):1519-21 Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993 Jun 3;363(6428):458-60 Implicated in Multiple Endocrine Neoplasia type 2 (MEN2), Hirschprung's disease (HSCR). Somatic rearranged forms of RET (RET/PTC) are detected in human papillary thyroid carcinoma. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fékété C, Ponder BA, Munnich A. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994 Jan 27;367(6461):378-80 Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener JW, van Amstel HK, Romeo G. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994 Jan 27;367(6461):375-6 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. 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 crestderived 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, Delbridge L, Eng C, Robinson BG. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf). 1996 Mar;44(3):24957 Bunone G, Uggeri M, Mondellini P, Pierotti MA, Bongarzone I. RET receptor expression in thyroid follicular epithelial cellderived tumors. Cancer Res. 2000 Jun 1;60(11):2845-9 Jhiang SM. The RET proto-oncogene in human cancers. Oncogene. 2000 Nov 20;19(49):5590-7 Manié S, Santoro M, Fusco A, Billaud M. The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet. 2001 Oct;17(10):580-9 Takahashi M. The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev. 2001 Dec;12(4):361-73 This article should be referenced as such: Niccoli-Sire P. RET (REarranged during Transfection). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):7-8. 8 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review ZFHX3 (zinc finger homeobox 3) Nadine Van Roy, Frank Speleman Center for Medical Genetics, Ghent University Hospital, 1K5, De Pintelaan 185, B-9000 Gent, Belgium (NV, FS) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/ATBF1ID357.html DOI: 10.4267/2042/38035 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Localisation Identity Nuclear. Other names: AT motif-binding factor 1; Alphafetoprotein enhancer binding protein HGNC (Hugo): ZFHX3 Location: 16q22.3-q23.1 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 Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Somatic DNA/RNA Two isoforms ATBF1-A and ATBF1-B, due to alternative promotor usage combined with alternative splicing, mRNA-size: 11893 bp. 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. Protein Implicated in Description Early neural crest derived cell line (SJNB-12) Description 10 exons, DNA size: 261.32 kb. Transcription 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. Prognosis Unknown. Cytogenetics Several structural and numerical chromosomal aberrations and presence of extrachromosomally double minutes and homogenously staining regions, presence of a reciprocal unbalanced t(8;16)(q24.3;q22.3). Expression Embryonic and neonatal brain. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 9 ZFHX3 (zinc finger homeobox 3) Van Roy N, Speleman F Kataoka H, Joh T, Miura Y, Tamaoki T, Senoo K, Ohara H, Nomura T, Tada T, Asai K, Kato T, Itoh M. AT motif binding factor 1-A (ATBF1-A) negatively regulates transcription of the aminopeptidase N gene in the crypt-villus axis of small intestine. Biochem Biophys Res Commun. 2000 Jan 7;267(1):91-5 Oncogenesis Amplification in one neural crest derived cell line (SJNB-12), non-syntenic co-amplification with MYC. Alpha-fetoprotein producing gastric cancer cell lines (GCIY and Ist-I) Kaushik N, Malaspina A, de Belleroche J. Characterization of trinucleotide- and tandem repeat-containing transcripts obtained from human spinal cord cDNA library by high-density filter hybridization. DNA Cell Biol. 2000 May;19(5):265-73 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. Sawada Y, Miura Y, Umeki K, Tamaoki T, Fujinaga K, Ohtaki S. Cloning and characterization of a novel RNA-binding protein SRL300 with RS domains. Biochim Biophys Acta. 2000 Jun 21;1492(1):191-5 Berry FB, Miura Y, Mihara K, Kaspar P, Sakata N, HashimotoTamaoki T, Tamaoki T. Positive and negative regulation of myogenic differentiation of C2C12 cells by isoforms of the multiple homeodomain zinc finger transcription factor ATBF1. J Biol Chem. 2001 Jul 6;276(27):25057-65 References Morinaga T, Yasuda H, Hashimoto T, Higashio K, Tamaoki T. A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers. Mol Cell Biol. 1991 Dec;11(12):6041-9 Kataoka H, Miura Y, Joh T, Seno K, Tada T, Tamaoki T, Nakabayashi H, Kawaguchi M, Asai K, Kato T, Itoh M. Alphafetoprotein producing gastric cancer lacks transcription factor ATBF1. Oncogene. 2001 Feb 15;20(7):869-73 Yasuda H, Mizuno A, Tamaoki T, Morinaga T. ATBF1, a multiple-homeodomain zinc finger protein, selectively downregulates AT-rich elements of the human alpha-fetoprotein gene. Mol Cell Biol. 1994 Feb;14(2):1395-401 Kawaguchi M, Miura Y, Ido A, Morinaga T, Sakata N, Oya T, Hashimoto-Tamaoki T, Sasahara M, Koizumi F, Tamaoki T. DNA/RNA-dependent ATPase activity is associated with ATBF1, a multiple homeodomain-zinc finger protein. Biochim Biophys Acta. 2001 Dec 17;1550(2):164-74 Miura Y, Tam T, Ido A, Morinaga T, Miki T, Hashimoto T, Tamaoki T. Cloning and characterization of an ATBF1 isoform that expresses in a neuronal differentiation-dependent manner. J Biol Chem. 1995 Nov 10;270(45):26840-8 Van Roy N, Van Limbergen H, Vandesompele J, Van Gele M, Poppe B, Salwen H, Laureys G, Manoel N, De Paepe A, Speleman F. Combined M-FISH and CGH analysis allows comprehensive description of genetic alterations in neuroblastoma cell lines. Genes Chromosomes Cancer. 2001 Oct;32(2):126-35 Scheidl TM, Miura Y, Yee HA, Tamaoki T. Automated fluorescent dye-terminator sequencing of G+C-rich tracts with the aid of dimethyl sulfoxide. Biotechniques. 1995 Nov;19(5):691-4 Li H, Huang CJ, Choo KB. Expression of homeobox genes in cervical cancer. Gynecol Oncol. 2002 Feb;84(2):216-21 Yamada K, Miura Y, Scheidl T, Yoshida MC, Tamaoki T. Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3-q23.1. Genomics. 1995 Sep 20;29(2):552-3 Ninomiya T, Mihara K, Fushimi K, Hayashi Y, HashimotoTamaoki T, Tamaoki T. Regulation of the alpha-fetoprotein gene by the isoforms of ATBF1 transcription factor in human hepatoma. Hepatology. 2002 Jan;35(1):82-7 Tamaoki T, Hashimoto T. [ZFH/ATBF1 gene family: transcription factors containing both homeo- and zinc fingerdomains]. Tanpakushitsu Kakusan Koso. 1996 Sep;41(11):1550-9 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. ATBF1-A protein, but not ATBF1-B, is preferentially expressed in developing rat brain. J Comp Neurol. 2003 Oct 6;465(1):57-71 Watanabe M, Miura Y, Ido A, Sakai M, Nishi S, Inoue Y, Hashimoto T, Tamaoki T. Developmental changes in expression of the ATBF1 transcription factor gene. Brain Res Mol Brain Res. 1996 Dec;42(2):344-9 This article should be referenced as such: Chen H, Egan JO, Chiu JF. Regulation and activities of alphafetoprotein. Crit Rev Eukaryot Gene Expr. 1997;7(1-2):11-41 Van Roy N, Speleman F. ZFHX3 (zinc finger homeobox 3). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):9-10. Kaspar P, Dvoráková M, Králová J, Pajer P, Kozmik Z, Dvorák M. Myb-interacting protein, ATBF1, represses transcriptional activity of Myb oncoprotein. J Biol Chem. 1999 May 14;274(20):14422-8 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 10 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review LPHN2 (latrophilin 2) Jim Heighway Roy Castle International Centre for Lung Cancer Research, Liverpool, UK (JH) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/LPHH1ID313.html DOI: 10.4267/2042/38040 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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 390 kb from exon 1 which makes the total size of the gene at least 550 kb. Identity Other names: LPHH1; LEC1; KIAA0786 HGNC (Hugo): LPHN2 Location: 1p31.1 Local order: --ELTD1---LPHH1----FLJ23033---PRKACB-- 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. DNA/RNA 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 154 kb. However, the 5'end Pseudogene No known pseudogene. Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 11 LPHN2 (latrophilin 2) Heighway J 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. 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. 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 Gprotein/receptor interactions. Protein 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. Localisation Likely to be plasma membrane. Function Expression Likely role in coupling cell adhesion to cell signalling. Protein likely to be ubiquitously expressed in adherent Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 12 LPHN2 (latrophilin 2) Heighway J Note None reported. 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. Implicated in References Breast carcinoma Hayflick JS. A family of heptahelical receptors with adhesionlike domains: a marriage between two super families. J Recept Signal Transduct Res. 2000 May-Aug;20(2-3):119-31 Homology Latrophilin 2 is part of a small sub-family of 7 TMs which includes latrophilins 1 and 3. Latrophilin 1 is the receptor for Black Widow spider toxin: -latrotoxin. Mutations 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. White GR, Varley JM, Heighway J. Genomic structure and expression profile of LPHH1, a 7TM gene variably expressed in breast cancer cell lines. Biochim Biophys Acta. 2000 Apr 25;1491(1-3):75-92 Lung carcinoma This article should be referenced as such: Note Heighway J. LPHN2 (latrophilin 2). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):11-13. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 13 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review MNX1 (motor neuron and pancreas homeobox 1) Anne RM von Bergh, H Berna Beverloo Department of Clinical Genetics, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands (ARMVB, HBB) Published in Atlas Database: December 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/HLXB9ID393.html DOI: 10.4267/2042/38041 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Function Identity Putative transcription factor. Other names: HLXB9 (homeo box HB9); HB9; HOXHB9; SCRA1; Mnr1 HGNC (Hugo): MNX1 Location: 7q36.3 Note: Telomeric to c7orf3 and SHH. Homology Related to Mnr2. Mutations Note Mutations in HLXB9 cause an autosomal dominant form of sacral agenesis, known as Currarino syndrome. DNA/RNA Description Implicated in 3 exons stretched over an area of 5-6 kb. Transcription t(7;12)(q36;p13) – associated infant acute myeloid leukemia (AML) In a telomere to centromere direction; 2061 bp mRNA, 1206 bp open reading frame. 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). Hybrid/Mutated gene 5' HLXB9 _ 3' ETV6 Abnormal protein N-term HLXB9, including its polyalanine repeat, is fused to a large C-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. 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 14 MNX1 (homeo box HB9) von Bergh ARM, Beverloo HB 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. 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. A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat Genet. 1998 Dec;20(4):358-61 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. Beverloo HB, Panagopoulos I, Isaksson M, van Wering E, van Drunen E, de Klein A, Johansson B, Slater R. Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Cancer Res. 2001 Jul 15;61(14):5374-7 References This article should be referenced as such: Harrison KA, Druey KM, Deguchi Y, Tuscano JM, Kehrl JH. A novel human homeobox gene distantly related to proboscipedia is expressed in lymphoid and pancreatic tissues. J Biol Chem. 1994 Aug 5;269(31):19968-75 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) von Bergh ARM, Beverloo HB. MNX1 (motor neuron and pancreas homeobox 1). