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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] The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 4 times a year by ARMGHM, a non profit organisation. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France). 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 Jean-Loup Huret (Poitiers, France) Volume 3, Number 4, October - December 1999 Table of contents Gene Section ATM (ataxia telangiectasia mutated) Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti 10 NBS1 (Nijmegen breakage syndrome 1) Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti 175 WT1 (Wilms' tumor suppressor gene) Manfred Gessler 177 ATF1 (activating transcription factor 1) Jean-Loup Huret 179 ETV6 (ETS variant gene 6 (TEL oncogene)) Serge Pierrick Romana 181 IL3 (interleukin-3) Jean-Loup Huret 183 MXI1 (MAX interactor 1) Niels B Atkin 185 Leukaemia Section T-cell prolymphocytic leukemia (T-PLL) Martin Yuille 187 del (13q) in chronic lymphoproliferative diseases Antonio Cuneo 189 del(13q) in non-Hodgkin's lymphoma Antonio Cuneo 191 t(1;22)(p13;q13) Jean-Loup Huret 193 t(1;7)(p36;q34) Antonio Cuneo 195 t(8;14)(q11;q32) Jean-Loup Huret 196 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS del(17p) in myeloïd malignancies Valérie Soenen-Cornu, Claude Preudhomme, Jean-Luc Laï, Marc Zandecki, Pierre Fenaux 198 M0 acute non lymphocytic leukemia (M0-ANLL) Jean-Loup Huret 202 t(5;14)(q31;q32) Jean-Loup Huret 203 Solid Tumour Section Bladder: Squamous cell carcinoma Jean-Loup Huret, Claude Léonard 205 Soft tissue tumors: Malignant melanoma of soft parts Jérôme Couturier 207 Cancer Prone Disease Section Ataxia telangiectasia Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti 209 Dysplastic nevus syndrome (DNS) Claude Viguié 212 Nijmegen breakage syndrome Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti 215 WAGR (Wilms' tumor/aniridia/genitourinary anomalies/mental retardation syndrome) Manfred Gessler 217 Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) John A Martignetti 219 Deep Insight Section Familial chronic lymphocytic leukaemia Martin Yuille 222 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review ATM (ataxia telangiectasia mutated) Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France (NU, JOB, RAG) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Genes/ATM123.html DOI: 10.4267/2042/37550 This article is an update of: Huret JL. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol.1998;2(3):77-78. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Homology Location : 11q22.3-q23.1 Phosphatidylinositol 3-kinase (PI3K)-like proteins, most closely related to ATR and the DNA-PK catalytic subunit. DNA/RNA Mutations Description Germinal 66 exons spanning 184 kb of genomic DNA; numerous Alu and Lime sequences. Various types of mutations have been described, dispersed throughout the gene, and therefore most patients are compound heterozygotes; most mutations appear to inactivate the ATM protein by truncation, large deletions, or annulation of initiation or termination, although missense mutations have been described in the PI3 kinase domain and the leucine zipper motif. Transcription Alternative exons 1a and 1b; initiation codon lies within exon 4; 12 kb transcript with a 9.2 kb of coding sequence. The ATM promotor is bi-directional and also directs the transcription of the E14/NPAT/CAND3 gene. Protein Somatic Description Biallelic mutation can occur in T-prolymphocytic leukaemia. 3056 amino acids; 350 kDa; contains a Pl 3-kinase-like domain (phosphatidylinositol 3-prime kinase). Implicated in Expression Ataxia telangiectasia Found in all tissues. Disease Ataxia telangiectasia is a progressive cerebellar degenerative disease with telangiectasia, immunodeficiency, cancer risk, radiosensitivity, and chromosomal instability. Prognosis Poor: median age at death: 17 years; survival rarely exceeds 30 years, though survival is increasing with improved medical care. Localisation Mostly in the nucleus throughout all stages of the cell cycle. Function Initiates cell cycle checkpoints in response to doublestrand DNA breaks by phosphorylating p53, cAbl, IkBalpha and chk1, as well as other targets; in certain types of tissues ATM inhibits radiation-induced, p53dependent apoptosis; a possible role in intercellular signaling has also been suggested. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 173 ATM (ataxia telangiectasia mutated) Uhrhammer N et al. Yang H, Concannon P, Gatti RA. CAND3: a ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 11q23.1. Mamm Genome. 1997 Feb;8(2):129-33 Cytogenetics Spontaneous chromatid/chromosome breaks; non clonal stable chromosome rearrangements involving immunoglobulin superfamilly genes e.g. inv(7)(p14q35); clonal rearrangements. Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A. Ataxia-telangiectasia locus: sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene. Genome Res. 1997 Jun;7(6):592-605 References Gorlin RJ, Cohen MM, Levin LS.. Syndromes of the Head and Neck. Oxford monographs on Medical Genetics No 19, Oxford University Press (1990), p. 469. Shiloh Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet. 1997;31:635-62 Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994 Dec;66(6 Suppl):S177-82 Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, Döhner H. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med. 1997 Oct;3(10):1155-9 Greenwell PW, Kronmal SL, Porter SE, Gassenhuber J, Obermaier B, Petes TD. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell. 1995 Sep 8;82(5):823-9 Vorechovský I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarström L, Webster AD, Yuille MA. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet. 1997 Sep;17(1):96-9 Hari KL, Santerre A, Sekelsky JJ, McKim KS, Boyd JB, Hawley RS.. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell. 1995 Sep 8;82(5):815-21. Westphal CH. Cell-cycle signaling: Atm displays its many talents. Curr Biol. 1997 Dec 1;7(12):R789-92 Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995 Jun 23;268(5218):1749-53 Ziv Y, Bar-Shira A, Pecker I, Russell P, Jorgensen TJ, Tsarfati I, Shiloh Y. Recombinant ATM protein complements the cellular A-T phenotype. Oncogene. 1997 Jul 10;15(2):159-67 Gatti RA.. Ataxia-telangiectasia. B Vogelstein and K W Kinzler, Editors, The Genetic Basis of Human Cancer, McGraw-Hill, Inc., New York. 1998: 275-300. Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet. 1995 Nov;4(11):2025-32 Telatar M, Teraoka S, Wang Z, Chun HH, Liang T, CastellviBel S, Udar N, Borresen-Dale AL, Chessa L, BernatowskaMatuszkiewicz E, Porras O, Watanabe M, Junker A, Concannon P, Gatti RA. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. 1998 Jan;62(1):86-97 Zakian VA. ATM-related genes: what do they tell us about functions of the human gene? Cell. 1995 Sep 8;82(5):685-7 Xie G, Habbersett RC, Jia Y, Peterson SR, Lehnert BE, Bradbury EM, D'Anna JA. Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpoints. Oncogene. 1998 Feb 12;16(6):721-36 Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, WynshawBoris A. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996 Jul 12;86(1):159-71 Janin N, Andrieu N, Ossian K, Laugé A, Croquette MF, Griscelli C, Debré M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. Br J Cancer. 1999 Jun;80(7):1042-5 Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood. 1996 Jan 15;87(2):423-38 Brown KD, Ziv Y, Sadanandan SN, Chessa L, Collins FS, Shiloh Y, Tagle DA. The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not upregulated following genome damage. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1840-5 This article should be referenced as such: Uhrhammer N, Bay JO, Gatti RA. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):173-174. Chen X, Yang L, Udar N, Liang T, Uhrhammer N, Xu S, Bay JO, Wang Z, Dandakar S, Chiplunkar S, Klisak I, Telatar M, Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 174 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review NBS1 (Nijmegen breakage syndrome 1) Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France (NU, JOB, RAG) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Genes/NBS1ID160.html DOI: 10.4267/2042/37551 This article is an update of: Huret JL. NBS1 (Nijmegen breakage syndrome 1). Atlas Genet Cytogenet Oncol Haematol.1999;3(1):13-14. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Homology Identity No known homology. Location : 8q21.3 Mutations DNA/RNA Germinal Description 4.4 and 2.6 kb (alternative polyadenylation); open reading frame of 2265 nucleotides. Missense mutations in the BRCT domain or truncating mutations downstream the BRCT are found in Nijmegen breakage syndrome (see below); most mutations are a 5 bases deletion at codon 218, called 657del5, and are due to a founder effect. Protein Implicated in Description Nijmegen breakage syndrome The 754 amino acid protein is called nibrin; predicted MW 85 kDa, 95 kDa by SDS-PAGE; contains in Nterm a forkhead associated domain (amino acids 24100) and a breast cancer domain (BRCT; amino acids 105-190), both domains being found in the various DNA damage responsive cell cycle checkpoint proteins; 4 possible nuclear localization domains in the C-term half; identified as the p95 subunit of the Rad50/Mre11/p95 double-strand DNA break repair complex. Disease Nijmegen breakage syndrome is a chromosome instability syndrome/cancer prone disease at risk of non Hodgkin lymphomas. Cytogenetics Chromosome rearrangements involving immunoglobulin superfamilly genes, in particular inv(7)(p13q35). Spans over 51 kb; 16 exons. Transcription References Expression Jongmans W, Vuillaume M, Chrzanowska K, Smeets D, Sperling K, Hall J. Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation. Mol Cell Biol. 1997 Sep;17(9):5016-22 Wide; shorter transcript expressed at higher level in the testis (may have a role in meiotic recombination, as ATM does). Function Maser RS, Monsen KJ, Nelms BE, Petrini JH. hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks. Mol Cell Biol. 1997 Oct;17(10):6087-96 Member of the MRE/RAD50/nibrin double-strand break repair complex of 1600 kDa; necessary for localization of Rad50/Mre11 at DSB sites, and for the nucleolytic activities of this complex. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH. The 175 NBS1 (Nijmegen breakage syndrome 1) Uhrhammer N et al. hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell. 1998 May 1;93(3):477-86 Dong Z, Zhong Q, Chen PL. The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage. J Biol Chem. 1999 Jul 9;274(28):19513-6 Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S, Endo S, Smeets D, Solder B, Belohradsky BH, Der Kaloustian VM, Oshimura M, Isomura M, Nakamura Y, Komatsu K. Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet. 1998 Jun;19(2):179-81 Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH. Association of BRCA1 with the hRad50hMre11-p95 complex and the DNA damage response. Science. 