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):14-15. 15 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review SYNPO2 (synaptopodin 2) Jian-Hua Luo Gene Array Laboratory, Univeristy of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA (JHL) Published in Atlas Database: December 2003 Online updated version : http://AtlasGeneticsOncology.org/Genes/SYNPO2ID488.html DOI: 10.4267/2042/38042 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Pseudogene Identity Unknown. Other names: Myopodin; synaptopodin 2 HGNC (Hugo): SYNPO2 Location: 4q27 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. Protein Description A nuclear localization signal is identified in N-terminus region of myopodin. Myopodin also contains six stretches of homologous sequences with synaptopodin 1. Expression DNA/RNA Skeletal muscle, prostate, large and small intestine. Description Localisation The genome sequence of myopodin contains 6.8 Kb, while synaptopodin 2 38 kb. Nucleus, cytoplasm. Function Transcription Actin bundling. A typical messenger RNA of myopodin is 4.2-4.4 kb, and synaptopodin 2 6.7 kb. Homology Synaptopodin. Genome structure of myopodin and synaptopodin 2. Green represents exons of myopodin, and orange synaptopodin 2. Introns are indicated with lines. Protein structure of myopodin and synaptopodin 2. Orange represents sequence unique to synaptopodin 2, Green myopodin. Black stripe represents sequence homologous to synaptopodin 1. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 16 SYNPO2 (synaptopodin 2) Luo JH Mutations References Germinal Lin F, Yu YP, Woods J, Cieply K, Gooding B, Finkelstein P, Dhir R, Krill D, Becich MJ, Michalopoulos G, Finkelstein S, Luo JH. Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers. Am J Pathol. 2001 Nov;159(5):1603-12 Not known. Somatic Deletion. Weins A, Schwarz K, Faul C, Barisoni L, Linke WA, Mundel P. Differentiation- and stress-dependent nuclear cytoplasmic redistribution of myopodin, a novel actin-bundling protein. J Cell Biol. 2001 Oct 29;155(3):393-404 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Sanchez-Carbayo M, Schwarz K, Charytonowicz E, CordonCardo C, Mundel P. Tumor suppressor role for myopodin in bladder cancer: loss of nuclear expression of myopodin is cellcycle dependent and predicts clinical outcome. Oncogene. 2003 Aug 14;22(34):5298-305 This article should be referenced as such: Luo JH. SYNPO2 (synaptopodin 2). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):16-17. 17 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication 11p15 rearrangements leukemia in treatment related Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/11p15TreatRelLeukID1299.html DOI: 10.4267/2042/38043 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Prognosis Identity 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. 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. Cytogenetics Additional anomalies Clinics and pathology 11p15 rearrangements included inv(11)(p15q23) in 35% of cases, 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%. 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. Result of the chromosomal anomaly Epidemiology Hybrid gene 11p15 rearrangements were found in 3% of t-MDS/tANLL and have been reported to be found in 5% of childhood t-MDS/t-ANLL; sex ratio: 4M/13F. Description 5' NUP98 -3' partner. References Clinics Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K, Olney HJ, Baer MR. Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):401-12 Age at diagnosis of the primary disease 45 yrs (range 270); 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%. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) This article should be referenced as such: Huret JL. 11p15 rearrangements in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):18. 18 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication 12p13 rearrangements in treatment related leukemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/12p13TreatRelLeukID1301.html DOI: 10.4267/2042/38044 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Prognosis Identity Median survival was very poor: 4 mths, with 15% of patients surviving at 1 yr, and none at 2 yrs. 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. Cytogenetics Additional anomalies 12p13 rearrangements included: t(1;12)(q21;p13), t(4;12)(q12;p13), t(7;12)(p15;p13), t(8;12)(p12;p13), t(12;20)p13;q11), and t(12;22)(p13;q11) and other rearrangements. Complex karyotypes were found in 7 of 9 cases; -7/del(7q) and/or -5/del(5q) were found in 6 of 9 cases. 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. Result of the chromosomal anomaly Hybrid gene Description 5' ETV6 -3' partner where ETV6 is known to be involved. Epidemiology 12p13 rearrangements were found in 2% of t-MDS/tANLL; sex ratio: 5M/4F. References Clinics Block AW, et al. Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):401-12 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) This article should be referenced as such: Huret JL. 12p13 rearrangements in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):19. 19 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review 21q22 rearrangements leukemia in treatment related Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/21q22TreatRelLeukID1296.html DOI: 10.4267/2042/38045 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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). 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. 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 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. Phenotype/cell stem origin MDS cases were frequently refractory anemia with excess of blasts cases; 58% of ANLL cases were M2 ANLL. Etiology Frequent antracyclin exposure. Cytogenetics Epidemiology Cytogenetics morphological 21q22 rearrangements were found in 15% of t-MDS/tANLL; 1M to 1F sex ratio t(8;21)(q22;q22) (ETO / AML1) was found in 56% of cases, 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), Clinics Age at diagnosis of the primary disease was 47 yrs (range 2-75); age at diagnosis of the t-MDS/t- Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 20 21q22 rearrangements in treatment related leukemia Huret JL t(9;21)(p22;q22), t(10;21)(p12;q22), t(15;21)(q2122;q22), t(17;21)(q12;q22), and t(20;21)(q11;q22). Result of the chromosomal anomaly Additional anomalies -7/del(7q) in 23% of cases (espacially in cases with alkylating agents 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)). Hybrid gene Description 5' AML1 - 3' partner. References Genes involved and proteins Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):37994 AML1 partner This article should be referenced as such: Huret JL. 21q22 rearrangements in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):20-21. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 21 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review inv(16)(p13q22) in treatment related leukemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/inv16p13q22TreatRelID1297.html DOI: 10.4267/2042/38046 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics Identity Age at diagnosis of the primary disease 43 yrs (range 675); 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%. 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. 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. inv(16) diagram and FISH - Courtesy Hossein Mossafa; insert: first row: inv(16)(p13q22) G-banding - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services; second row: R- banding - Courtesy Hossein Mossafa. Clinics and pathology Disease Cytogenetics 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. Additional anomalies The inv(16) was found solely in 46% of cases; additional 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 Epidemiology Hybrid gene inv(16)(p13q22) was found in 9% of t-MDS/t-ANLL; sex ratio: 18M/30F. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Description 5'CBFB -3' MYH11. 22 inv(16)(p13q22) in treatment related leukemia Huret JL References an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):395-400 Andersen MK, Larson RA, Mauritzson N, Schnittger S, Jhanwar SC, Pedersen-Bjergaard J. Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from This article should be referenced as such: Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Huret JL. inv(16)(p13q22) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):22-23. 23 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review t(15;17)(q22;q21) in treatment related leukemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1517q22q21TreatRelID1298.html DOI: 10.4267/2042/38051 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. t(15;17)(q22;q21) (or t(15;17)(q24;q21), since PML sits in 15q24, and RARA in 17q21) Top: G-banding - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services; Bottom and right: R- banding and FISH - Courtesy Hossein Mossafa. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 24 t(15;17)(q22;q21) in treatment related leukemia Huret JL Clinics and pathology 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. 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. Cytogenetics Additional anomalies The t(15;17) was found solely in 59% of cases; additional anomalies were: +8 in 12% , -5/del(5q) in 5%, or -7/del(7q). Result of the chromosomal anomaly Epidemiology t(15;17)(q22;q21) was found in 8% of t-MDS/t-ANLL; sex ratio: 15M/26F. Hybrid gene Clinics Description 5' PML -3' RARA. 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: 9175). 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%. References Andersen MK, Larson RA, Mauritzson N, Schnittger S, Jhanwar SC, Pedersen-Bjergaard J. Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):395-400 Prognosis This article should be referenced as such: Median survival was 29 mths. Outcome was better than the outcome of patients with 11q23 rearrangement, 3q21q26 rearrangement, 12p13 Huret JL. t(15;17)(q22;q21) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):24-25. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 25 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(3;21)(q26;q22) in treatment related leukemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0321q26q22TreatRelID1294.html DOI: 10.4267/2042/38047 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. t(3;21)(q26;q22) G- banding - Courtesy Melanie Zenger and Claudia Haferlach. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 26 t(3;21)(q26;q22) in treatment related leukemia Huret JL or inv(16) treatment related leukemias, and similar to the outcome of patients with 11q23 rearrangement. Clinics and pathology Disease Cytogenetics Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL). Additional anomalies The t(3;21) was found solely in 31% of cases; additional anomaly was: -7/del(7q) in 31% of cases, +8 was not observed. A complex karyotype was found in 25% of cases. 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 tANLL in cases with t(8;21)); no case of acute lymphoblastic leukaemia. Result of the chromosomal anomaly Epidemiology Hybrid gene t(3;21)(q26;q22) was found in 3% of t-MDS/t-ANLL; sex ratio: 5M/11F. Description 5' AML1 - 3' MDS1-EVI1; breakpoint is most often in the AML1 intron 6. 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: 17139). 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). References Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):37994 Prognosis This article should be referenced as such: Median survival was 8 mths. Outcome was worse than the outcome of patients with t(8;21)(q22;q22), t(15;17) Huret JL. t(3;21)(q26;q22) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):26-27. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 27 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(8;16)(p11;p13) in treatment related leukemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0816p11p13TreatRelID1302.html DOI: 10.4267/2042/38048 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology progression to ANLL accounted for 1 of 9 cases, and tANLL for the remaining 8 cases; no case of acute lymphoblastic leukaemia. 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. Epidemiology t(8;16)(p11;p13) was found in 2% of t-MDS/t-ANLL; sex ratio: 5M/4F. Clinics Age at diagnosis of the primary disease 33 yrs (range 670); age at diagnosis of the t-MDS/t-ANLL: 41 yrs (range 7-71). Median interval was 17 mths (range: 13202). Primary disease was a solid tumor in 9 of 9 cases; treatment was radiotherapy in 1 case, chemotherapy in 2 of 9 cases, or both (6/9). Treatment included topoisomerase II inhibitors in 6 of 8 cases and alkylating agents in 7/8. Prognosis Median survival was very poor: 5 mths, with 39% of patients surviving at 1 yr, and none at 2 yrs. Cytogenetics Additional anomalies Complex karyotypes were found in 4 of 9 cases. t(8;16)(p11;p13) G- banding - Courtesy Melanie Zenger and Claudia Haferlach. Result of the chromosomal anomaly Clinics and pathology Disease Hybrid gene Treatment related myelodysplasia (t-MDS) or acute non lymphocytic leukaemias (t-ANLL). Note The study included 9 cases; t-MDS with Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Description 5' MOZ -3' CBP 28 t(8;16)(p11;p13) in treatment related leukemia Huret JL References This article should be referenced as such: Huret JL. t(8;16)(p11;p13) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):28-29. Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K, Olney HJ, Baer MR. Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):401-12 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 29 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(8;21)(q22;q22) in treatment related leukemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0821q22q22TreatRelID1293.html DOI: 10.4267/2042/38049 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Prognosis 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. Median survival was 17 mths 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. Clinics and pathology Cytogenetics Disease Additional anomalies 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. The t(8;21) was found solely in 25% of cases; additional 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. Epidemiology Result of the chromosomal anomaly t(8;21)(q22;q22) was found in 9% of t-MDS/t-ANLL; 1M to 1F sex ratio. Hybrid gene Description 5' AML1 - 3' ETO; breakpoint is most often in the AML1 intron 5. Clinics Age at diagnosis of the primary disease 45 yrs (range 275); 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%). References Slovak ML, Bedell V, Popplewell L, Arber DA, Schoch C, Slater R. 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):37994 This article should be referenced as such: Huret JL. t(8;21)(q22;q22) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):30. Cytology Cell morphology was similar to those of de novo t(8;21). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 30 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(9;22)(q34;q11) in treatment related leukemia Jean-Loup Huret Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F86021 Poitiers, France (JLH) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0922q34q11TreatRelID1300.html DOI: 10.4267/2042/38050 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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. 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. Prognosis Median survival was very poor: 5 mths, with 14% of patients surviving at 1 yr, and none at 2 yrs. Clinics and pathology Cytogenetics Disease Additional anomalies Treatment related acute non lymphocytic leukaemias (tANLL) 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). Complex karyotypes were found in 6 of 10 cases. Result of the chromosomal anomaly Hybrid gene Description 5' BCR -3' ABL. Epidemiology References t(9;22)(q34;q11) was found in 2% of treatment related acute leukaemias; sex ratio: 2M/8F. Block AW, Carroll AJ, Hagemeijer A, Michaux L, van Lom K, Olney HJ, Baer MR. Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):401-12 Clinics Age at diagnosis of the primary disease 45 yrs (range 376); 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 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) This article should be referenced as such: Huret JL. t(9;22)(q34;q11) in treatment related leukemia. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):31. 31 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review Acute megakaryoblastic leukemia (AMegL) M7 acute non lymphocytic leukemia (M7-ANLL) Antonio Cuneo, Francesco Cavazzini, Gianluigi Castoldi Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC, FC) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/M7ANLLID1100.html DOI: 10.4267/2042/38052 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics Identity 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. Alias: AML-M7 Note: Sometimes presenting as "acute myelofibrosis" Clinics and pathology Phenotype/cell stem origin This leukemia is thought to derive from the transformation of a multipotent myeloid progenitor cell. In the adult patient multilineage 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. 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 not specific for 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. Epidemiology Treatment 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. Myeloablative treatment followed, whenever possible, by allogeneic or autologous bone marrow transplant is the treatment of choice. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Prognosis In general, the prognosis is severe. 30-to-50 % of the adult patients achieve a complete morphologic 32 Acute megakaryoblastic leukemia (AMegL), M7 acute non lymphocytic leukemia (M7-ANLL) 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. Cuneo A et al. Result of the chromosomal anomaly Hybrid gene Note The fusion gene OTT-MAL is on the der(22) chromosome and contains almost all of the sequences of each gene. Cytogenetics Cytogenetics morphological References a) Adults 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. Breton-Gorius J, Reyes F, Duhamel G, Najman A, Gorin NC. Megakaryoblastic acute leukemia: identification by the ultrastructural demonstration of platelet peroxidase. Blood. 1978 Jan;51(1):45-60 Zipursky A, Peeters M, Poon A. Megakaryoblastic leukemia and Down's syndrome: a review. Pediatr Hematol Oncol. 1987;4(3):211-30 San Miguel JF, Gonzalez M, Cañizo MC, Ojeda E, Orfao A, Caballero MD, Moro MJ, Fisac P, Lopez Borrasca A. Leukemias with megakaryoblastic involvement: clinical, hematologic, and immunologic characteristics. Blood. 1988 Aug;72(2):402-7 Cuneo A, Mecucci C, Kerim S, Vandenberghe E, Dal Cin P, Van Orshoven A, Rodhain J, Bosly A, Michaux JL, Martiat P. Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients. Blood. 1989 Oct;74(5):1781-90 Tallman MS, Neuberg D, Bennett JM, Francois CJ, Paietta E, Wiernik PH, Dewald G, Cassileth PA, Oken MM, Rowe JM. Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Blood. 2000 Oct 1;96(7):2405-11 Alvarez S, MacGrogan D, Calasanz MJ, Nimer SD, Jhanwar SC. Frequent gain of chromosome 19 in megakaryoblastic leukemias detected by comparative genomic hybridization. Genes Chromosomes Cancer. 2001 Nov;32(3):285-93 Cytogenetics molecular 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. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet. 2001 Jul;28(3):220-1 Partial trisomy 19, involving the q13 band, can be shown to occur at a 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. Mercher T, Coniat MB, Monni R, Mauchauffe M, Nguyen Khac F, Gressin L, Mugneret F, Leblanc T, Dastugue N, Berger R, Bernard OA. Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5776-9 Genes involved and proteins Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Léonard C, BilhouNabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R. Cytogenetic profile OTT (one twenty-two) or RBM15 (Rnabinding motif protein 15) Location 1p13 of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood. 2002 Jul 15;100(2):618-26 MAL (Megakaryocytic acute leukemia) or MLK1 (megakaryoblastic leukemia-1) Dastugue N, Lafage-Pochitaloff M, Pagès MP, Radford I, Bastard C, Talmant P, Mozziconacci MJ, Léonard C, BilhouNabéra C, Cabrol C, Capodano AM, Cornillet-Lefebvre P, Location 22q13 Lessard M, Mugneret F, Pérot C, Taviaux S, Fenneteaux O, Duchayne E, Berger R. Cytogenetic profile of childhood and Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 33 Acute megakaryoblastic leukemia (AMegL), M7 acute non lymphocytic leukemia (M7-ANLL) adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood. 2002 Jul 15;100(2):618-26 and childhood cases by the Groupe Français d'Hématologie Cellulaire (GFHC). Leuk Lymphoma. 2003 Jan;44(1):49-58 This article should be referenced as such: Nimer SD, MacGrogan D, Jhanwar S, Alvarez S. Chromosome 19 abnormalities are commonly seen in AML, M7. Blood. 2002 Nov 15;100(10):3838; author reply 3838-9 Cuneo A, Cavazzini F, Castoldi GL. Acute megakaryoblastic leukemia (AMegL), M7 acute non lymphocytic leukemia (M7ANLL). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):3234. Duchayne E, Fenneteau O, Pages MP, Sainty D, Arnoulet C, Dastugue N, Garand R, Flandrin G. Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Cuneo A et al. 34 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review Refractory anemia (RA) Antonio Cuneo, Gianluigi Castoldi Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC, GC) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/RAID1104.html DOI: 10.4267/2042/38054 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology In the WHO classification RA shows anemia, no or rare blasts in the peripheral blood, isolated erythroid 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. 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. Cytology Clinics and pathology Pathology Phenotype/cell stem origin 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. 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). RA is a clonal disorder originating from a totipotent stem cell or from a multipotent myeloid progenitor cell, characterized by ineffective hemopoiesis and diserythropoiesis. Treatment Epidemiology 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. 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. 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. 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 35 Refractory anemia (RA) Cuneo A, Castoldi GL Prognosis References 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. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982 Jun;51(2):189-99 Gattermann N, Aul C, Schneider W. Two types of acquired idiopathic sideroblastic anaemia (AISA) Br J Haematol. 1990 Jan;74(1):45-52 Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J, Callat MP, Accard F, Chaperon J. Prognostic factors of myelodysplastic syndromes--a simplified 3-D scoring system. Leuk Res. 1990;14(3):255-62 Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H, Hirashima K, Hotta T, Kuramoto A, Kuriya S. Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Leukemia. 1993 Apr;7(4):499-508 Maschek H, Gutzmer R, Choritz H, Georgii A. Life expectancy in primary myelodysplastic syndromes: a prognostic score based upon histopathology from bone marrow biopsies of 569 patients. Eur J Haematol. 