1999 Jul 30;285(5428):747-50 This article should be referenced as such: Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998 May 1;93(3):467-76 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Uhrhammer N, Bay JO, Gatti RA. NBS1 (Nijmegen breakage syndrome 1). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):175-176. 176 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review WT1 (Wilms' tumor suppressor gene) Manfred Gessler Theodor-Boveri-Institut fuer Biowissenschaften, Lehrstuhl Physiol. Chemie I, Am Hubland, D-97074 Wuerzburg, Germany (MG) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Genes/WT1ID78.html DOI: 10.4267/2042/37552 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Mutations HGNC (Hugo): WT1 Location: 11p13 Local order: Cen- RAG1/2-CAT-CD59-WT1-RCNPAX6-FSHB -tel. Germinal Various types of mutations, mostly affecting zinc fingers in exons 7-10. (WAGR syndrome, genitourinary (GU) anomalies, Denys-Drash-syndrome, Frasier syndrome; see below). DNA/RNA Somatic Description Biallelic inactivation in Wilms' tumors (<15%) and some mesotheliomas and granulosa cell tumors. 10 exons spanning 48 kb of genomic DNA. Transcription Implicated in 3 kb mRNA; four alternative splice forms: +/- exon 5 and alternative splice donor sites at exon 9. Wilms' tumor Disease Nephroblastoma of childhood. Prognosis Good with treatment according to NWTS or SIOP. Cytogenetics 11p13 deletions/translocations can be seen in some cases. Oncogenesis Up to 15% of tumors show mainly biallelic inactivation of WT1 through deletion or mutation. Protein Description Four major isoforms (429-449 aa) due to alternative splicing; there are eight minor isoforms resulting from different initiation sites (upstream CTG: 502-522 aa, downstream ATG: 303-323 aa). Expression Kidney, spleen, mesothelia. Localisation Desmoplastic small round cell tumor (DSRCT) Nuclear staining, either diffuse or in speckles, depending on isoform and mutations. Prognosis Poor. Cytogenetics Translocations, t(11;22)(p13;q12). Abnormal protein With EWS: EWS-WT; in frame fusion of EWS exons 1-7 and WT1 exons 8-10. Function Zinc finger transcription factor (4 C2H2-type fingers). Homology p1, Egr-1. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 177 WT1 (Wilms' tumor suppressor gene) Gessler M 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 Denys-Drash syndrome (DDS) Disease Defined by: mesangial sclerosis with kidney failure (age 2 yrs), gonadal dysgenesis, risk of Wilms' tumors. Prognosis Kidney failure at age 0-5 years. Hybrid/Mutated gene Dominant negative mutations, especially missense mutations within the zinc fingers (aa 394 Arg -> Trp) but very few nonsense mutations. Oncogenesis High risk of Wilms' tumor development. Gessler M, König A, Bruns GA. The genomic organization and expression of the WT1 gene. Genomics. 1992 Apr;12(4):80713 Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB. The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo. Mech Dev. 1993 Jan;40(12):85-97 Gessler M, König A, Arden K, Grundy P, Orkin S, Sallan S, Peters C, Ruyle S, Mandell J, Li F. Infrequent mutation of the WT1 gene in 77 Wilms' Tumors. Hum Mutat. 1994;3(3):212-22 Frasier syndrome Varanasi R, Bardeesy N, Ghahremani M, Petruzzi MJ, Nowak N, Adam MA, Grundy P, Shows TB, Pelletier J. Fine structure analysis of the WT1 gene in sporadic Wilms tumors. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3554-8 Disease Defined by: complete gonadal dysgenesis, focal glomerular sclerosis, gonadoblastoma; in karyotypic females the syndrome may be limited to focal glomerular sclerosis with regular gonadal development and function. Prognosis Kidney failure at age 10-30 years. Hybrid/Mutated gene Heterozygous point mutations of alternative splice donor site in exon 9 with imbalance of WT1 isoform ratio. Oncogenesis Gonadoblatoma may occur within streak gonads. Gerald WL, Rosai J, Ladanyi M. Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):1028-32 Larsson SH, Charlieu JP, Miyagawa K, Engelkamp D, Rassoulzadegan M, Ross A, Cuzin F, van Heyningen V, Hastie ND. Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell. 1995 May 5;81(3):391-401 Bruening W, Pelletier J. A non-AUG translational initiation event generates novel WT1 isoforms. J Biol Chem. 1996 Apr 12;271(15):8646-54 Barbaux S, Niaudet P, Gubler MC, Grünfeld JP, Jaubert F, Kuttenn F, Fékété CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet. 1997 Dec;17(4):467-70 References Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990 Feb 9;60(3):509-20 Little M, Wells C. A clinical overview of WT1 gene mutations. Hum Mutat. 1997;9(3):209-25 Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, Gessler M. Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet. 1998 Apr;7(4):709-14 Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774-8 Scharnhorst V, Dekker P, van der Eb AJ, Jochemsen AG. Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties. J Biol Chem. 1999 Aug 13;274(33):23456-62 Rauscher FJ 3rd, Morris JF, Tournay OE, Cook DM, Curran T. Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. Science. 1990 Nov 30;250(4985):1259-62 This article should be referenced as such: Gessler M. WT1 (Wilms' tumor suppressor gene). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):177-178. Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE. Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9618-22 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 178 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication ATF1 (activating transcription factor 1) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: November 1999 Online updated version : http://AtlasGeneticsOncology.org/Genes/ATF1ID81.html DOI: 10.4267/2042/37553 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Homology Identity Members of the CREB protein family. Other names: TREB36 HGNC (Hugo): ATF1 Location: 12q13 Implicated in Malignant melanoma of soft parts Disease Very rare neuroectodermal tumour. Prognosis Very poor. Cytogenetics Characterised by the translocation t(12;22)(q13;q12). Hybrid/Mutated gene 5' EWSR1- 3' ATF1. Abnormal protein The chimaeric protein is composed of the N-terminal domain of EWS linked to the bZIP domain of ATF-1. Oncogenesis Binds to ATF sites present in cAMP-responsive promoters via the ATF1 bZIP domain and activates transcription constitutively, dependent on the activation domain (EAD) present in EWSR1. Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. DNA/RNA Transcription 816 bp mRNA. Protein Description 271 amino acids; possess a basic motif and a leucinezipper; dimerisation with other ATF family members (e.g. ATF-1 homodimers and ATF-1/CREB heterodimers). References Yoshimura T, Fujisawa J, Yoshida M. Multiple cDNA clones encoding nuclear proteins that bind to the tax-dependent enhancer of HTLV-1: all contain a leucine zipper structure and basic amino acid domain. EMBO J. 1990 Aug;9(8):2537-42 Localisation Nuclear. Rehfuss RP, Walton KM, Loriaux MM, Goodman RH. The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A. J Biol Chem. 1991 Oct 5;266(28):18431-4 Function DNA binding protein, binds the consensus sequence: 5'GTGACGT(A/C)(A/G)-3'; cAMP-inducible transcription factor (cAMP-responsive enhancerbinding protein (CRE), like CREB. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G. EWS and 179 ATF1 (activating transcription factor 1) Huret JL ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993 Aug;4(4):341-5 Pan S, Ming KY, Dunn TA, Li KK, Lee KA. The EWS/ATF1 fusion protein contains a dispersed activation domain that functions directly. Oncogene. 1998 Mar 26;16(12):1625-31 Guo B, Stein JL, van Wijnen AJ, Stein GS. ATF1 and CREB trans-activate a cell cycle regulated histone H4 gene at a distal nuclear matrix associated promoter element. Biochemistry. 1997 Nov 25;36(47):14447-55 This article should be referenced as such: Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Huret JL. ATF1 (activating transcription factor 1). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):179-180. 180 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review ETV6 (ETS variant gene 6 (TEL oncogene)) Serge Pierrick Romana Service de Cytogenetique (Unite de Cytogenetique Moleculaire), Hopital Necker-Enfants-Malades, 149, rue de Sevres, 75015 Paris, France (SPR) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Genes/ETV6ID38.html DOI: 10.4267/2042/37554 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Expression Other names: TEL (translocation ets leukemia) Location: 12p13.1 In mouse, the TEL proteins are more expressed in the neural tube, in cranial node, in mesenchymateus tissue adjacent to the primitive intestine. DNA/RNA Localisation Description Immunofluorescent experiences revealed a nucleus localization of the TEL proteins. The gene spans a region of 240 kb. Function Transcription Transcription is from telomere to centromere; there are three species of transcripts: 2400 kb, 4300 kb and 6200 kb; the gene encodes for a 1356 kb cDNA. TEL proteins belong to the ETS family transcription factors; different mouse KO experiences have demonstrated that TEL are important in the vitelline angiogenesis and in the bone marrow hematopoiesis. Protein Implicated in Description Leukemia and sarcoma Two TEL human protein isoforms have been characterized: one of 53 kDa and one of 57 kDa; these correspond respectively to translational initiation from the second in frame methionine (codon 43) and from the first in frame methionine (codon 1); it has been demonstrated that these two isoforms are phosphorylated; these proteins belong to the ETS transcription factors family characterized by the presence of 85 amino acids, the ETS domain; this domain is responsible for the sequence specific DNAbinding activity GGAA/T flanked by a 5-8 nucleotides contributing to the specificity of each proteins ETS members; TEL possesses an N-terminal domain called NH2 terminal conserved region (NCR) which is found in other ETS proteins. This TEL domain unlike most of the other NCR domains is responsible for the TEL protein homotypic olimerization capacity. References Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Wessels JW, Fibbe WE, van der Keur D, Landegent JE, van der Plas DC, den Ottolander GJ, Roozendaal KJ, Beverstock GC. t(5;12)(q31;p12). A clinical entity with features of both myeloid leukemia and chronic myelomonocytic leukemia. Cancer Genet Cytogenet. 1993 Jan;65(1):7-11 Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P, Morgan E, Raimondi SC, Rowley JD, Gilliland DG. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4917-21 Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood. 1997 Oct 1;90(7):2535-40 181 ETV6 (ETS variant gene 6 (TEL oncogene)) Romana SP Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P. Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders. Cancer Res. 1997 Feb 15;57(4):564-9 Cools J, Bilhou-Nabera C, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P. Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11q12;p13). Blood. 1999 Sep 1;94(5):1820-4 Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K. Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Genes Chromosomes Cancer. 1999 Nov;26(3):192-202 Suto Y, Sato Y, Smith SD, Rowley JD, Bohlander SK. A t(6;12)(q23;p13) results in the fusion of ETV6 to a novel gene, STL, in a B-cell ALL cell line. Genes Chromosomes Cancer. 1997 Apr;18(4):254-68 Chase A, Reiter A, Burci L, Cazzaniga G, Biondi A, Pickard J, Roberts IA, Goldman JM, Cross NC. Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood. 1999 Feb 1;93(3):1025-31 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) This article should be referenced as such: Romana SP. ETV6 (ETS variant gene 6 (TEL oncogene)). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):181-182. 182 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review IL3 (interleukin-3) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Genes/IL3ID60.html DOI: 10.4267/2042/37555 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Implicated in HGNC (Hugo) : IL3 Location : 5q31 t(5;14)(q31;q32) Disease B-cell acute lymphoblastic leukemia (ALL) with hypereosinophilia. Prognosis Poor. Cytogenetics t(5;14) may be the sole anomaly or accompanied with other anomalies. Hybrid/Mutated gene Break in the promoter region of IL3 and in the Jh region of IgH. Abnormal protein The immunoglobulin gene promoter controls the expression of IL3. Oncogenesis Over-expression of IL3. DNA/RNA Description 5 exons. Transcription 674 bp transcript with a 458 bp of coding sequence. Protein Description 152 amino acids; 17 kDa. Expression IL3 is produced by activated monocytes/macrophages and stroma cells. T cells, Function References Cytokine; multipotent hematopoietic growth factor; induces proliferation, maturation and probably selfrenewal of pluripotent hematopoietic stem cells and cells of myeloid, erythroid and megakaryocytic lineages; IL-3 plays a more specialized role on basophil and mast cells; role through activation of the IL-3 receptor (IL-3R) complex consisting of alpha and beta subunits, which in turn induces activation of JAK2/STAT5, and induction of c-myc (cell-cycle progression and DNA synthesis), and activation of the Ras pathway (suppression of apoptosis); IL3 and GMCSF have overlapping but distinct biological properties. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG. Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell. 1986 Oct 10;47(1):3-10 Grimaldi JC, Meeker TC. The t(5;14) chromosomal translocation in a case of acute lymphocytic leukemia joins the interleukin-3 gene to the immunoglobulin heavy chain gene. Blood. 1989 Jun;73(8):2081-5 Nimer SD, Uchida H. Regulation of granulocyte-macrophage colony-stimulating factor and interleukin 3 expression. Stem Cells. 1995 Jul;13(4):324-35 183 IL3 (interleukin-3) Huret JL Hara T, Miyajima A. Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis. Stem Cells. 1996 Nov;14(6):605-18 Mangi MH, Newland AC. Interleukin-3 in hematology and oncology: current state of knowledge and future directions. Cytokines Cell Mol Ther. 1999 Jun;5(2):87-95 Burdach S, Nishinakamura R, Dirksen U, Murray R. The physiologic role of interleukin-3, interleukin-5, granulocytemacrophage colony-stimulating factor, and the beta c receptor system. Curr Opin Hematol. 1998 May;5(3):177-80 This article should be referenced as such: Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Huret JL. IL3 (interleukin-3). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):183-184. 184 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review MXI1 (MAX interactor 1) Niels B Atkin Department of Cancer Research, Mount Vernon Hospital, Northwood, Middlesex, UK (NBA) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Genes/MXI1ID209.html DOI: 10.4267/2042/37556 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Homology Identity Belongs to the basic helix-loop-helix (bhlh) family of transcription factors. HGNC (Hugo): MXI1 Location: 10q24-25 Mutations DNA/RNA Somatic Description Mutations have been described in some sporadic prostate cancers but no germline mutations were found in a study of 38 families with possible predisposition to this disease; a correlation between a polymorphic repeat in the 3' untranslated region in Mxil mRNA and regulation of its transcription and degradation has been suggested. The gene spans approximately 60 kb; 6 exons. Transcription 2.6 kb mRNA; two transcription initiation sites. Protein Description Implicated in 228 amino acids; 26 kDa; contains a basic region/helixloop-helix/leucine zipper (B-HLH-LZ) motif that is similar to that found in Myc family. Implicated in some sporadic cases of prostate cancer and glioblastoma as a tumour suppressor gene Expression Tissue specific; differentiation. induced during cells References terminal Zervos AS, Gyuris J, Brent R. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell. 1993 Jan 29;72(2):223-32 Localisation Nuclear. Albarosa R, DiDonato S, Finocchiaro G. Redefinition of the coding sequence of the MXI1 gene and identification of a polymorphic repeat in the 3' non-coding region that allows the detection of loss of heterozygosity of chromosome 10q25 in glioblastomas. Hum Genet. 1995 Jun;95(6):709-11 Function Mxil, discovered in 1993, is, with Mad, one of the proteins that can regulate Max, a human protein containing a basic helix-loop-helix leucine zipper (bHLH-zip) that allows the formation of cMyc-Max heterodimers and that activates transcription; Mad and Mxil may be involved in tumour suppression since they can compete with Myc proteins for the interaction with Max; Mxil normally functions to suppress cell growth: experimental induction of the gene resulted in the accumulation of cells in G2-M phase. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Eagle LR, Yin X, Brothman AR, Williams BJ, Atkin NB, Prochownik EV. Mutation of the MXI1 gene in prostate cancer. Nat Genet. 1995 Mar;9(3):249-55 Kawamata N, Park D, Wilczynski S, Yokota J, Koeffler HP. Point mutations of the Mxil gene are rare in prostate cancers. Prostate. 1996 Sep;29(3):191-3 Lacombe L, Orlow I, Reuter VE, Fair WR, Dalbagni G, Zhang ZF, Cordon-Cardo C. Microsatellite instability and deletion analysis of chromosome 10 in human prostate cancer. Int J Cancer. 1996 Apr 22;69(2):110-3 185 MXI1 MAX interactor 1 Atkin NB Shimizu E, Shirasawa H, Kodama K, Sato T, Simizu B. Expression, regulation and polymorphism of the mxi1 genes. Gene. 1996 Oct 17;176(1-2):45-8 Benson LQ, Coon MR, Krueger LM, Han GC, Sarnaik AA, Wechsler DS. Expression of MXI1, a Myc antagonist, is regulated by Sp1 and AP2. J Biol Chem. 1999 Oct 1;274(40):28794-802 Edwards SM, Dearnaley DP, Ardern-Jones A, Hamoudi RA, Easton DF, Ford D, Shearer R, Dowe A, Eeles RA. No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group. Br J Cancer. 1997;76(8):992-1000 Foley KP, Eisenman RN. Two MAD tails: what the recent knockouts of Mad1 and Mxi1 tell us about the MYC/MAX/MAD network. Biochim Biophys Acta. 1999 May 31;1423(3):M37-47 Lee TC, Ziff EB. Mxi1 is a repressor of the c-Myc promoter and reverses activation by USF. J Biol Chem. 1999 Jan 8;274(2):595-606 Wechsler DS, Shelly CA, Petroff CA, Dang CV. MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells. Cancer Res. 1997 Nov 1;57(21):4905-12 This article should be referenced as such: Atkin NB. MXI1 (MAX interactor 1). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):185-186. Schreiber-Agus N, DePinho RA. Repression by the Mad(Mxi1)Sin3 complex. Bioessays. 1998 Oct;20(10):808-18 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 186 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review T-cell prolymphocytic leukemia (T-PLL) Martin Yuille Institute of Cancer Research, Academic Department of Haematology and Cytogenetics, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK (MY) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/TPLL.html DOI: 10.4267/2042/37557 This article is an update of: Michaux L. T-cell prolymphocytic leukemia (T-PLL). Atlas Genet Cytogenet Oncol Haematol.1997;1(2):83-84. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics and pathology Cytogenetics Disease Cytogenetics morphological Chronic T-cell lymphoproliferative syndrome. Few cases have been reported in the literature. So far; karyotypes are usually complex. 14q11 abnormalities: very frequent, either as an inv(14)(q11q32) or as a translocation t(14;14)(q11;q32); another reported change involving 14q11 is a translocation t(X;14)(q28;q11), similar to the translocation observed in ataxia-telangectasia, involving the Mature T-cell Prolymphocyte 1 (MTCP1) gene located at Xq28. Other recurrent changes involve chromosome 8 either as i(8)(q10) or as der(8) t(8;8). Finally, some aberrations involving 12p have been reported. Phenotype/cell stem origin Disease affecting mature T-cells; T-cell prolymphocytes usually express CD3, CD5 and CD7; they have either a T-helper (CD4+/CD8-) or a Tsuppressor (CD4-/CD8+) phenotype; a small number of cases may co-express CD4 and CD8; this finding is more prevalent in the small cell variant of T-PLL than in classic T-PLL. Epidemiology Very rare disease; represents 20% of prolymphocytic leukemias; the disease occurs at advanced age, typically in the 7th or 8th decade; slight male predominance. Genes involved and proteins Note As with other T-cell neoplasms, T-PLL exhibits clonal rearrangement of T-cell receptor genes; translocation t(X;14)(q28;q11) may result into fusion of MTCP1 with TRA/D genes; finally, the TCL1 locus on chromosome 14q32 might also been involved. In Ataxia Telangiectasia- a rare recessive pleiotropic disease (including elevated cancer predisposition) mapping to 11q23 and caused by mutations of theATM gene - a recurrent malignancy is observed that is similar to T-PLL; its frequency in A-T patients is higher than in the non-A-T related form; A-T related TPLL has a similar course, a similar immunophenotype and similar cytogenetics (with the notable exception Clinics Splenomegaly is common; lymphadenopathy at presentation is unusual but more frequent than in BPLL; blood data: high leucocyte counts usually exceeding 100x109/l; T-cell prolymphocytes have the same morphologic features than B-cell prolymphocytes; a small cell variant of T-PLL has been described. Prognosis Evolution: progresses rapidly and is generally more aggressive than B-PLL; prognosis: poor response to chemotherapy is observed; median survival is approximatively 7 months from diagnosis. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 187 T-cell prolymphocytic leukemia (T-PLL) Yuille M alpha/delta locus in mature T cell proliferations. Oncogene. 