1994 Nov;53(5):280-7 Cytogenetics Cytogenetics morphological 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. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88 There is no specific chromosome marker for patients with RA, 70 to 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci C, Morra E, Saglio G, Visani G, Tura S. Myelodysplastic syndromes: recent advances. Haematologica. 2001 Nov;86(11):1124-57 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. Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Leukemia. 2001 Dec;15(12):1841-7 Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002 Oct 1;100(7):2292-302 This article should be referenced as such: Cuneo A, Castoldi GL. Refractory anemia (RA). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):35-36. 36 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review Refractory anemia with excess blasts (RAEB) Antonio Cuneo, Gianluigi Castoldi Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC, GC) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/RAEBID1105.html DOI: 10.4267/2042/38053 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics Identity 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. Alias: RAEB-1 and RAEB-2 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. 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. Micromegakaryocytes, large mononuclear forms and multiple separated nuclei are major signs of dysmegakaryocytopoiesis. Clinics and pathology Phenotype/cell stem origin RAEB is a clonal disorder originating from a totipotent stem cell or from a multipotent myeloid progenitor cell, characterized by ineffective hemopoiesis and diserythropoiesis. The blast cells present in the BM are usually CD34+ and express myeloid markers (i.e. CD33 and/or CD13). Pathology Epidemiology Treatment 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. 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 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 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. 37 Refractory anemia with excess blasts (RAEB) Cuneo A, Castoldi GL recurrent structural anomalies which can also be found in acute myeloid leukemia include: 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. 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 patients 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). References Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982 Jun;51(2):189-99 Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J, Callat MP, Accard F, Chaperon J. Prognostic factors of myelodysplastic syndromes--a simplified 3-D scoring system. Leuk Res. 1990;14(3):255-62 Prognosis Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H, Hirashima K, Hotta T, Kuramoto A, Kuriya S. Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Leukemia. 1993 Apr;7(4):499-508 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. Maschek H, Gutzmer R, Choritz H, Georgii A. Life expectancy in primary myelodysplastic syndromes: a prognostic score based upon histopathology from bone marrow biopsies of 569 patients. Eur J Haematol. 1994 Nov;53(5):280-7 Cytogenetics Lai JL, Preudhomme C, Zandecki M, Flactif M, Vanrumbeke M, Lepelley P, Wattel E, Fenaux P. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations. Leukemia. 1995 Mar;9(3):370-81 Cytogenetics morphological Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic syndromes. Semin Hematol. 1996 Apr;33(2):127-38 There is no specific chromosome marker for patients with RAEB, up to 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 elderly males. Rare Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 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. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88 Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci C, Morra E, Saglio G, Visani G, Tura S. Myelodysplastic syndromes: recent advances. Haematologica. 2001 Nov;86(11):1124-57 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. Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Leukemia. 2001 Dec;15(12):1841-7 Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002 Oct 1;100(7):2292-302 This article should be referenced as such: Cuneo A, Castoldi GL. Refractory anemia with excess blasts (RAEB). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):37-38. 38 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review Refractory (RARS) anemia with ringed sideroblasts Antonio Cuneo, Gianluigi Castoldi Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC, GC) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/RARSID1106.html DOI: 10.4267/2042/38055 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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 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. 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 (RCMDRS), 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. Cytology RARS is a clonal disorder originating from a totipotent stem cell or from a multipotent myeloid progenitor cell, characterized by ineffective hemopoiesis and diserythropoiesis. 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 ferric form (Fe3+) in the matrix. Epidemiology Pathology 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. 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. Clinics and pathology Phenotype/cell stem origin 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. Clinics RARS usually presents with hypercellular bone marrow (BM) and anemia. There may be leukopenia and/or and Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 39 Refractory anemia with ringed sideroblasts (RARS) Cuneo A, Castoldi GL Gattermann N, Aul C, Schneider W. Two types of acquired idiopathic sideroblastic anaemia (AISA) Br J Haematol. 1990 Jan;74(1):45-52 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. Goasguen JE, Garand R, Bizet M, Bremond JL, Gardais J, Callat MP, Accard F, Chaperon J. Prognostic factors of myelodysplastic syndromes--a simplified 3-D scoring system. Leuk Res. 1990;14(3):255-62 Toyama K, Ohyashiki K, Yoshida Y, Abe T, Asano S, Hirai H, Hirashima K, Hotta T, Kuramoto A, Kuriya S. Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan. Leukemia. 1993 Apr;7(4):499-508 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 20qisolated; 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. Wattel E, Laï JL, Hebbar M, Preudhomme C, Grahek D, Morel P, Bauters F, Fenaux P. De novo myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 20: a subtype of MDS with distinct hematological and prognostic features? Leuk Res. 1993 Nov;17(11):921-6 Maschek H, Gutzmer R, Choritz H, Georgii A. Life expectancy in primary myelodysplastic syndromes: a prognostic score based upon histopathology from bone marrow biopsies of 569 patients. Eur J Haematol. 1994 Nov;53(5):280-7 Fenaux P, Morel P, Lai JL. Cytogenetics of myelodysplastic syndromes. Semin Hematol. 1996 Apr;33(2):127-38 Cytogenetics 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. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88 Cytogenetics morphological There is no specific chromosome marker for patients with RARS, 70 to 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 clonal aberrations. A chromosome 11q 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. Alessandrino EP, Amadori S, Cazzola M, Locatelli F, Mecucci C, Morra E, Saglio G, Visani G, Tura S. Myelodysplastic syndromes: recent advances. Haematologica. 2001 Nov;86(11):1124-57 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. Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype. Leukemia. 2001 Dec;15(12):1841-7 Greenberg P, Young N, Gattermann N. Myelodysplastic syndromes. ASH Education Program Book. Philadelphia, Pennsylvania. December 6-10, 2002 Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002 Oct 1;100(7):2292-302 References This article should be referenced as such: Cuneo A, Castoldi GL. Refractory anemia with ringed sideroblasts (RARS). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):39-40. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982 Jun;51(2):189-99 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 40 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Review Bladder: Urothelial carcinomas Angela van Tilborg, Bas van Rhijn Department of Pathology, Josephine Nefkens Institute, Erasmus University, 3000 DR Rotterdam, The Netherlands (AVT, BVR) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Tumors/blad5001.html DOI: 10.4267/2042/38056 This article is an update of: Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol Haematol.2000;4(4):212-217. Huret JL, Léonard C. Bladder: Transitional cell carcinoma. Atlas Genet Cytogenet Oncol Haematol.1999;3(4):205-206. Huret JL, Léonard C. Bladder cancer. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):32-33. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Bladder cancer : gross pathology : the bladder wall is massively infiltered by an ulcerated and hemorragic tumor. Courtesy Pierre Bedossa. Classification Clinics and pathology Histologic types: Urothelial carcinoma of the bladder, herein described, Squamous cell carcinoma, Adenocarcinoma (2%), rare, Poorly differenciated carcinoma/small cell carcinoma, exceptional. Disease Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 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 41 Bladder: Urothelial carcinomas van Tilborg AA, van Rhijn BW Staging – Editor. squamous 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. 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). Clinics Hematuria, irritation. 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. Cytogenetics Cytogenetics Morphological Karyotype 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. Treatment Resection (more or less extensive: electrofulguration -> cystectomy); chemo and/or radiotherapy, BCGtherapy. 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 3 yrs) 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 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 42 Bladder: Urothelial carcinomas van Tilborg AA, van Rhijn BW 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 3p24.225), 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. 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 hotspot 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% 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Cytogenetics Molecular (Matrix) CGH 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 FGFR3 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 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 43 Bladder: Urothelial carcinomas van Tilborg AA, van Rhijn BW gains in bladder cancer detected by fluorescence in situ hybridization. Am J Pathol. 1995 May;146(5):1131-9 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. Sauter G, Moch H, Carroll P, Kerschmann R, Mihatsch MJ, Waldman FM. Chromosome-9 loss detected by fluorescence in situ hybridization in bladder cancer. Int J Cancer. 1995 Apr 21;64(2):99-103 TP53 Sauter G, Moch H, Wagner U, Novotna H, Gasser TC, Mattarelli G, Mihatsch MJ, Waldman FM. Y chromosome loss detected by FISH in bladder cancer. Cancer Genet Cytogenet. 1995 Jul 15;82(2):163-9 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. Shackney SE, Berg G, Simon SR, Cohen J, Amina S, Pommersheim W, Yakulis R, Wang S, Uhl M, Smith CA. Origins and clinical implications of aneuploidy in early bladder cancer. Cytometry. 1995 Dec 15;22(4):307-16 HRAS Note HRAS mutations are found in approximately 15% of cases. Tanaka M, Müllauer L, Ogiso Y, Fujita H, Moriya S, Furuuchi K, Harabayashi T, Shinohara N, Koyanagi T, Kuzumaki N. Gelsolin: a candidate for suppressor of human bladder cancer. Cancer Res. 1995 Aug 1;55(15):3228-32 References Voorter C, Joos S, Bringuier PP, Vallinga M, Poddighe P, Schalken J, du Manoir S, Ramaekers F, Lichter P, Hopman A. Detection of chromosomal imbalances in transitional cell carcinoma of the bladder by comparative genomic hybridization. Am J Pathol. 1995 Jun;146(6):1341-54 Elder PA, Bell SM, Knowles MA. Deletion of two regions on chromosome 4 in bladder carcinoma: definition of a critical 750kB region at 4p16.3. Oncogene. 1994 Dec;9(12):3433-6 Mao L, Schoenberg MP, Scicchitano M, Erozan YS, Merlo A, Schwab D, Sidransky D. Molecular detection of primary bladder cancer by microsatellite analysis. Science. 1996 Feb 2;271(5249):659-62 Herr HW. Uncertainty, stage and outcome of invasive bladder cancer. J Urol. 1994 Aug;152(2 Pt 1):401-2 Sandberg AA, Berger CS. Review of chromosome studies in urological tumors. II. Cytogenetics and molecular genetics of bladder cancer. J Urol. 1994 Mar;151(3):545-60 Saran KK, Gould D, Godec CJ, Verma RS. Genetics of bladder cancer. J Mol Med. 1996 Aug;74(8):441-5 Spruck CH 3rd, Ohneseit PF, Gonzalez-Zulueta M, Esrig D, Miyao N, Tsai YC, Lerner SP, Schmütte C, Yang AS, Cote R. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res. 1994 Feb 1;54(3):784-8 Simoneau AR, Spruck CH 3rd, Gonzalez-Zulueta M, Gonzalgo ML, Chan MF, Tsai YC, Dean M, Steven K, Horn T, Jones PA. 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. Cancer Res. 1996 Nov 1;56(21):5039-43 Wang MR, Perissel B, Taillandier J, Kémény JL, Fonck Y, Lautier A, Benkhalifa M, Malet P. Nonrandom changes of chromosome 10 in bladder cancer. Detection by FISH to interphase nuclei. Cancer Genet Cytogenet. 1994 Mar;73(1):810 Stadler WM, Olopade OI. The 9p21 region in bladder cancer cell lines: large homozygous deletion inactivate the CDKN2, CDKN2B and MTAP genes. Urol Res. 1996;24(4):239-44 Chang WY, Cairns P, Schoenberg MP, Polascik TJ, Sidransky D. Novel suppressor loci on chromosome 14q in primary bladder cancer. Cancer Res. 1995 Aug 1;55(15):3246-9 Takle LA, Knowles MA. Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer. Oncogene. 1996 Mar 7;12(5):1083-7 Droller MJ. New efforts to stage bladder cancer. J Urol. 1995 Aug;154(2 Pt 1):385-6 Voorter CE, Ummelen MI, Ramaekers FS, Hopman AH. Loss of chromosome 11 and 11 p/q imbalances in bladder cancer detected by fluorescence in situ hybridization. Int J Cancer. 1996 Jan 26;65(3):301-7 Kallioniemi A, Kallioniemi OP, Citro G, Sauter G, DeVries S, Kerschmann R, Caroll P, Waldman F. Identification of gains and losses of DNA sequences in primary bladder cancer by comparative genomic hybridization. Genes Chromosomes Cancer. 1995 Mar;12(3):213-9 Cappellen D, Gil Diez de Medina S, Chopin D, Thiery JP, Radvanyi F. Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Oncogene. 1997 Jun 26;14(25):3059-66 Nemoto R, Nakamura I, Uchida K, Harada M. Numerical chromosome aberrations in bladder cancer detected by in situ hybridization. Br J Urol. 1995 Apr;75(4):470-6 Chaturvedi V, Li L, Hodges S, Johnston D, Ro JY, Logothetis C, von Eschenbach AC, Batsakis JG, Czerniak B. Superimposed histologic and genetic mapping of chromosome 17 alterations in human urinary bladder neoplasia. Oncogene. 1997 May 1;14(17):2059-70 Orlow I, Lacombe L, Hannon GJ, Serrano M, Pellicer I, Dalbagni G, Reuter VE, Zhang ZF, Beach D, Cordon-Cardo C. Deletion of the p16 and p15 genes in human bladder tumors. J Natl Cancer Inst. 1995 Oct 18;87(20):1524-9 Gibas Z, Gibas L. Cytogenetics of bladder cancer. Cancer Genet Cytogenet. 1997 May;95(1):108-15 Sarkis AS, Bajorin DF, Reuter VE, Herr HW, Netto G, Zhang ZF, Schultz PK, Cordon-Cardo C, Scher HI. Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol. 1995 Jun;13(6):1384-90 Habuchi T, Yoshida O, Knowles MA. A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC. Hum Mol Genet. 1997 Jun;6(6):913-9 Sauter G, Carroll P, Moch H, Kallioniemi A, Kerschmann R, Narayan P, Mihatsch MJ, Waldman FM. c-myc copy number Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Richter J, Jiang F, Görög JP, Sartorius G, Egenter C, Gasser TC, Moch H, Mihatsch MJ, Sauter G. Marked genetic 44 Bladder: Urothelial carcinomas van Tilborg AA, van Rhijn BW differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res. 1997 Jul 15;57(14):2860-4 Aveyard JS, Skilleter A, Habuchi T, Knowles MA. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer. 1999 May;80(5-6):904-8 Wagner U, Bubendorf L, Gasser TC, Moch H, Görög JP, Richter J, Mihatsch MJ, Waldman FM, Sauter G. Chromosome 8p deletions are associated with invasive tumor growth in urinary bladder cancer. Am J Pathol. 1997 Sep;151(3):753-9 Baud E, Catilina P, Bignon YJ. p16 involvement in primary bladder tumors: analysis of deletions and mutations. Int J Oncol. 1999 Mar;14(3):441-5 Benedict WF, Lerner SP, Zhou J, Shen X, Tokunaga H, Czerniak B. Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. Oncogene. 1999 Feb 4;18(5):1197-203 Bartlett JM, Watters AD, Ballantyne SA, Going JJ, Grigor KM, Cooke TG. Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder? Br J Cancer. 1998 Jun;77(12):2193-8 Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999 Sep;23(1):18-20 Baud E, Catilina P, Boiteux JP, Bignon YJ. Human bladder cancers and normal bladder mucosa present the same hot spot of heterozygous chromosome-9 deletion. Int J Cancer. 1998 Sep 11;77(6):821-4 Chi SG, Chang SG, Lee SJ, Lee CH, Kim JI, Park JH. Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer. Cancer Res. 1999 Jun 15;59(12):27913 Bruch J, Wöhr G, Hautmann R, Mattfeldt T, Brüderlein S, Möller P, Sauter S, Hameister H, Vogel W, Paiss T. Chromosomal changes during progression of transitional cell carcinoma of the bladder and delineation of the amplified interval on chromosome arm 8q. Genes Chromosomes Cancer. 1998 Oct;23(2):167-74 Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman JG, Bose S, Wang SI, Parsons R, Sidransky D. Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene. 1998 Jun 18;16(24):3215-8 Czerniak B, Chaturvedi V, Li L, Hodges S, Johnston D, Roy JY, Luthra R, Logothetis C, Von Eschenbach AC, Grossman HB, Benedict WF, Batsakis JG. Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer. Oncogene. 1999 Feb 4;18(5):1185-96 Erbersdobler A, Friedrich MG, Schwaibold H, Henke RP, Huland H. Microsatellite alterations at chromosomes 9p, 13q, and 17p in nonmuscle-invasive transitional cell carcinomas of the urinary bladder. Oncol Res. 1998;10(8):415-20 Herr HW, Bajorin DF, Scher HI, Cordon-Cardo C, Reuter VE. Can p53 help select patients with invasive bladder cancer for bladder preservation? J Urol. 1999 Jan;161(1):20-2; discussion 22-3 Halachmi S, Madjar S, Moskovitz B, Nativ O. Genetic alterations in bladder cancer. Cancer J. 1998;11:86-8. Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T, Knowles MA. Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene. 1999 Apr 22;18(16):2657-61 Hovey RM, Chu L, Balazs M, DeVries S, Moore D, Sauter G, Carroll PR, Waldman FM. Genetic alterations in primary bladder cancers and their metastases. Cancer Res. 1998 Aug 15;58(16):3555-60 Junker K, Werner W, Mueller C, Ebert W, Schubert J, Claussen U. Interphase cytogenetic diagnosis of bladder cancer on cells from urine and bladder washing. Int J Oncol. 1999 Feb;14(2):309-13 Kavaler E, Landman J, Chang Y, Droller MJ, Liu BC. Detecting human bladder carcinoma cells in voided urine samples by assaying for the presence of telomerase activity. Cancer. 1998 Feb 15;82(4):708-14 Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK. Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. Cancer Genet Cytogenet. 1999 Apr 15;110(2):87-93 Simon R, Bürger H, Brinkschmidt C, Böcker W, Hertle L, Terpe HJ. Chromosomal aberrations associated with invasion in papillary superficial bladder cancer. J Pathol. 1998 Aug;185(4):345-51 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. Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res. 1999 Jul 1;59(13):3068-72 Tsutsumi M, Tsai YC, Gonzalgo ML, Nichols PW, Jones PA. Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer. Oncogene. 1998 Dec 10;17(23):3021-7 Mahdy E, Yoshihiro S, Zech L, Wester K, Pan Y, Busch C, Döhner H, Kallioniemi O, Bergerheim U, Malmström PU. Comparison of comparative genomic hybridization, fluorescence in situ hybridization and flow cytometry in urinary bladder cancer. Anticancer Res. 1999 Jan-Feb;19(1A):7-12 Van Tilborg AA, Hekman AC, Vissers KJ, van der Kwast TH, Zwarthoff EC. 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. Int J Cancer. 1998 Jan 5;75(1):9-14 Neuhaus M, Wagner U, Schmid U, Ackermann D, Zellweger T, Maurer R, Alund G, Knönagel H, Rist M, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Polysomies but not Y chromosome losses have prognostic significance in pTa/pT1 urinary bladder cancer. Hum Pathol. 1999 Jan;30(1):81-6 Aaltonen V, Boström PJ, Söderström KO, Hirvonen O, Tuukkanen J, Nurmi M, Laato M, Peltonen J. Urinary bladder transitional cell carcinogenesis is associated with downregulation of NF1 tumor suppressor gene in vivo and in vitro. Am J Pathol. 1999 Mar;154(3):755-65 Ohgaki K, Iida A, Ogawa O, Kubota Y, Akimoto M, Emi M. Localization of tumor suppressor gene associated with distant metastasis of urinary bladder cancer to a 1-Mb interval on 8p22. Genes Chromosomes Cancer. 1999 May;25(1):1-5 Adshead JM, Ogden CW, Penny MA, Stuart ET, Kessling AM. The expression of PAX5 in human transitional cell carcinoma of the bladder: relationship with de-differentiation. BJU Int. 1999 Jun;83(9):1039-44 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Pycha A, Mian C, Hofbauer J, Brössner C, Haitel A, Wiener H, Marberger M. Multifocality of transitional cell carcinoma results 45 Bladder: Urothelial carcinomas van Tilborg AA, van Rhijn BW from genetic instability of entire transitional epithelium. Urology. 1999 Jan;53(1):92-7 multifocal bladder cancer. Eur J Cancer. 2000 Jul;36(11):144151 Richter J, Wagner U, Schraml P, Maurer R, Alund G, Knönagel H, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res. 1999 Nov 15;59(22):5687-91 Muscheck M, Sükösd F, Pesti T, Kovacs G. High density deletion mapping of bladder cancer localizes the putative tumor suppressor gene between loci D8S504 and D8S264 at chromosome 8p23.3. Lab Invest. 2000 Jul;80(7):1089-93 Salem C, Liang G, Tsai YC, Coulter J, Knowles MA, Feng AC, Groshen S, Nichols PW, Jones PA. Progressive increases in de novo methylation of CpG islands in bladder cancer. Cancer Res. 2000 May 1;60(9):2473-6 Simoneau M, Aboulkassim TO, LaRue H, Rousseau F, Fradet Y. Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31. Oncogene. 1999 Jan 7;18(1):157-63 van Tilborg AA, de Vries A, de Bont M, Groenfeld LE, van der Kwast TH, Zwarthoff EC. Molecular evolution of multiple recurrent cancers of the bladder. Hum Mol Genet. 2000 Dec 12;9(20):2973-80 Stacey M, Matas N, Drake M, Payton M, Fakis G, Greenland J, Sim E. 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. Genes Chromosomes Cancer. 1999 Aug;25(4):376-83 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. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol. 2001 Jun;158(6):1955-9 Thygesen P, Risch A, Stacey M, Fakis G, Giannoulis F, Takle L, Knowles M, Sim E. Genes for human arylamine Nacetyltransferases in relation to loss of the short arm of chromosome 8 in bladder cancer. Pharmacogenetics. 1999 Feb;9(1):1-8 Le Frère-Belda MA, Cappellen D, Daher A, Gil-Diez-de-Medina S, Besse F, Abbou CC, Thiery JP, Zafrani ES, Chopin DK, Radvanyi F. p15(INK4b) in bladder carcinomas: decreased expression in superficial tumours. Br J Cancer. 