1993 Sep;8(9):2475-83 that 11q23 breakpoints are recurrent in the sporadic but not the A-T related form of the disease); an initial report of ATM mutations in T-PLL demonstrated the principle that ATM was a candidate cancer gene in sporadic forms of malignancies prevalent in A-T; the identification of lesions in ATM associated with T-PLL has shown that: Homozygous truncating mutations are present in some cases; this suggests ATM can appear to act like a conventional tumour suppressor with biallelic inactivation in the tumour cell. Missense mutations cluster in the carboxy-terminal phosphatidyl-3-kinase (PIK) domain; this suggests impairment of this domain can contribute to - and may constitute a distinct step in – tumourigenesis. Rearrangement of the gene is frequent; some rearrangements are consistent with a translocation event, in agreement with cytogenetic data implicating 11q23 in T-PLL; others involve transposition of a segment of the ATM gene elsewhere in the genome. One allele only is mutated (by rearrangement) in some cases; this is probably not associated with a concomitant epigenetic event such as abnormal promoter methylation. No T-PLL case has been reported with germline ATM mutation; this may reflect the small numbers investigated; all the same, the hypothesis is excluded that this rare disease is due solely to germline ATM mutation. Virgilio L, Isobe M, Narducci MG, Carotenuto P, Camerini B, Kurosawa N, Abbas-ar-Rushdi, Croce CM, Russo G. Chromosome walking on the TCL1 locus involved in T-cell neoplasia. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9275-9 Heinonen K, Mahlamäki E, Hämäläinen E, Nousiainen T, Mononen I. Multiple karyotypic abnormalities in three cases of small cell variant of T-cell prolymphocytic leukemia. Cancer Genet Cytogenet. 1994 Nov;78(1):28-35 Mossafa H, Brizard A, Huret JL, Brizard F, Lessard M, Guilhot F, Tanzer J. Trisomy 8q due to i(8q) or der(8) t(8;8) is a frequent lesion in T-prolymphocytic leukaemia: four new cases and a review of the literature. Br J Haematol. 1994 Apr;86(4):780-5 Schlegelberger B, Himmler A, Gödde E, Grote W, Feller AC, Lennert K. Cytogenetic findings in peripheral T-cell lymphomas as a basis for distinguishing low-grade and high-grade lymphomas. Blood. 1994 Jan 15;83(2):505-11 Thick J, Mak YF, Metcalfe J, Beatty D, Taylor AM. A gene on chromosome Xq28 associated with T-cell prolymphocytic leukemia in two patients with ataxia telangiectasia. Leukemia. 1994 Apr;8(4):564-73 Madani A, Choukroun V, Soulier J, Cacheux V, Claisse JF, Valensi F, Daliphard S, Cazin B, Levy V, Leblond V, Daniel MT, Sigaux F, Stern MH. Expression of p13MTCP1 is restricted to mature T-cell proliferations with t(X;14) translocations. Blood. 1996 Mar 1;87(5):1923-7 Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, Döhner H. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med. 1997 Oct;3(10):1155-9 References Vorechovský I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarström L, Webster AD, Yuille MA. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet. 1997 Sep;17(1):96-9 Brito-Babapulle V, Pittman S, Melo JV, Pomfret M, Catovsky D. Cytogenetic studies on prolymphocytic leukemia. 1. B-cell prolymphocytic leukemia. Hematol Pathol. 1987;1(1):27-33 Brito-Babapulle V, Pomfret M, Matutes E, Catovsky D. Cytogenetic studies on prolymphocytic leukemia. II. T cell prolymphocytic leukemia. Blood. 1987 Oct;70(4):926-31 Luo L, Lu FM, Hart S, Foroni L, Rabbani H, Hammarström L, Yuille MR, Catovsky D, Webster AD, Vorechovský I. Ataxiatelangiectasia and T-cell leukemias: no evidence for somatic ATM mutation in sporadic T-ALL or for hypermethylation of the ATM-NPAT/E14 bidirectional promoter in T-PLL. Cancer Res. 1998 Jun 1;58(11):2293-7 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. FrenchAmerican-British (FAB) Cooperative Group. J Clin Pathol. 1989 Jun;42(6):567-84 Maljaei SH, Brito-Babapulle V, Hiorns LR, Catovsky D. Abnormalities of chromosomes 8, 11, 14, and X in Tprolymphocytic leukemia studied by fluorescence in situ hybridization. Cancer Genet Cytogenet. 1998 Jun;103(2):110-6 Brito-Babapulle V, Catovsky D. Inversions and tandem translocations involving chromosome 14q11 and 14q32 in Tprolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia. Cancer Genet Cytogenet. 1991 Aug;55(1):1-9 Stoppa-Lyonnet D, Soulier J, Laugé A, Dastot H, Garand R, Sigaux F, Stern MH. Inactivation of the ATM gene in T-cell prolymphocytic leukemias. Blood. 1998 May 15;91(10):3920-6 Matutes E, Brito-Babapulle V, Swansbury J, Ellis J, Morilla R, Dearden C, Sempere A, Catovsky D. Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. Blood. 1991 Dec 15;78(12):3269-74 Yuille MA, Coignet LJ, Abraham SM, Yaqub F, Luo L, Matutes E, Brito-Babapulle V, Vorechovský I, Dyer MJ, Catovsky D. ATM is usually rearranged in T-cell prolymphocytic leukaemia. Oncogene. 1998 Feb 12;16(6):789-96 Fisch P, Forster A, Sherrington PD, Dyer MJ, Rabbitts TH. The chromosomal translocation t(X;14)(q28;q11) in T-cell prolymphocytic leukaemia breaks within one gene and activates another. Oncogene. 1993 Dec;8(12):3271-6 This article should be referenced as such: Yuille M. T-cell prolymphocytic leukemia (T-PLL). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):187-188. Stern MH, Soulier J, Rosenzwajg M, Nakahara K, Canki-Klain N, Aurias A, Sigaux F, Kirsch IR. MTCP-1: a novel gene on the human chromosome Xq28 translocated to the T cell receptor Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 188 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review del (13q) in chronic lymphoproliferative diseases Antonio Cuneo Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC) Published in Atlas Database: November 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del13qCLDID2065.html DOI: 10.4267/2042/37558 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Note: A spectrum of B-cell chronic lymphoproliferative disorders (CLD) may carry a chromosome 13q deletion; among these, three forms other than chronic lymphocytic leukemia (CLL) were identified by the FAB group which may frequently carry a 13q- chromosome: atypical CLL, splenic lymphoma with villous lymphocytes, corresponding to splenic marginal zone B-cell lymphoma, and mantle cell lymphoma (MCL) in leukemic phase. Clones dJ1154H7 (top) and dJ1013C9 (bottom) for 13q14 deletions, in normal cells - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Epidemiology del(13q) is found in approximately 10-15% of all CLLs. Clinics The clinical course may be more aggressive than in typical CLL, depending on stage at presentation and % of prolymphocytes. Clinics and pathology Disease Atypical CLL, including the CLL/PL (prolymphocytic leukemia) or CLL mixed-cell-type variant by FAB criteria. Phenotype/cell stem origin Virgin CD5+ recirculating B-cell. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 189 del (13q) in chronic lymphoproliferative diseases Cuneo A The incidence of 13q- in splenic marginal zone B-cell lymphoma is low by conventional cytogenetic analysis. FISH studies detected a 12-47% incidence for cryptic 13q deletion, the highest frequency having been reported using a 13q14 Rb probe; the 13q- is usually associated with other chromosome changes, including +12, 14q+. As is the case with classical MCL, a 40-60% incidence for 13q14 deletion was reported in leukemic MCL/mantle cell leukemia by interphase FISH. Disease Splenic lymphoma with villous lymphocytes. Phenotype/cell stem origin Chronic proliferation originating from the marginal zone B-lymphocytes. Epidemiology The disorder appears to be relatively rare, but it is probably underdiagnosed. Clinics The clinical course is indolent. References Disease Neilson JR, Fegan CD, Milligan DW. Mantle cell leukaemia? Br J Haematol. 1996 May;93(2):494-5 Leukemic mantle cell lymphoma. Note The majority of mantle cell lymphomas show peripheral blood (PB) involvement at diagnosis or at disease evolution; there is a disease variant presenting as a de novo leukemic condition, presenting heterogeneous cytological features with PB and BM lymphocytosis, without adenopathy, with or withour splenomegaly; some of these cases may fulfill the FAB criteria for the diagnosis of atypical CLL; because these cases usually carry the t(11;14)(q13;q32) and a mantlecell phenotype, they have also been referred to as 'mantle cell leukemia': it is reasonable to assume that the transformation of a mantle cell may give rise to a spectrum of diseases ranging from the classical lymphomatous form of MCL to an overt leukemic condition, as is the case with small lymphocytic lymphoma and chronic lymphocytic leukemia. Phenotype/cell stem origin Proliferation of cells of follicle mantle lineage (CD5/CD19/CD22 positive, CD23 negative, bright sIg expression). Bigoni R, Cuneo A, Roberti MG, Bardi A, Rigolin GM, Piva N, Scapoli G, Spanedda R, Negrini M, Bullrich F, Veronese ML, Croce CM, Castoldi G. Chromosome aberrations in atypical chronic lymphocytic leukemia: a cytogenetic and interphase cytogenetic study. Leukemia. 1997 Nov;11(11):1933-40 Cuneo A, Bigoni R, Negrini M, Bullrich F, Veronese ML, Roberti MG, Bardi A, Rigolin GM, Cavazzini P, Croce CM, Castoldi G. Cytogenetic and interphase cytogenetic characterization of atypical chronic lymphocytic leukemia carrying BCL1 translocation. Cancer Res. 1997 Mar 15;57(6):1144-50 García-Marco JA, Nouel A, Navarro B, Matutes E, Oscier D, Price CM, Catovsky D. Molecular cytogenetic analysis in splenic lymphoma with villous lymphocytes: frequent allelic imbalance of the RB1 gene but not the D13S25 locus on chromosome 13q14. Cancer Res. 1998 Apr 15;58(8):1736-40 Stilgenbauer S, Nickolenko J, Wilhelm J, Wolf S, Weitz S, Döhner K, Boehm T, Döhner H, Lichter P. Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Oncogene. 1998 Apr 9;16(14):1891-7 Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Campioni D, Minotto C, Agostini P, Milani R, Bullrich F, Negrini M, Croce C, Castoldi G. 13q14 deletion in non-Hodgkin's lymphoma: correlation with clinicopathologic features. Haematologica. 1999 Jul;84(7):589-93 Cytogenetics Levy V, Ugo V, Delmer A, Tang R, Ramond S, Perrot JY, Vrhovac R, Marie JP, Zittoun R, Ajchenbaum-Cymbalista F. Cyclin D1 overexpression allows identification of an aggressive subset of leukemic lymphoproliferative disorder. Leukemia. 1999 Sep;13(9):1343-51 Cytogenetics morphological The frequency of 13q- as an isolated chromosome change in atypical CLL is much lower than in typical CLL; however FISH studies detected an appoximately 40% incidence for this anomaly using a 13q14 probe; additional chromosome anomaly included +12, 6q- and complex karyotypes. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) This article should be referenced as such: Cuneo A. del (13q) in chronic lymphoproliferative diseases. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):189-190. 190 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review del(13q) in non-Hodgkin's lymphoma Antonio Cuneo Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC) Published in Atlas Database: November 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del13qNHLID2070.html DOI: 10.4267/2042/37559 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Epidemiology Identity Incidence. SLL: 5-10% of all NHL diagnosed by surgical biopsy. MCL: 5-10% of all NHL in western countries. MZBCL: 0-15% of NHL, including the extra-nodal form the nodal and the splenic form. FCCL: 30-40% of NHL. DLCL: 30-40% of NHL. Note: the chromosome 13q deletion is a relatively common finding in chronic myeloproliferative disorders and lymphoid neoplasias, including B-cell chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Whereas the commonly deleted region comprise a 100kb gene-rich segment at the 13q14 chromosome band in CLL, the commonly deleted segment in NHL was not characterized in detail. Clinics SLL: low-grade histology, usually running an indolent course; survival largely dependent on clinical stage at presentation. MCL: intermediate-grade histology, poor response to therapy, median survival 3-4 years. MZBCL: low-grade histology, indolent disease, median survival >5 years. FCCL: low-grade histology, indolent disease, median survival > 5 years. DLCL: high grade histology, aggressive disease, survival influenced by age, stage at presentation, performance status. del(13)(q14q21) in NHL (G-banding) - Antonio Cuneo; the vertical bar indicates the missing chromosome segment (left); del(13)(q14q33) R- banding (right) – Editor. Prognosis Clinics and pathology The significance of 13q- is uncertain because of heterogeneity of patients population and histology; a low CR rate was described but it is not clear whether this depends on its close association with MCL. Disease B-NHL Phenotype/cell stem origin Cytogenetics Peripheral B-cells at different stages of differentiation. Pre germinal centre: small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL). Post-germinal centre: marginal zone B-cell lymphoma (MZBCL) follicle centre cell lymphoma (FCCL), diffuse large cell lymphoma (DLCL). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Additional anomalies With the notable exception of SLL/CLL the 13q deletion is not found as an isolated change in NHL; 191 del(13q) in non-Hodgkin's lymphoma Cuneo A myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood. 1995 Dec 1;86(11):42506 it was reported as a stemline-associated anomaly in most cases having complex karyotypes, suggesting that it may represent a relatively early event in the cytogenetic history of NHL; the association with other anomalies reflects the incidence of the 13qchromosome in distinct histologic subsets: thus it was frequently found in karyotypes presenting the t(11;14)(q13;q32); many patients with the inv(14)(q11q32), associated with T-cell lymphoid neoplasias, were found to carry a 13q- chromosome. Corcoran MM, Rasool O, Liu Y, Iyengar A, Grander D, Ibbotson RE, Merup M, Wu X, Brodyansky V, Gardiner AC, Juliusson G, Chapman RM, Ivanova G, Tiller M, Gahrton G, Yankovsky N, Zabarovsky E, Oscier DG, Einhorn S. Detailed molecular delineation of 13q14.3 loss in B-cell chronic lymphocytic leukemia. Blood. 1998 Feb 15;91(4):1382-90 La Starza R, Wlodarska I, Aventin A, Falzetti D, Crescenzi B, Martelli MF, Van den Berghe H, Mecucci C. Molecular delineation of 13q deletion boundaries in 20 patients with myeloid malignancies. Blood. 1998 Jan 1;91(1):231-7 Genes involved and proteins Note Involved loci: the few characterized cases showed a deletion of the D13S319 marker, located between the Rb locus and the D13S25 marker; FISH studies were performed using probes targeting the Rb locus or the loci comprised between Rb and the D13S25 marker. Stilgenbauer S, Nickolenko J, Wilhelm J, Wolf S, Weitz S, Döhner K, Boehm T, Döhner H, Lichter P. Expressed sequences as candidates for a novel tumor suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Oncogene. 1998 Apr 9;16(14):1891-7 Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Campioni D, Minotto C, Agostini P, Milani R, Bullrich F, Negrini M, Croce C, Castoldi G. 13q14 deletion in non-Hodgkin's lymphoma: correlation with clinicopathologic features. Haematologica. 1999 Jul;84(7):589-93 References Johansson B, Mertens F, Mitelman F. Cytogenetic evolution patterns in non-Hodgkin's lymphoma. Blood. 1995 Nov 15;86(10):3905-14 Wada M, Okamura T, Okada M, Teramura M, Masuda M, Motoji T, Mizoguchi H. Frequent chromosome arm 13q deletion in aggressive non-Hodgkin's lymphoma. Leukemia. 1999 May;13(5):792-8 Liu Y, Hermanson M, Grandér D, Merup M, Wu X, Heyman M, Rasool O, Juliusson G, Gahrton G, Detlofsson R, Nikiforova N, Buys C, Söderhäll S, Yankovsky N, Zabarovsky E, Einhorn S. 13q deletions in lymphoid malignancies. Blood. 1995 Sep 1;86(5):1911-5 This article should be referenced as such: Cuneo A. del(13q) in non-Hodgkin's lymphoma. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):191-192. Tricot G, Barlogie B, Jagannath S, Bracy D, Mattox S, Vesole DH, Naucke S, Sawyer JR. Poor prognosis in multiple Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 192 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(1;22)(p13;q13) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: November 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0122.html DOI: 10.4267/2042/37561 This article is an update of: Huret JL. t(1;22)(p13;q13). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):17. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Epidemiology Identity About 40 known cases; 0% to 3% of paediatric ANLL; 70 to 100% of infants M7; age: infants: median age 4 months; 20% are <1 month; 80% are <1 year; 95% are <2 years; sex ratio: 15M/24F (non significant). Clinics No preceeding myelodysplasia, and no history of transient leukemoid reaction; prominent organomegaly; blood data: moderate WBC; thrombocytopenia; myelofibrosis and fibrosis of other organs. Cytology Platelet-specific markers: platelet-peroxidase by electron microscopy, or platelet glycoproteins IIb/IIIa (CD41) or IIIa (CD61). Treatment Bone marrow transplantation is indicated. t(1;22)(p13;q13) G- and R- banding. Prognosis Clinics and pathology Complete remission in only 50% of cases; median survival: 8 months; a few long survivors; absence of a prognostic indicator. Disease Only found so far in M7 ANLL (acute megakaryocytic leukaemia); not found in Down syndrome (DS), and yet, DS is a disease with highly elevated risk of M7 (see leukaemia and Down Syndrome); misdiagnoses of a solid tumour have been documented. Cytogenetics Additional anomalies 60% of cases (mostly patients under 6 months of age) have the t(1;22) as a single anomaly; the remaining third of cases (mainly patients above the age of 6 months) exhibit complex and hyperploid clones, with a highly monomorph pattern: +2, +19, +der(1)t(1;22), +6, +21 were found in more than 50% of cases each, Phenotype/cell stem origin Megakaryocytic. Etiology No known toxic exposure. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 193 t(1;22)(p13;q13) Huret JL megakaryoblastic leukemia: a Pediatric Oncology Group Study. Blood. 1991 Aug 1;78(3):748-52 +10, +7, +15, +18, +8, +20, del(1p), +4, +9, +14, +17, add(21p) are also recurrent; survival was equivalent in cases with or without a complex karyotype; the frequent presence of an additional der(1) indicates that the crucial event is likely to lie on the der(1)t(1;22). Lion T, Haas OA, Harbott J, Bannier E, Ritterbach J, Jankovic M, Fink FM, Stojimirovic A, Herrmann J, Riehm HJ. The translocation t(1;22)(p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children. Blood. 1992 Jun 15;79(12):3325-30 Variants Lion T, Haas OA. Acute megakaryocytic leukemia with the t(1;22)(p13;q13). Leuk Lymphoma. 1993 Sep;11(1-2):15-20 One case of complex t(1;22) with a third chromosome has been described. Martinez-Climent JA, Lane NJ, Rubin CM, Morgan E, Johnstone HS, Mick R, Murphy SB, Vardiman JW, Larson RA, Le Beau MM. Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia de novo. Leukemia. 1995 Jan;9(1):95-101 Genes involved and proteins Note Genes involved in this leukaemia are still unknown. Bernstein J, Dastugue N, Haas OA, Harbott J, Heerema NA, Huret JL, Landman-Parker J, LeBeau MM, Leonard C, Mann G, Pages MP, Perot C, Pirc-Danoewinata H, Roitzheim B, Rubin CM, Slociak M, Viguie F. Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia. 2000 Jan;14(1):216-8 To be noted Note Individual data on the 39 published cases of t(1;22) and a complete bibiography can be found in our t(1;22) study group page. This article should be referenced as such: References Huret JL. t(1;22)(p13;q13). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):193-194. Carroll A, Civin C, Schneider N, Dahl G, Pappo A, Bowman P, Emami A, Gross S, Alvarado C, Phillips C. The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 194 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(1;7)(p36;q34) Antonio Cuneo Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC) Published in Atlas Database: November 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0107ID1157.html DOI: 10.4267/2042/37560 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Cytogenetics Note This translocation may be related to a 1p;7q translocation described in myelodysplastic syndrome, whereas it must be distinguished from the T-ALL associated t(1;7)(p32;q34), involving the TCR gene and a more proximal breakpoint on 7q. Cytogenetics morphological The translocation is easy to visualize in G-banded preparations because the dark 7q35 band moves on top of the derivative 1p. Probes Partial karyotype (G-banding) showing the t(1;7)(p36;q34). Partial chromosome paints for the 7q31-qter region. Clinics and pathology Additional anomalies Disease Associated / additional anomalies may include +8 and the classical t(6;9)(p23;q34). Acute non lymphocytic leukemia (ANLL), presenting as a de novo condition or after preceeding myelodysplastic syndrome or exposure to myelotoxic agents. Genes involved and proteins Note The involved genes are unknown. Phenotype/cell stem origin M2/M4 by FAB criteria, frequently with trilineage myelodysplasia: positivity for myeloid markers (i.e. CD13, CD33) as well as for CD117, CD34 and TdT; lymphoid-associated markers tested negative in the reported cases. References Stefănescu DT, Colită D, Nicoară S, Călin G. t(1;7)(p36;q32): a new recurring abnormality in primary myelodysplastic syndrome. Cancer Genet Cytogenet. 1994 Jul 15;75(2):103-5 Epidemiology Hwang LY, Baer RJ. The role of chromosome translocations in T cell acute leukemia. Curr Opin Immunol. 1995 Oct;7(5):65964 The frequency of this anomaly in ANLL is < 1%. Prognosis Specchia G, Cuneo A, Liso V, Contino R, Pastore D, Gentile E, Rocchi M, Castoldi GL. A novel translocation t(1;7)(p36;q34) in three patients with acute myeloid leukaemia. Br J Haematol. 1999 Apr;105(1):208-14 The cells may be susceptible to chemotherapy since all reported cases achieved complete remission, despite the presence of other unfavourable prognostic factors. This article should be referenced as such: Cuneo A. t(1;7)(p36;q34). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):195. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 195 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(8;14)(q11;q32) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: November 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0814ID1112.html DOI: 10.4267/2042/37562 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics and pathology References Disease Hayata I, Sakurai M, Kakati S, Sandberg AA. Chromosomes and causation of human cancer and leukemia. XVI. Banding studies of chronic myelocytic leukemia, including five unusual Ph11 translocations. Cancer. 1975 Oct;36(4):1177-91 Acute lymphoblastic leukemia (ALL) most often (14 cases); chronic myelogenous leukemia (CML) (3 cases); one case of histiocyte-rich B-cell lymphoma. Kardon NB, Slepowitz G, Kochen JA. Childhood acute lymphoblastic leukemia associated with an unusual 8;14 translocation. Cancer Genet Cytogenet. 