2001 Nov 16;85(10):1515-21 van Tilborg AA, Groenfeld LE, van der Kwast TH, Zwarthoff EC. 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. Br J Cancer. 1999 May;80(3-4):489-94 van Rhijn BW, Lurkin I, Radvanyi F, Kirkels WJ, van der Kwast TH, Zwarthoff EC. The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Res. 2001 Feb 15;61(4):1265-8 Yokomizo A, Mai M, Tindall DJ, Cheng L, Bostwick DG, Naito S, Smith DI, Liu W. Overexpression of the wild type p73 gene in human bladder cancer. Oncogene. 1999 Feb 25;18(8):162933 Zhao J, Richter J, Wagner U, Roth B, Schraml P, Zellweger T, Ackermann D, Schmid U, Moch H, Mihatsch MJ, Gasser TC, Sauter G. Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Cancer Res. 1999 Sep 15;59(18):4658-61 van Tilborg AA, de Vries A, Zwarthoff EC. The chromosome 9q genes TGFBR1, TSC1, and ZNF189 are rarely mutated in bladder cancer. J Pathol. 2001 May;194(1):76-80 Ørntoft TF, Thykjaer T, Waldman FM, Wolf H, Celis JE. Genome-wide study of gene copy numbers, transcripts, and protein levels in pairs of non-invasive and invasive human transitional cell carcinomas. Mol Cell Proteomics. 2002 Jan;1(1):37-45 Awata S, Sakagami H, Tozawa K, Sasaki S, Ueda K, Kohri K. Aberration of chromosomes 8 and 11 in bladder cancer as detected by fluorescence in situ hybridization. Urol Res. 2000 Jun;28(3):185-90 van Rhijn BW, Montironi R, Zwarthoff EC, Jöbsis AC, van der Kwast TH. Frequent FGFR3 mutations in urothelial papilloma. J Pathol. 2002 Oct;198(2):245-51 Böhm M, Kleine-Besten R, Wieland I. Loss of heterozygosity analysis on chromosome 5p defines 5p13-12 as the critical region involved in tumor progression of bladder carcinomas. Int J Cancer. 2000 Mar 20;89(2):194-7 van Rhijn BW, van Tilborg AA, Lurkin I, Bonaventure J, de Vries A, Thiery JP, van der Kwast TH, Zwarthoff EC, Radvanyi F. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Eur J Hum Genet. 2002 Dec;10(12):819-24 Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, Vineis P, Lopez-Abente G, Tzonou A, Chang-Claude J, Bolm-Audorff U, Jöckel KH, Donato F, Serra C, Wahrendorf J, Hours M, T'Mannetje A, Kogevinas M, Boffetta P. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies. Int J Cancer. 2000 Apr 15;86(2):289-94 van Tilborg AA, de Vries A, de Bont M, Groenfeld LE, Zwarthoff EC. The random development of LOH on chromosome 9q in superficial bladder cancers. J Pathol. 2002 Nov;198(3):352-8 Choi C, Kim MH, Juhng SW, Oh BR. Loss of heterozygosity at chromosome segments 8p22 and 8p11.2-21.1 in transitionalcell carcinoma of the urinary bladder. Int J Cancer. 2000 May 15;86(4):501-5 Williams SV, Sibley KD, Davies AM, Nishiyama H, Hornigold N, Coulter J, Kennedy WJ, Skilleter A, Habuchi T, Knowles MA. Molecular genetic analysis of chromosome 9 candidate tumor-suppressor loci in bladder cancer cell lines. Genes Chromosomes Cancer. 2002 May;34(1):86-96 Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA, Hodges S, Benedict WF. Genetic modeling of human urinary bladder carcinogenesis. Genes Chromosomes Cancer. 2000 Apr;27(4):392-402 Dyrskjøt L, Thykjaer T, Kruhøffer M, Jensen JL, Marcussen N, Hamilton-Dutoit S, Wolf H, Orntoft TF. Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet. 2003 Jan;33(1):90-6 Louhelainen J, Wijkström H, Hemminki K. Allelic losses demonstrate monoclonality of multifocal bladder tumors. Int J Cancer. 2000 Aug 15;87(4):522-7 Hoque MO, Lee CC, Cairns P, Schoenberg M, Sidransky D. Genome-wide genetic characterization of bladder cancer: a comparison of high-density single-nucleotide polymorphism Louhelainen J, Wijkström H, Hemminki K. Initiationdevelopment modelling of allelic losses on chromosome 9 in Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 46 Bladder: Urothelial carcinomas van Tilborg AA, van Rhijn BW arrays and PCR-based microsatellite analysis. Cancer Res. 2003 May 1;63(9):2216-22 progression using cDNA microarrays. Am J Pathol. 2003 Aug;163(2):505-16 Munro NP, Knowles MA. Fibroblast growth factors and their receptors in transitional cell carcinoma. J Urol. 2003 Feb;169(2):675-82 Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE, DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, CordonCardo C, Jain AN, Waldman FM. Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res. 2003 Jun 1;63(11):2872-80 Obermann EC, Junker K, Stoehr R, Dietmaier W, Zaak D, Schubert J, Hofstaedter F, Knuechel R, Hartmann A. Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses. J Pathol. 2003 Jan;199(1):50-7 This article should be referenced as such: van Tilborg AA, van Rhijn BW. Bladder: Urothelial carcinomas. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):41-47. Sanchez-Carbayo M, Socci ND, Lozano JJ, Li W, Charytonowicz E, Belbin TJ, Prystowsky MB, Ortiz AR, Childs G, Cordon-Cardo C. Gene discovery in bladder cancer Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 47 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Review Ovary: Sex cord-stromal tumors Lisa Lee-Jones Tumour Molecular Genetics Group, Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK (LLJ) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Tumors/OvarSexCordStromID5223.html DOI: 10.4267/2042/38058 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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 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. 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Epidemiology The frequency of sex cord-stromal tumours is similar 48 Ovary: Sex cord-stromal tumors Lee-Jones L 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. 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#target1 ). Macrofollicular granulosa cell tumours contain one or more large cysts lined with granulosa cells. Granulosa cells are organised into nests and bands in the trabecular and insular histologies, with an intervening fibrothecomatous stroma present in the trabecular type. The diffuse subtype contains sheets of cells arranged in no pattern (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 welldifferentiated 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). Fibromas 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. 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 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). Intraabdominal 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 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 49 Ovary: Sex cord-stromal tumors Lee-Jones L 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. 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.nagoyau.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 Leydiglike cells, 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. 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. Cytogenetics Treatment Cytogenetics Morphological 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. Trisomy 12 is a recurrent finding, often as the sole anomaly in benign 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 50 Ovary: Sex cord-stromal tumors Lee-Jones L 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 SertoliLeydig 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 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 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 Molecular CGH and FISH analysis of an ovarian metastasising Sertoli-Leydig 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 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 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 51 Ovary: Sex cord-stromal tumors Lee-Jones L Pejovic T, Heim S, Alm P, Iosif S, Himmelmann A, Skjaerris J, Mitelman F. Isochromosome 1q as the sole karyotypic abnormality in a Sertoli cell tumor of the ovary. Cancer Genet Cytogenet. 1993 Jan;65(1):79-80 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 DenysDrash attributable 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 the first study. Taruscio D, Carcangiu ML, Ward DC. Detection of trisomy 12 on ovarian sex cord stromal tumors by fluorescence in situ hybridization. Diagn Mol Pathol. 1993 Jun;2(2):94-8 Ferry JA, Young RH, Engel G, Scully RE. Oxyphilic Sertoli cell tumor of the ovary: a report of three cases, two in patients with the Peutz-Jeghers syndrome. Int J Gynecol Pathol. 1994 Jul;13(3):259-66 Hales SA, Cree IA, Pinion S. A poorly differentiated SertoliLeydig cell tumour associated with an ovarian sex cord tumour with annular tubules in a woman with Peutz-Jeghers syndrome. Histopathology. 1994 Oct;25(4):391-3 Shashi V, Golden WL, von Kap-Herr C, Andersen WA, Gaffey MJ. Interphase fluorescence in situ hybridization for trisomy 12 on archival ovarian sex cord-stromal tumors. Gynecol Oncol. 1994 Dec;55(3 Pt 1):349-54 Srivatsa PJ, Keeney GL, Podratz KC. Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz-Jeghers syndrome. Gynecol Oncol. 1994 May;53(2):256-64 References Izutsu T, Kudo T, Miura F, Nishiya I. Numerical and structural chromosome abnormalities in an ovarian fibrothecoma. Cancer Genet Cytogenet. 1995 Aug;83(1):84-6 Solh HM, Azoury RS, Najjar SS. Peutz-Jeghers syndrome associated with precocious puberty. J Pediatr. 1983 Oct;103(4):593-5 King LA, Okagaki T, Gallup DG, Twiggs LB, Messing MJ, Carson LF. Mitotic count, nuclear atypia, and immunohistochemical determination of Ki-67, c-myc, p21-ras, c-erbB2, and p53 expression in granulosa cell tumors of the ovary: mitotic count and Ki-67 are indicators of poor prognosis. Gynecol Oncol. 1996 May;61(2):227-32 Lappöhn RE, Burger HG, Bouma J, Bangah M, Krans M, de Bruijn HW. Inhibin as a marker for granulosa-cell tumors. N Engl J Med. 1989 Sep 21;321(12):790-3 Mrózek K, Nedoszytko B, Babińska M, Mrózek E, Hrabowska M, Emerich J, Limon J. Trisomy of chromosome 12 in a case of thecoma of the ovary. Gynecol Oncol. 1990 Mar;36(3):413-6 Liu FS, Ho ES, Lai CR, Chen JT, Shih RT, Yang CH, Tsao CM. Overexpression of p53 is not a feature of ovarian granulosa cell tumors. Gynecol Oncol. 1996 Apr;61(1):50-3 Pejovic T, Heim S, Mandahl N, Elmfors B, Flodérus UM, Furgyik S, Helm G, Willén H, Mitelman F. Trisomy 12 is a consistent chromosomal aberration in benign ovarian tumors. Genes Chromosomes Cancer. 1990 May;2(1):48-52 Shen Y, Mamers P, Jobling T, Burger HG, Fuller PJ. Absence of the previously reported G protein oncogene (gip2) in ovarian granulosa cell tumors. J Clin Endocrinol Metab. 1996 Nov;81(11):4159-61 Fletcher JA, Gibas Z, Donovan K, Perez-Atayde A, Genest D, Morton CC, Lage JM. Ovarian granulosa-stromal cell tumors are characterized by trisomy 12. Am J Pathol. 1991 Mar;138(3):515-20 Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature. 1996 Dec 5;384(6608):470-4 Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in DenysDrash syndrome. Cell. 1991 Oct 18;67(2):437-47 Ala-Fossi SL, Mäenpää J, Aine R, Koivisto P, Koivisto AM, Punnonen R. Prognostic significance of p53 expression in ovarian granulosa cell tumors. Gynecol Oncol. 1997 Sep;66(3):475-9 Yang-Feng TL, Li SB, Leung WY, Carcangiu ML, Schwartz PE. Trisomy 12 and K-ras-2 amplification in human ovarian tumors. Int J Cancer. 1991 Jul 9;48(5):678-81 Bale AE. The nevoid basal cell carcinoma syndrome: genetics and mechanism of carcinogenesis. Cancer Invest. 1997;15(2):180-6 Dal Cin P, Moerman P, De Wever I, Van den Berghe H. Numerical chromosome aberrations in fibrothecoma. Tumori. 1992 Apr 30;78(2):140-2 Dal Cin P, Qi H, Pauwels P, Backx C, Van den Berghe H. Monosomy 22 in a fibrothecoma. Cancer Genet Cytogenet. 1997 Dec;99(2):129-31 Matzuk MM, Finegold MJ, Su JG, Hsueh AJ, Bradley A. Alphainhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature. 