1982 Aug;6(4):339-43 Etiology Strikingly, of 18 patients, 4 have Down syndrome, 1 has neurofibromatosis Type I, and another one is dysmorphic and mentally retarded. Carroll AJ, Castleberry RP, Crist WM. Lack between abnormalities of the chromosome 9 either "lymphomatous" features or T cell childhood acute lymphocytic leukemia. Mar;69(3):735-8 Epidemiology Highly unbalanced sex ratio (13M/2F). of association short arm and phenotype in Blood. 1987 Crist W, Carroll A, Shuster J, Jackson J, Head D, Borowitz M, Behm F, Link M, Steuber P, Ragab A. Philadelphia chromosome positive childhood acute lymphoblastic leukemia: clinical and cytogenetic characteristics and treatment outcome. A Pediatric Oncology Group study. Blood. 1990 Aug 1;76(3):489-94 Clinics Still poorly known. Cytogenetics Hayashi Y, Pui CH, Behm FG, Fuchs AH, Raimondi SC, Kitchingman GR, Mirro J Jr, Williams DL. 14q32 translocations are associated with mixed-lineage expression in childhood acute leukemia. Blood. 1990 Jul 1;76(1):150-6 Cytogenetics morphological Sole anomaly in 4 ALL cases; accompany a t(9;22)(q34;q11) in 4 of the 14 ALL cases (and in the CML cases); unbalanced form with a der(14) t(8;14) in 3 cases, indicating that the crucial event is likely to lie on der(14). Hu N, Bian ML, Le Beau MM, Rowley JD. Cytogenetic analysis of 51 patients with chronic myeloid leukemia. Chin Med J (Engl). 1990 Oct;103(10):831-9 Wodzinski MA, Watmore AE, Lilleyman JS, Potter AM. Chromosomes in childhood acute lymphoblastic leukaemia: karyotypic patterns in disease subtypes. J Clin Pathol. 1991 Jan;44(1):48-51 Additional anomalies t(8;14) seems to be typically an anomaly secondary to t(9;22) (7/18 cases (40%), see above); anomalies additional to t(8;14) are +X, and +8 (2 cases each). Genes involved and proteins Pui CH, Carroll AJ, Raimondi SC, Schell MJ, Head DR, Shuster JJ, Crist WM, Borowitz MJ, Link MP, Behm FG. Isochromosomes in childhood acute lymphoblastic leukemia: a collaborative study of 83 cases. Blood. 1992 May 1;79(9):2384-91 Note The gene involved in 8q11 is unknown; the gene involved in 14q32 is IgH, found rearranged in a case where it was tested. Secker-Walker LM, Hawkins JM, Prentice HG, Mackie PH, Heerema NA, Provisor AJ. Two Down syndrome patients with an acquired translocation, t(8;14)(q11;q32), in early B-lineage acute lymphoblastic leukemia. Cancer Genet Cytogenet. 1993 Oct 15;70(2):148-50 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 196 t(8;14)(q11;q32) Huret JL Testoni N, Zaccaria A, Martinelli G, Pelliconi S, Buzzi M, Farabegoli P, Panzica G, Tura S. t(8;14)(q11;q32) in acute lymphoid leukemia: description of two cases. Cancer Genet Cytogenet. 1993 May;67(1):55-8 Sun T, Susin M, Tomao FA, Brody J, Koduru P, Hajdu SI. Histiocyte-rich B-cell lymphoma. Hum Pathol. 1997 Nov;28(11):1321-4 Forrest DL, Nevill TJ, Horsman DE, Brockington DA, Fung HC, Toze CL, Conneally EA, Hogge DE, Sutherland HJ, Nantel SH, Shepherd JD, Barnett MJ. Bone marrow transplantation for adults with acute leukaemia and 11q23 chromosomal abnormalities. Br J Haematol. 1998 Dec;103(3):630-8 Shearer P, Parham D, Kovnar E, Kun L, Rao B, Lobe T, Pratt C. Neurofibromatosis type I and malignancy: review of 32 pediatric cases treated at a single institution. Med Pediatr Oncol. 1994;22(2):78-83 Litz CE, Davies S, Brunning RD, Kueck B, Parkin JL, Gajl Peczalska K, Arthur DC. Acute leukemia and the transient myeloproliferative disorder associated with Down syndrome: morphologic, immunophenotypic and cytogenetic manifestations. Leukemia. 1995 Sep;9(9):1432-9 Whitehead VM, Vuchich MJ, Cooley LD, Lauer SJ, Mahoney DH, Shuster JJ, Payment C, Koch PA, Akabutu JJ, Bowen T, Kamen BA, Ravindranath Y, Emami A, Look AT, Beardsley GP, Pullen DJ, Camitta B. Accumulation of methotrexate polyglutamates, ploidy and trisomies of both chromosomes 4 and 10 in lymphoblasts from children with B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Leuk Lymphoma. 1998 Nov;31(5-6):507-19 Schoch C, Rieder H, Stollmann-Gibbels B, Freund M, Tischler HJ, Silling-Engelhardt G, Fonatsch C. 17p anomalies in lymphoid malignancies: diagnostic and prognostic implications. Leuk Lymphoma. 1995 Apr;17(3-4):271-9 This article should be referenced as such: Lee AC, Chan LC, Kwong KW. Down syndrome, acute lymphoblastic leukemia, and t(8;14)(q11;q32) Cancer Genet Cytogenet. 1996 May;88(1):92 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Huret JL. t(8;14)(q11;q32). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):196-197. 197 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review del(17p) in myeloïd malignancies Valérie Soenen-Cornu, Claude Preudhomme, Jean-Luc Laï, Marc Zandecki, Pierre Fenaux Laboratoire d'Hématologie A Hôpital Albert, Calmette - CHRU de Lille, Boulevard du Pr Leclercq 59037, Lille Cedex, France (VSC, CP, JLL, MZ, PF) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del17pID1142.html DOI: 10.4267/2042/37563 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Alias: 17p syndrome in myeloïd malignancies Note: Recently, we and others reported in ANLL and MDS a strong correlation between 17p deletion (a clonal cytogenetic anomaly consisting of a deletion of the short arm of chromosome 17), and a particular form of morphological dysgranulopoiesis, we also found in such cases a strong correlation between 17p deletion and p53 mutation; these correlations suggest that ANLL and MDS with 17p deletion constitute a new morphologicalcytogenetic-molecular entity, the " 17p syndrome " 17p syndrome R- banding: various rearrangements of chromosomes 5 and/or 7, and 17 - Courtesy Jean-Luc Lai. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 198 del(17p) in myeloïd malignancies Soenen-Cornu V et al. Clinics and pathology Epidemiology Disease 3 to 4% of ANLL and MDS. Mean age > 60 years. Sex ratio : about 1M/1F. Acute non lymphocytic leuemia/myelodysplastic syndromes (ANLL/MDS), chronic myelogenous leukemia (CML) in blast crisis. Clinics Not specific (consequences of cytopenias infection, bleeding, anemia) Phenotype/cell stem origin Mainly refractory anemia with excess of blasts RAEB/RAEB-t in MDS, often M2 or M6 in ANLL / multi-lineage involvement. Cytology Most cases of ANLL and MDS with 17p deletion have a particular form of morphological dysgranulopoiesis, combining both nuclear and cytoplasmic abnormalities in at least 5% of neutrophils; affected cells have reduced size and are mostly mature; nucleus is bi- or non-lobulated and chromatin is well- or heavilyclumped; cytoplasm contains variable number of small clear vacuoles and sometimes a reduced number of granules; these morphological abnormalities involve neutrophilic, Etiology About 30% of ANLL and MDS with 17p deletion are therapy related; t-ANLL and t-MDS occur after a lymphoïd neoplasm or a solid tumor treated by chemotherapy with an alkylating agent or after essential thrombocytemia or polycythemia vera treated by hydroxyurea alone or associated with other drugs. 17p syndrome - Courtesy Georges Flandrin. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 199 del(17p) in myeloïd malignancies Soenen-Cornu V et al. but also eosinophilic and basophilic lineages; such abnormalities can be observed both in the bone marrow and in the peripheral blood; however, in the latter instance, it may be difficult to demonstrate pseudoPelger Huët anomaly, due to frequent neutropenia; these nuclear changes mimick those found in the socalled constitutional Pelger-Huët hypolobulation of polymorphonuclear leukocytes. Dysgranulopoiesis features are frequently associated with variable degree of dyserythropoiesis and dysmegakaryocytopoiesis. Genes involved and proteins Pathology Description Inactivation of the P53 gene by deletion of one allele and mutation of the non deleted allele. Detection p53 deletion: conventional cytogenetics, FISH with p53 specific probes. p53 mutation: SSCP or immunocytochemistry. P53 Location 17p13.1 Result of the chromosomal anomaly Hybrid gene Not reported. Treatment Classical anthracycline-Ara C chemotherapy gives poor results; the only possibility of cure appears to be by allogeneic stem cell transplantation, but very few allografted cases have been reported. Evolution To be noted Worsening of cytopenias, progression to ANLL. Note In few 17p deletion cases, whole chromosomal painting and fluorescence in situ hybridization (FISH) analysis with p53 specific probe demonstrate that unidentified ring or marker chromosomes observed in conventional cytogenetic can contain 17p material including the second p53 allele; in these few cases, the particular form of morphological dysgranulopoiesis abnormalities observed in 17p- syndrome are not observed. Prognosis Very poor, median survival: 4 months. Cytogenetics Cytogenetics morphological 17p deletions result mainly from unbalanced translocation between 17p and another chromosome and less frequently from monosomy 17, isochromosome 17q and partial 17p deletion; chromosome 5 is the partner chromosome the most frequently involved in the unbalanced translocation, other involved chromosomes are mainly chromosomes 7, 12, 18, 21 and 22. References Kuriyama K, Tomonaga M, Matsuo T, Ginnai I, Ichimaru M. Diagnostic significance of detecting pseudo-Pelger-Huët anomalies and micro-megakaryocytes in myelodysplastic syndrome. Br J Haematol. 1986 Aug;63(4):665-9 Sessarego M, Ajmar F. Correlation between acquired pseudoPelger-Huet anomaly and involvement of chromosome 17 in chronic myeloid leukemia. Cancer Genet Cytogenet. 1987 Apr;25(2):265-70 Cytogenetics molecular The breakpoint on chromosome 17 and the extent of the deletion of 17p are variable, but the breakpoint is always proximal to the p53 gene; the variable extent of 17p deletion suggests the presence of tumor suppressor gene(s) on 17p, inactivated by the deletion. The p53 gene is a good candidate. Laï JL, Zandecki M, Fenaux P, Le Baron F, Bauters F, Cosson A, Deminatti M. Translocations (5;17) and (7;17) in patients with de novo or therapy-related myelodysplastic syndromes or acute nonlymphocytic leukemia. A possible association with acquired pseudo-Pelger-Huët anomaly and small vacuolated granulocytes. Cancer Genet Cytogenet. 1990 Jun;46(2):173-83 Additional anomalies Fenaux P, Jonveaux P, Quiquandon I, Laï JL, Pignon JM, Loucheux-Lefebvre MH, Bauters F, Berger R, Kerckaert JP. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Blood. 1991 Oct 1;78(7):1652-7 Chromosome 17p rearrangement or monosomy 17 are frequently associated to at least 2 other chromosomal rearrangements and are therefore part of complex abnormalities; the most frequent additional abnormalities include chromosomes 5 and/or 7, but also chromosomes 12, 16 and 11; complex karyotypes are associated in some cases with unidentified ring or marker chromosomes; however, some cases of iso(17q) are isolated or associated with a few additional chromosome anomalies. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Jonveaux P, Fenaux P, Quiquandon I, Pignon JM, Laï JL, Loucheux-Lefebvre MH, Goossens M, Bauters F, Berger R. Mutations in the p53 gene in myelodysplastic syndromes. Oncogene. 1991 Dec;6(12):2243-7 Fenaux P, Preudhomme C, Quiquandon I, Jonveaux P, Laï JL, Vanrumbeke M, Loucheux-Lefebvre MH, Bauters F, Berger R, Kerckaert JP. Mutations of the P53 gene in acute myeloid leukaemia. Br J Haematol. 1992 Feb;80(2):178-83 200 del(17p) in myeloïd malignancies Soenen-Cornu V et al. Lepelley P, Preudhomme C, Vanrumbeke M, Quesnel B, Cosson A, Fenaux P. Detection of p53 mutations in hematological malignancies: comparison between immunocytochemistry and DNA analysis. Leukemia. 1994 Aug;8(8):1342-9 Soenen V, Preudhomme C, Roumier C, Daudignon A, Laï JL, Fenaux P. 17p Deletion in acute myeloid leukemia and myelodysplastic syndrome. Analysis of breakpoints and deleted segments by fluorescence in situ. Blood. 1998 Feb 1;91(3):1008-15 Preudhomme C, Vanrumbeke M, Lai JL, Lepelley P, Wattel E, Fenaux P. Inactivation of the p53 gene in leukemias and myelodysplastic syndrome (MDS) with 17p monosomy. Leukemia. 1994 Dec;8(12):2241-2 Soenen V, Preudhomme C, Roumier C, Laï JL, Lepelley P, Facon T, Pagniez D, Fenaux P. Myelodysplasia during the course of myeloma. Restriction of 17p deletion and p53 overexpression to myeloid cells. Leukemia. 1998 Feb;12(2):238-41 Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, Morel P, Fenaux P. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994 Nov 1;84(9):3148-57 Sterkers Y, Preudhomme C, Laï JL, Demory JL, Caulier MT, Wattel E, Bordessoule D, Bauters F, Fenaux P. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Blood. 1998 Jan 15;91(2):616-22 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 Merlat A, Lai JL, Sterkers Y, Demory JL, Bauters F, Preudhomme C, Fenaux P. Therapy-related myelodysplastic syndrome and acute myeloid leukemia with 17p deletion. A report on 25 cases. Leukemia. 1999 Feb;13(2):250-7 Jary L, Mossafa H, Fourcade C, Genet P, Pulik M, Flandrin G. The 17p-syndrome: a distinct myelodysplastic syndrome entity? Leuk Lymphoma. 1997 Mar;25(1-2):163-8 This article should be referenced as such: Soenen-Cornu V, Preudhomme C, Laï JL, Zandecki M, Fenaux P. del(17p) in myeloïd malignancies. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):198-201. Preudhomme C, Fenaux P. The clinical significance of mutations of the P53 tumour suppressor gene in haematological malignancies. Br J Haematol. 1997 Sep;98(3):502-11 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 201 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication M0 acute non lymphocytic leukemia (M0-ANLL) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/M0ANLLID1057.html DOI: 10.4267/2042/37564 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology 7/del(7q), or rearrangements of chromosome 5 and/or 7 in 15-20%; chromosome 11 rearrangements (11q23 in particular), and chromosome 8 involvement (+8) in 1015%; t(9;22)(q34;q11) in 5%; normal karyotype in 20%. Identity Alias: Minimally leukemia differentiated acute myeloid Clinics and pathology References Epidemiology Costello R, Mallet F, Chambost H, Sainty D, Arnoulet C, Gastaut JA, Olive D. The immunophenotype of minimally differentiated acute myeloid leukemia (AML-M0): reduced immunogenicity and high frequency of CD34+/CD38- leukemic progenitors. Leukemia. 1999 Oct;13(10):1513-8 Rare: 3-5% of ANLL; med age 45 years; 20% are children; unbalanced sex ratio in the adults: 1.6 M/1 F, p<0.01. Cytology Stasi R, Amadori S. AML-M0: a review of laboratory features and proposal of new diagnostic criteria. Blood Cells Mol Dis. 1999 Apr;25(2):120-9 Cytochemistry: negative for myeloperoxydase, positive for myeloid markers and negative for specific markers of the lymphoid or megakaryocytic lineages; immunophenotype: CD34+, HLA-DR+, CD117+ (corresponding to c-KIT), TdT+, CD7+. Béné MC, Bernier M, Casasnovas RO, Castoldi G, Doekharan D, van der Holt B, Knapp W, Lemez P, Ludwig WD, Matures E, Orfao A, Schoch C, Sperling C, van 't Veer MB, on behalf of the European Group for the Immunological Characterization of Leukemias (EGIL). Acute myeloid leukemia (AML) M0: clinical characteristics and outcome. an analysis in 263 patients. Blood 1999;94 Suppl 1, p 67a, Abst 287 Prognosis Poor: CR in 50% of cases, med survival: 8 months. Cytogenetics This article should be referenced as such: Cytogenetics morphological Huret JL. M0 acute non lymphocytic leukemia (M0-ANLL). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):202. High percentage of complex (20%) and unbalanced karyotypes; partial or complete monosomy (5/del(5q), - Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 202 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(5;14)(q31;q32) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t514ID1111.html DOI: 10.4267/2042/37565 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Cytogenetics Additional anomalies Sole anomaly or accompanied with various secondary anomalies: +X, (i(7q), del(12p), +19. Genes involved and proteins IL3 Location 5q31 Protein 152 amino acids; growth factor; colony stimulating factor involved in the survival, proliferation and differentiation of multipotent hematopoietic cells. t(5;14)(q31;q32) G- banding - Courtesy Melanie Zenger and Claudia Haferlach. Clinics and pathology Disease IgH B-cell acute lymphoblastic leukemia (ALL) with hypereosinophilia. Location 14q32 Phenotype/cell stem origin Result of the chromosomal anomaly CD19+, CD10+ ALL; eosinophils are not part of the leukemic cells and do not carry the t(5;14); they represent a reactive population (eosinophilia in association with ALL is usually reactive). Hybrid gene Epidemiology Description Break in the promoter region of IL3 and in the Jh region of IgH. Rarely described; 6M/1F; affects both children and adults, general features of ALL with hypereosinophilia are rarity, male predominance; and young age. Fusion protein Cytology Expression / Localisation The immunoglobulin gene promoter controls the expression of IL3. Oncogenesis Over-expression of IL3. Marked eosinophilia; basophilia; IL3 is over-expressed. Prognosis Prognosis appears to be poor, a feature of ALLs with hypereosinophilia. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 203 t(5;14)(q31;q32) Huret JL Fishel RS, Farnen JP, Hanson CA, Silver SM, Emerson SG. Acute lymphoblastic leukemia with eosinophilia. Medicine (Baltimore). 1990 Jul;69(4):232-43 References Tono-oka T, Sato Y, Matsumoto T, Ueno N, Ohkawa M, Shikano T, Takeda T. Hypereosinophilic syndrome in acute lymphoblastic leukemia with a chromosome translocation [t(5q;14q)]. Med Pediatr Oncol. 1984;12(1):33-7 Meeker TC, Hardy D, Willman C, Hogan T, Abrams J. Activation of the interleukin-3 gene by chromosome translocation in acute lymphocytic leukemia with eosinophilia. Blood. 1990 Jul 15;76(2):285-9 Hogan TF, Koss W, Murgo AJ, Amato RS, Fontana JA, VanScoy FL. Acute lymphoblastic leukemia with chromosomal 5;14 translocation and hypereosinophilia: case report and literature review. J Clin Oncol. 1987 Mar;5(3):382-90 Chen Z, Morgan R, Sandberg AA. Non-random involvement of chromosome 5 in ALL. Cancer Genet Cytogenet. 1992 Jul 1;61(1):106-7 McConnell TS, Foucar K, Hardy WR, Saiki J. Three-way reciprocal chromosomal translocation in an acute lymphoblastic leukemia patient with hypereosinophilia syndrome. J Clin Oncol. 1987 Dec;5(12):2042-4 Heerema NA, Palmer CG, Weetman R, Bertolone S. Cytogenetic analysis in relapsed childhood acute lymphoblastic leukemia. Leukemia. 1992 Mar;6(3):185-92 Knuutila S, Alitalo R, Ruutu T. Power of the MAC (morphologyantibody-chromosomes) method in distinguishing reactive and clonal cells: report of a patient with acute lymphatic leukemia, eosinophilia, and t(5;14). Genes Chromosomes Cancer. 1993 Dec;8(4):219-23 Baumgarten E, Wegner RD, Fengler R, Ludwig WD, SchulteOverberg U, Domeyer C, Schüürmann J, Henze G. Callapositive acute leukaemia with t(5q;14q) translocation and hypereosinophilia--a unique entity? Acta Haematol. 1989;82(2):85-90 This article should be referenced as such: Grimaldi JC, Meeker TC. The t(5;14) chromosomal translocation in a case of acute lymphocytic leukemia joins the interleukin-3 gene to the immunoglobulin heavy chain gene. Blood. 1989 Jun;73(8):2081-5 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Huret JL. t(5;14)(q31;q32). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):203-204. 204 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Mini Review Bladder: Squamous cell carcinoma Jean-Loup Huret, Claude Léonard Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH), Cytogénétique Laboratoire d'Anatomo Pathologie, CHU Bicêtre, 78 rue Leclerc, F94270 Le KremlinBicêtre, France (CL) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Tumors/bladdersquamousID5062.html DOI: 10.4267/2042/37567 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Epidemiology Classification Geographic areas of high incidence: represents 70 to 80% of the cases of badder cancer in the Middle East and in Africa, in particular in Egypt, were it is the most common adult cancer; only 5% in Europe and in the USA, where the transitional cell carcinoma represents 90-95 % of cases. Existence of different histologic types of bladder cancer: - Squamous cell carcinoma: herein described, - Transitional cell carcinoma, - Adenocarcinoma: rare, - Poorly differenciated carcinoma/small cell carcinoma, exceptional. Pathology Grading and staging: tumours are: Graded by the degree of cellular atypia (G0->G3), and staged: pTIS carcinoma in situ (but high grade), and pTa papillary carcinoma, both mucosally confined; pT1 lamina propria invasive; pT2 infiltrates the superficial muscle, and pT3a, the deep mucle; pT3b invasion into perivesical fat; pT4 extends into neighbouring structures and organs. Clinics and pathology Disease Cancer of the urothelium. Etiology Most often secondary to bilharzial infection (schistosoma haematobium), may be associated with other types of long term irritations: chronic infections, calculi, treatment with cyclophosphamid. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 205 Bladder: Squamous cell carcinoma Huret JL, Léonard C Prognosis References Considered to have a poorer prognosis than the transitional cell carcinoma. Wheeless LL, Reeder JE, Han R, O'Connell MJ, Frank IN, Cockett AT, Hopman AH. Bladder irrigation specimens assayed by fluorescence in situ hybridization to interphase nuclei. Cytometry. 