1992 Nov 26;360(6402):313-9 Kotlar TJ, Young RH, Albanese C, Crowley WF Jr, Scully RE, Jameson JL. A mutation in the follicle-stimulating hormone receptor occurs frequently in human ovarian sex cord tumors. J Clin Endocrinol Metab. 1997 Apr;82(4):1020-6 Mrózek K, Limon J, Debniak J, Emerich J. Trisomy 12 and 4 in a thecoma of the ovary. Gynecol Oncol. 1992 Apr;45(1):66-8 Speleman F, Dermaut B, De Potter CR, Van Gele M, Van Roy N, De Paepe A, Laureys G. Monosomy 22 in a mixed germ cell-sex cord-stromal tumor of the ovary. Genes Chromosomes Cancer. 1997 Jul;19(3):192-4 Coppes MJ, Ye Y, Rackley R, Zhao XL, Liefers GJ, Casey G, Williams BR. Analysis of WT1 in granulosa cell and other sex cord-stromal tumors. Cancer Res. 1993 Jun 15;53(12):2712-4 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 52 Ovary: Sex cord-stromal tumors Lee-Jones L Valle Virgen O, Valdés Banda-Gómez F, Valenzuela Espinoza A. [Ovarian fibroma. Report of two cases; familial incidence?]. Ginecol Obstet Mex. 1997 Oct;65:442-5 Van den Berghe I, Dal Cin P, De Groef K, Michielssen P, Van den Berghe H. Monosomy 22 and trisomy 14 may be early events in the tumorigenesis of adult granulosa cell tumor. Cancer Genet Cytogenet. 1999 Jul 1;112(1):46-8 Watson RH, Roy WJ Jr, Davis M, Hitchcock A, Campbell IG. Loss of heterozygosity at the alpha-inhibin locus on chromosome 2q is not a feature of human granulosa cell tumors. Gynecol Oncol. 1997 Jun;65(3):387-90 Connolly DC, Katabuchi H, Cliby WA, Cho KR. Somatic mutations in the STK11/LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz-Jegher's syndrome. Am J Pathol. 2000 Jan;156(1):339-45 Burger HG, Baillie A, Drummond AE, Healy DL, Jobling T, Mamers P, Robertson DM, Susil B, Cahir N, Shen Y, Verity K, Fuller PJ, Groome NP, Findlay JK. Inhibin and ovarian cancer. J Reprod Immunol. 1998 Aug;39(1-2):77-87 Gebhart JB, Roche PC, Keeney GL, Lesnick TG, Podratz KC. Assessment of inhibin and p53 in granulosa cell tumors of the ovary. Gynecol Oncol. 2000 May;77(2):232-6 Fuller PJ, Verity K, Shen Y, Mamers P, Jobling T, Burger HG. No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors. J Clin Endocrinol Metab. 1998 Jan;83(1):274-9 Giacaglia LR, Kohek MB da F, Carvalho FM, Fragoso MC, Mendonca B, Latronico AC. No evidence of somatic activating mutations on gonadotropin receptor genes in sex cord stromal tumors. Fertil Steril. 2000 Nov;74(5):992-5 Fuller PJ, Verity K, Shen Y, Mamers P, Jobling T, Burger HG. No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors. J Clin Endocrinol Metab. 1998 Jan;83(1):274-9 Manegold E, Tietze L, Günther K, Fleischer A, Amo-Takyi BK, Schröder W, Handt S. Trisomy 8 as sole karyotypic aberration in an ovarian metastasizing Sertoli-Leydig cell tumor. Hum Pathol. 2001 May;32(5):559-62 Riopel MA, Perlman EJ, Seidman JD, Kurman RJ, Sherman ME. Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cordstromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas. Int J Gynecol Pathol. 1998 Jan;17(1):46-53 Seracchioli R, Bagnoli A, Colombo FM, Missiroli S, Venturoli S. Conservative treatment of recurrent ovarian fibromas in a young patient affected by Gorlin syndrome. Hum Reprod. 2001 Jun;16(6):1261-3 Arcellana-Panlilio MY, Egeler RM, Ujack E, Magliocco A, Stuart GC, Robbins SM, Coppes MJ. Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors. Genes Chromosomes Cancer. 2002 Oct;35(2):176-81 Zung A, Shoham Z, Open M, Altman Y, Dgani R, Zadik Z. Sertoli cell tumor causing precocious puberty in a girl with Peutz-Jeghers syndrome. Gynecol Oncol. 1998 Sep;70(3):4214 Fuller PJ, Chu S, Jobling T, Mamers P, Healy DL, Burger HG. Inhibin subunit gene expression in ovarian cancer. Gynecol Oncol. 1999 May;73(2):273-9 Chu S, Rushdi S, Zumpe ET, Mamers P, Healy DL, Jobling T, Burger HG, Fuller PJ. FSH-regulated gene expression profiles in ovarian tumours and normal ovaries. Mol Hum Reprod. 2002 May;8(5):426-33 Lane AH, Lee MM, Fuller AF Jr, Kehas DJ, Donahoe PK, MacLaughlin DT. Diagnostic utility of Müllerian inhibiting substance determination in patients with primary and recurrent granulosa cell tumors. Gynecol Oncol. 1999 Apr;73(1):51-5 Mayr D, Kaltz-Wittmer C, Arbogast S, Amann G, Aust DE, Diebold J. Characteristic pattern of genetic aberrations in ovarian granulosa cell tumors. Mod Pathol. 2002 Sep;15(9):951-7 Ligtenberg MJ, Siers M, Themmen AP, Hanselaar TG, Willemsen W, Brunner HG. Analysis of mutations in genes of the follicle-stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors. J Clin Endocrinol Metab. 1999 Jun;84(6):2233-4 Papageorgiou T, Stratakis CA. Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz-Jeghers syndrome, von Hippel-Lindau disease, Cowden's disease). Int J Gynecol Cancer. 2002 JulAug;12(4):337-47 Ligtenberg MJ, Siers M, Themmen AP, Hanselaar TG, Willemsen W, Brunner HG. Analysis of mutations in genes of the follicle-stimulating hormone receptor signaling pathway in ovarian granulosa cell tumors. J Clin Endocrinol Metab. 1999 Jun;84(6):2233-4 Jones MB, Michener CM, Blanchette JO, Kuznetsov VA, Raffeld M, Serrero G, Emmert-Buck MR, Petricoin EF, Krizman DB, Liotta LA, Kohn EC. The granulin-epithelin precursor/PCcell-derived growth factor is a growth factor for epithelial ovarian cancer. Clin Cancer Res. 2003 Jan;9(1):44-51 Robertson DM, Cahir N, Burger HG, Mamers P, Groome N. Inhibin forms in serum from postmenopausal women with ovarian cancers. Clin Endocrinol (Oxf). 1999 Mar;50(3):381-6 This article should be referenced as such: Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Lee-Jones L. Ovary: Sex cord-stromal tumors. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):48-53. 53 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Mini Review Soft tissue tumors: Elastofibroma Roberta Vanni Dip Scienze e Tecnologie Biomediche, Sezione di Biologia e Genetica, Universita di Cagliari, Cittadella Universitaria, 09142 Monserrato (CA), Italy (RV) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Tumors/ElastofibromaID5173.html DOI: 10.4267/2042/38057 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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 onethird of cases, suggesting that its origin may be influenced genetically. Identity Alias: Elastofibroma dorsi 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. Epidemiology Clinics and pathology Elastofibroma is a rare condition whose exact incidence is unknown. 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. Etiology The etiology of this lesion remains unclear. It seems likely that the pseudotumor mass is the product of abnormal elastogenesis rather than of 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 54 Soft tissue tumors: Elastofibroma Vanni R 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. 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. 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. 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 Morphological The prominent cytogenetic feature of elastofibroma is remarkably high 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. 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 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Cytogenetics Molecular One study performed using comparative genomic hybridization showed the presence of DNA imbalances in 33% of the examined cases, with DNA gains at Xq12-q22 being the most common. 55 Soft tissue tumors: Elastofibroma Vanni R Batstone P, Forsyth L, Goodlad J. Clonal chromosome aberrations secondary to chromosome instability in an elastofibroma. Cancer Genet Cytogenet. 2001 Jul 1;128(1):467 References JARVI O, SAXEN E. Elastofibroma dorse. Acta Pathol Microbiol Scand Suppl. 1961;51(Suppl 144):83-4 Järvi OH, Saxén AE, Hopsu-Havu VK, Wartiovaara JJ, Vaissalo VT. Elastofibroma--a degenerative pseudotumor. Cancer. 1969 Jan;23(1):42-63 McComb EN, Feely MG, Neff JR, Johansson SL, Nelson M, Bridge JA. Cytogenetic instability, predominantly involving chromosome 1, is characteristic of elastofibroma. Cancer Genet Cytogenet. 2001 Apr 1;126(1):68-72 Nagamine N, Nohara Y, Ito E. Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Cancer. 1982 Nov 1;50(9):1794-805 Weiss SW, Goldblum JR. Benign fibrous tissue tumors. In: Soft Tissue Tumors. Enzinger FM and Weiss SW (eds). 4th edition. Mosby Year Book, St. Louis, 2001; pp286-289. Schepel JA, Wille J, Seldenrijk CA, van Ramshorst B. Elastofibroma: a familial occurrence. Eur J Surg. 1998 Jul;164(7):557-8 Zissin R, Shapiro-Feinberg M. Elastofibroma dorsi: CT appearance. Isr Med Assoc J. 2001 Oct;3(10):780 Nishio JN, Iwasaki H, Ohjimi Y, Ishiguro M, Koga T, Isayama T, Naito M, Kikuchi M. Gain of Xq detected by comparative genomic hybridization in elastofibroma. Int J Mol Med. 2002 Sep;10(3):277-80 Vanni R, Marras S, Faa G, Uccheddu A, Dal Cin P, Sciot R, Samson I, Van den Berghe H. Chromosome instability in elastofibroma. Cancer Genet Cytogenet. 1999 Jun;111(2):1823 Dalal A, Miller TT, Kenan S. Sonographic detection of elastofibroma dorsi. J Clin Ultrasound. 2003 Sep;31(7):375-8 Bui-Mansfield LT, Chew FS, Stanton CA. Elastrofibroma dorsi of the chest wall. AJR Am J Roentgenol. 2000 Jul;175(1):244 This article should be referenced as such: Mojica WD, Kuntzman T. Elastofibroma dorsi: elaboration of cytologic features and review of its pathogenesis. Diagn Cytopathol. 2000 Dec;23(6):393-6 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Vanni R. Soft tissue tumors: Elastofibroma. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):54-56. 56 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Mini Review Testis: Spermatocytic seminoma Ewa Rajpert-De Meyts Dept. of Growth & Reproduction, Copenhagen University Hospital, Rigshospitalet, Section GR-5064, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark (ERDM) Published in Atlas Database: November 2003 Online updated version : http://AtlasGeneticsOncology.org/Tumors/SpermatSeminID5119.html DOI: 10.4267/2042/38059 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Clinics and pathology Alias: Spermatocytoma 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. 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. Classification Phenotype / cell stem origin 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: Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) The origin of spermatocytic seminoma from the germ cell lineage has been clearly demonstrated by a number of studies, however the cell of 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. 57 Testis: Spermatocytic seminoma Rajpert-De Meyts E En example of spermatocytic seminoma, HE-stained. A high power image showing characteristic polymorphism of the cell nucleus size of spermatocytic seminoma. 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 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 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 58 Testis: Spermatocytic seminoma Rajpert-De Meyts E nuclear size: large, small and intermediate. Some nuclei may exhibit a presence of nuclear thread-like chromatin. Evolution Some cases of spermatocytic seminoma may undergo sarcomatous transformation and spread outside the testis. An anaplastic variant was also described. Pathology There is no specific marker for spermatocytic seminoma. Proteins/antigens that are highly expressed in spermatogonia (most of them also present in gonocytes and primary spermatocytes), such as SSX (synovial sarcoma on X chromosome), NSE (neuronspecific 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. 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 Molecular Only one molecular study of 4 spermatocytic seminomas was 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. Treatment Spermatocytic seminoma (orchiectomy). is treated by surgery 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). Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 59 Testis: Spermatocytic seminoma Rajpert-De Meyts E Delgado R, Rathi A, Albores-Saavedra J, Gazdar AF. Expression of the RNA component of human telomerase in adult testicular germ cell neoplasia. Cancer. 1999 Nov 1;86(9):1802-11 References Rosai J, Silber I, Khodadoust K. Spermatocytic seminoma. I. Clinicopathologic study of six cases and review of the literature. Cancer. 1969 Jul;24(1):92-102 Kraggerud SM, Berner A, Bryne M, Pettersen EO, Fossa SD. Spermatocytic seminoma as compared to classical seminoma: an immunohistochemical and DNA flow cytometric study. APMIS. 1999 Mar;107(3):297-302 Pugh RC. Testicular tumours - Introduction. In: Pugh RC (ed.) Pathology of the testis. Blackwell Scientific, Oxford 1976, 139159 Ulbright TM, Amin MB, Young RH. Tumors of the testis, adnexa, spermatic cord, and scrotum. In: Atlas of Tumor Pathology. Third Series, Fascicle 25. Armed Forces Institute of Pathology, Washington DC, 1999, 1-375 Mostofi FK. Comparison of various clinical and pathological classifications of tumors of testes. Semin Oncol. 1979 Mar;6(1):26-30 Romanenko AM, Persidskiĭ IuV. [Ultrastructure and histogenesis of spermatocytic seminoma]. Vopr Onkol. 1983;29(7):60-6 Stoop H, van Gurp R, de Krijger R, Geurts van Kessel A, Köberle B, Oosterhuis W, Looijenga L. Reactivity of germ cell maturation stage-specific markers in spermatocytic seminoma: diagnostic and etiological implications. Lab Invest. 2001 Jul;81(7):919-28 Müller J, Skakkebaek NE, Parkinson MC. The spermatocytic seminoma: views on pathogenesis. Int J Androl. 1987 Feb;10(1):147-56 Satie AP, Rajpert-De Meyts E, Spagnoli GC, Henno S, Olivo L, Jacobsen GK, Rioux-Leclercq N, Jégou B, Samson M. The cancer-testis gene, NY-ESO-1, is expressed in normal fetal and adult testes and in spermatocytic seminomas and testicular carcinoma in situ. Lab Invest. 2002 Jun;82(6):775-80 Dekker I, Rozeboom T, Delemarre J, Dam A, Oosterhuis JW. Placental-like alkaline phosphatase and DNA flow cytometry in spermatocytic seminoma. Cancer. 1992 Feb 15;69(4):993-6 Grigor KM. A new classification of germ cell tumours of the testis. Eur Urol. 1993;23(1):93-100; discussion 101-3 Rajpert-De Meyts E, Jacobsen GK, Bartkova J, Aubry F, Samson M, Bartek J, Skakkebaek NE. The immunohistochemical expression pattern of Chk2, p53, p19INK4d, MAGE-A4 and other selected antigens provides new evidence for the premeiotic origin of spermatocytic seminoma. Histopathology. 2003 Mar;42(3):217-26 Eble JN. Spermatocytic seminoma. Hum Pathol. 1994 Oct;25(10):1035-42 Albores-Saavedra J, Huffman H, Alvarado-Cabrero I, Ayala AG. Anaplastic variant of spermatocytic seminoma. Hum Pathol. 1996 Jul;27(7):650-5 This article should be referenced as such: Rosenberg C, Mostert MC, Schut TB, van de Pol M, van Echten J, de Jong B, Raap AK, Tanke H, Oosterhuis JW, Looijenga LH. Chromosomal constitution of human spermatocytic seminomas: comparative genomic hybridization supported by conventional and interphase cytogenetics. Genes Chromosomes Cancer. 1998 Dec;23(4):286-91 Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Rajpert-De Meyts E. Testis: Spermatocytic seminoma. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):57-60. 60 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Familial clear cell renal cancer Anita Bonné, Danielle Bodmer, Marc Eleveld, Eric Schoenmakers, Ad Geurts van Kessel Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, the Netherlands (AB, DB, ME, ES, AGVK) Published in Atlas Database: October 2003 Online updated version : http://AtlasGeneticsOncology.org/Kprones/FamClearCellRenalID10081.html DOI: 10.4267/2042/38060 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2004 Atlas of Genetics and Cytogenetics in Oncology and Haematology carcinomas, with median age 45 yrs at diagnosis (range 18-79 yrs, most cases being between 35 and 55 yrs old). 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. 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 Clear-cell renal cell carcinomas are associated with chromosome 3 translocations and deletions of 3p. Genes involved and proteins FHIT Clinics 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. No phenotypic sign. TRC8 Neoplastic risk Location 8q24 Multiple and/or bilateral nonpapillary renal cell Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) 61 Familial clear cell renal cancer Bonné A et al. Note TRC8 is a breakpoint spanning gene on chromosome 8 in a constitutional familial case of a t(3;8)(p14;q24) translocation. References Wegner RD. A new inducible fragile site on chromosome 3(p14.2) in human lymphocytes. Hum Genet. 1983;63(3):297-8 Wang N, Perkins KL. Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet Cytogenet. 1984 Apr;11(4):479-81 DIRC2 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. Bodmer D, Eleveld MJ, Ligtenberg MJ, Weterman MA, Janssen BA, Smeets DF, de Wit PE, van den Berg A, van den Berg E, Koolen MI, Geurts van Kessel A. An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation. Am J Hum Genet. 1998 Jun;62(6):1475-83 Druck T, Podolski J, Byrski T, Wyrwicz L, Zajaczek S, Kata G, Borowka A, Lubinski J, Huebner K. The DIRC1 gene at chromosome 2q33 spans a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. J Hum Genet. 2001;46(10):583-9 Podolski J, Byrski T, Zajaczek S, Druck T, Zimonjic DB, Popescu NC, Kata G, Borowka A, Gronwald J, Lubinski J, Huebner K. Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. J Hum Genet. 2001;46(12):685-93 Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B, Weterman M, Schoenmakers E, Nickerson M, Linehan M, Zbar B, van Kessel AG. Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21). Hum Mol Genet. 2002 Mar 15;11(6):641-9 DIRC3 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. Gemmill RM, Bemis LT, Lee JP, Sozen MA, Baron A, Zeng C, Erickson PF, Hooper JE, Drabkin HA. The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. Oncogene. 2002 May 16;21(22):350716 Bodmer D, Schepens M, Eleveld MJ, Schoenmakers EF, Geurts van Kessel A. 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). Genes Chromosomes Cancer. 2003 Oct;38(2):107-16 DIRC1 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. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Meléndez B, Rodríguez-Perales S, Martínez-Delgado B, Otero I, Robledo M, Martínez-Ramírez A, Ruiz-Llorente S, Urioste M, Cigudosa JC, Benítez J. Molecular study of a new family with hereditary renal cell carcinoma and a translocation t(3;8)(p13;q24.1). Hum Genet. 2003 Feb;112(2):178-85 This article should be referenced as such: Bonné A, Bodmer D, Eleveld M, Schoenmakers EFPMG, Geurts van Kessel A. Familial clear cell renal cancer. Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1):61-62. 62 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Instructions to Authors Manuscripts submitted to the Atlas must be submitted solely to the Atlas. Iconography is most welcome: there is no space restriction. The Atlas publishes "cards", "deep insights", "case reports", and "educational items". Cards are structured review articles. Detailed instructions for these structured reviews can be found at: http://AtlasGeneticsOncology.org/Forms/Gene_Form.html for reviews on genes, http://AtlasGeneticsOncology.org/Forms/Leukaemia_Form.html for reviews on leukaemias, http://AtlasGeneticsOncology.org/Forms/SolidTumour_Form.html for reviews on solid tumours, http://AtlasGeneticsOncology.org/Forms/CancerProne_Form.html for reviews on cancer-prone diseases. According to the length of the paper, cards are divided, into "reviews" (texts exceeding 2000 words), "mini reviews" (between), and "short communications" (texts below 400 words). The latter category may not be accepted for indexing by bibliographic databases. Deep Insights are written as traditional papers, made of paragraphs with headings, at the author's convenience. No length restriction. Case Reports in haematological malignancies are dedicated to recurrent -but rare- chromosomes abnormalities in leukaemias/lymphomas. Cases of interest shall be: 1- recurrent (i.e. the chromosome anomaly has already been described in at least 1 case), 2- rare (previously described in less than 20 cases), 3- with well documented clinics and laboratory findings, and 4- with iconography of chromosomes. It is mandatory to use the specific "Submission form for Case reports": see http://AtlasGeneticsOncology.org/Reports/Case_Report_Submission.html. Educational Items must be didactic, give full information and be accompanied with iconography. Translations into French, German, Italian, and Spanish are welcome. Subscription: The Atlas is FREE! Corporate patronage, sponsorship and advertising Enquiries should be addressed to [email protected]. Rules, Copyright Notice and Disclaimer Conflicts of Interest: Authors must state explicitly whether potential conflicts do or do not exist. Reviewers must disclose to editors any conflicts of interest that could bias their opinions of the manuscript. The editor and the editorial board members must disclose any potential conflict. Privacy and Confidentiality – Iconography: Patients have a right to privacy. Identifying details should be omitted. If complete anonymity is difficult to achieve, informed consent should be obtained. Property: As "cards" are to evolve with further improvements and updates from various contributors, the property of the cards belongs to the editor, and modifications will be made without authorization from the previous contributor (who may, nonetheless, be asked for refereeing); contributors are listed in an edit history manner. Authors keep the rights to use further the content of their papers published in the Atlas, provided that the source is cited. Copyright: The information in the Atlas of Genetics and Cytogenetics in Oncology and Haematology is issued for general distribution. All rights are reserved. The information presented is protected under international conventions and under national laws on copyright and neighbouring rights. Commercial use is totally forbidden. Information extracted from the Atlas may be reviewed, reproduced or translated for research or private study but not for sale or for use in conjunction with commercial purposes. Any use of information from the Atlas should be accompanied by an acknowledgment of the Atlas as the source, citing the uniform resource locator (URL) of the article and/or the article reference, according to the Vancouver convention. Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favouring. The views and opinions of contributors and authors expressed herein do not necessarily state or reflect those of the Atlas editorial staff or of the web site holder, and shall not be used for advertising or product endorsement purposes. The Atlas does not make any warranty, express or implied, including the warranties of merchantability and fitness for a particular purpose, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, and shall not be liable whatsoever for any damages incurred as a result of its use. In particular, information presented in the Atlas is only for research purpose, and shall not be used for diagnosis or treatment purposes. No responsibility is assumed for any injury and/or damage to persons or property for any use or operation of any methods products, instructions or ideas contained in the material herein. See also: "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication - Updated October 2004": http://www.icmje.org. http://AtlasGeneticsOncology.org © ATLAS - ISSN 1768-3262 Familial clear cell renal cancer Atlas Genet Cytogenet Oncol Haematol. 2004; 8(1) Bonné A et al. 64