1994 Dec 1;17(4):319-26 Cytogenetics Gonzalez-Zulueta M, Shibata A, Ohneseit PF, Spruck CH 3rd, Busch C, Shamaa M, El-Baz M, Nichols PW, Gonzalgo ML, Elbaz M [corrected to El-Baz M. High frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder. J Natl Cancer Inst. 1995 Sep 20;87(18):1383-93 Cytogenetics Morphological Highly complex karyotypes, yet poorly known. Allelic losses are frequent; the most frequent regions involved in loss of heterozygocity (LOH) are 3p, 8p, 9p, 9q, 17p; the karyotype is more complex in advanced grades/stages, as in transitional cell carcinoma. Chromosome 7: trisomy 7 seems to be more frequent than in transitional cell carcinoma, and is found more often in advanced stages; unknown significance as +7 may also be found in normal tissues. Chromosome 9: monosomy 9 is an early event and might even occur at dysplastic stages; allelic losses are frequent, mainly in 9p (65%), more often than for transitional cell carcinoma; LOH are found in particular in the locus where CDKN2/P16 sits; homozygous deletion of P16 is frequent (50%) and may also be found in squamous metaplasias from cancerous patients (but not in squamous metaplasias from non cancerous patients); trisomy 9, on the other hand, would be frequent in advance diseases. Chromosome 17: P53 is often implicated, especially in high grades/stages; the profile of mutations of P53 is different from what is found in transitional cell carcinoma. Cytogenetics Molecular Comparative genomic hybridization (CGH) and multiFISH (M-FISH) are complementary tools to determine respectively unbalanced segments and structural rearrangements in these complex karyotypes. Ghaleb AH, Pizzolo JG, Melamed MR. Aberrations of chromosomes 9 and 17 in bilharzial bladder cancer as detected by fluorescence in situ hybridization. Am J Clin Pathol. 1996 Aug;106(2):234-41 Fadl-Elmula I, Gorunova L, Lundgren R, Mandahl N, Forsby N, Mitelman F, Heim S. Chromosomal abnormalities in two bladder carcinomas with secondary squamous cell differentiation. Cancer Genet Cytogenet. 1998 Apr 15;102(2):125-30 Pycha A, Mian C, Posch B, Haitel A, El-Baz M, Ghoneim MA, Marberger M. Numerical aberrations of chromosomes 7, 9 and 17 in squamous cell and transitional cell cancer of the bladder: a comparative study performed by fluorescence in situ hybridization. J Urol. 1998 Sep;160(3 Pt 1):737-40 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 Eissa S, Swelam M, Shaker Y, Abdel-Fattah M, Khalifa A. Expression of p21WAF1/CIP1 in bladder cancer: relation to schistosomiasis. IUBMB Life. 1999 Jul;48(1):115-9 Shaw ME, Elder PA, Abbas A, Knowles MA. Partial allelotype of schistosomiasis-associated bladder cancer. Int J Cancer. 1999 Mar 1;80(5):656-61 El-Rifai W, Kamel D, Larramendy ML, Shoman S, Gad Y, Baithun S, El-Awady M, Eissa S, Khaled H, Soloneski S, Sheaff M, Knuutila S. DNA copy number changes in Schistosoma-associated and non-Schistosoma-associated bladder cancer. Am J Pathol. 2000 Mar;156(3):871-8 Genes involved and proteins This article should be referenced as such: Note Multistep process; largely unknown. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Huret JL, Léonard C. Bladder: Squamous cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):205-206. 206 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Short Communication Soft tissue tumors: Malignant melanoma of soft parts Jérôme Couturier Department of Pathology, Institut Curie, Paris, France (JC) Published in Atlas Database: November 1999 Online updated version : http://AtlasGeneticsOncology.org/Tumors/MelanomaSoftID5024.html DOI: 10.4267/2042/37568 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology tendons or aponeuroses; mitotic index is generally low; the cells of nearly all cases express S-100 protein and the melanoma-associated antigen HMB45. Identity Alias: Clear cell sarcoma of soft parts. Treatment Classification The treatment protocols vary greatly according to the institutions; however, the melanoma of soft parts is a highly malignant tumour which requires surgical excision combined with radiotherapy and/or chemotherapy. This tumour, initially described by Enzinger as "clear cell sarcoma of tendons and aponeuroses", is of uncertain origin, but its immunohistochemical profile shows its melanocytic nature; however it has no genetic relationship with the cutaneous malignant melanoma. Evolution Clinics and pathology Being of melanocytic origin, this tumour should be classified as a neuroectodermal tumour. Many patients develop recurrences and regional and distant metastases, in lymph nodes, lung, and bones; in the series of Enzinger, the average time between diagnosis and recurrence was 2.6 years, between diagnosis and metastasis, 3.5 years. Etiology Prognosis Unknown. The prognosis is poor; in the series of 115 patients studied by Enzinger, 46% had died; of the 62 living patients, 21 experienced one or more recurrences, and 7 had a metastatic disease. Embryonic origin Epidemiology It is a very rare tumour representing a minority of all soft tissue sarcomas. Cytogenetics Clinics Cytogenetics Morphological The malignant melanoma of soft parts (MMSP) preferentially occurs in young adults, between ages of 20 and 40 years; the tumour develops mainly in the extremities, especially the legs (foot, knee, heel, ankle); it is usually deeply seated, and often bound to tendons and aponeuroses. This tumour is characterised by the presence of a chromosome translocation t(12;22)(q13;q12), which involves genes ATF-1, on chromosome 12, and EWS, on chromosome 22. Genes involved and proteins Pathology The tumours show compact nests and strands of round or fusiform cells with a clear cytoplasm, separated by fibrocollagenous tissue often connected to adjacent Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) EWSR1 Location 22q12 207 Soft tissue tumors: Malignant melanoma of soft parts Couturier J Protein RNA binding protein. References ATF-1 Zucman J, Delattre O, Desmaze C, Epstein AL, Stenman G, Speleman F, Fletchers CD, Aurias A, Thomas G. EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet. 1993 Aug;4(4):341-5 Location 12q13 Protein Transcription factor. Enzinger FM, Weiss SW. Malignant melanoma of soft parts In: Soft tissue tumors. 3rd ed. Mosby. St. Louis 1995. Fujimura Y, Ohno T, Siddique H, Lee L, Rao VN, Reddy ES. The EWS-ATF-1 gene involved in malignant melanoma of soft parts with t(12;22) chromosome translocation, encodes a constitutive transcriptional activator. Oncogene. 1996 Jan 4;12(1):159-67 Result of the chromosomal anomaly Fusion Protein Deenik W, Mooi WJ, Rutgers EJ, Peterse JL, Hart AA, Kroon BB. Clear cell sarcoma (malignant melanoma) of soft parts: A clinicopathologic study of 30 cases. Cancer. 1999 Sep 15;86(6):969-75 Description The chimaeric protein is composed of the N-terminal domain of EWS linked to the bZIP domain of ATF-1. Oncogenesis Binds to ATF sites present in cAMP-responsive promoters via the ATF1 bZIP domain and activates transcription constitutively, dependent on the activation domain (EAD) present in EWSR1. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) This article should be referenced as such: Couturier J. Soft tissue tumors: Malignant melanoma of soft parts. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):207208. 208 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Ataxia telangiectasia Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France (NU, JOB, RAG) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Kprones/ataxia.html DOI: 10.4267/2042/37569 This article is an update of: Huret JL. Ataxia telangiectasia. Atlas Genet Cytogenet Oncol Haematol.1998;2(4):153-154. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology malignancies, but not myeloid leukemia; carcinomas of the skin, ovary, breast, and stomach have also been described. Cancer treatment is complicated by radiation- and chemo-sensitivity. Identity Alias: Louis-Bar syndrome Note: See also, in Deep Insight section: AtaxiaTelangiectasia and variants. Inheritance: Autosomal recessive; frequency is about 1 to 2.5/105 newborns; heterozygotes are estimated to be 1% of the general population; founder effect are found in some isolated population. Evolution Progressive cerebellar degeneration: patients usually in a wheelchair by the age of ten. Prognosis Clinics Respiratory infection is the common cause of death, with cancer being the second most common. Survival is often into fourth decade today where optimal medical care is available. Note Ataxia telangiectasia is a chromosome instability syndrome with cerebellar degeneration, immunodeficiency, and an increased risk of cancers; AT cells are defective in recognizing double-strand DNA damage to signal for repair. Cytogenetics Inborn conditions Spontaneous chromatid/chromosome breaks, triradials, quadriradials (less prominent phenomenon than in Fanconi anaemia); telomeric associations. The best diagnosis test is on the (pathognomonic) highly elevated level (10% of mitoses) of inv(7)(p14q35), t(14;14)(q11;q32), and other non clonal stable chromosome rearrangements involving 2p12, 7p14, 7q35, 14q11, 14q32, and 22q11 (illegitimate recombinations between immunoglobulin superfamilly genes Ig and TCR); normal level of those rearrangements are: 1/500 (inv(14)), 1/200 (t(7;14)), 1/10 000 (inv(7)). Clonal rearrangements further occur in 10% of patients, but without manifestation of malignancy: t(14;14), inv(14), or t(X;14). Phenotype and clinics - Onset of the disease is often noted during the second year of life: there is progressive cerebellar ataxia (initially truncal, with further peripheral extension); ataxia is a constant feature in this disease; oculomotor apraxia, dysarthria, and dystonia; leading to muscular atrophia. - Telangiectasia: facial region exposed to sunlight, and eyes (conjunctiva). - Combined immunodeficiency (in 70%): thymus hypoplasia, and IgG2 and 4, IgA, IgE deficiency. - Other features: growth retardation; hypogonadism; occasionally diabetes mellitus. Neoplastic risk Risk of cancers is X 100, consisting mainly of T-cell malignancies (a 70-fold and 250-fold increased risks of leukemia and lymphoma respectively) and B-cell Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) are Cytogenetics of cancer Clonal rearrangements in T-cell ALL and T-PLL (prolymphocytic leukaemia) in AT patients are 209 Ataxia telangiectasia Uhrhammer N et al. complex, with the frequent involvement of t(14;14)(q11;q32), or t(X;14)(q28;q11), implicating the genes TCL1 or MTCP1 respectively, as is found in TPLL in non-AT patients. References Gorlin RJ, Cohen MM, Levin LS.. Syndromes of the Head and Neck. Oxford monographs on Medical Genetics No 19, Oxford University Press (1990), p. 469 Other findings Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994 Dec;66(6 Suppl):S177-82 Note - High sensitivity to ionizing radiations and to radiomimetic drugs (diagnostic may in part be based on the hypersensitivity of AT lymphocytes to killing by gamma irradiation); cell irradiation does not inhibit S phase (DNA synthesis): this is quite pathognomonic of AT, and shows that G1 checkpoint is deficient; there is a lack of P53, GADD45 and P21 induction, and a fall in radiation-induced apoptosis; P53 phosphorylation at ser15 is deficient. - Lenthening of the cell cycle. - Difficult to grow cells with phytohemaglutinin: karyotypes should be performed with interleukin 2 in 4 days cultures. - Other: increased level of serum alpha-fetoprotein. Greenwell PW, Kronmal SL, Porter SE, Gassenhuber J, Obermaier B, Petes TD. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell. 1995 Sep 8;82(5):823-9 Hari KL, Santerre A, Sekelsky JJ, McKim KS, Boyd JB, Hawley RS.. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell. 1995 Sep 8;82(5):815-21. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995 Jun 23;268(5218):1749-53 Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G. The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum Mol Genet. 1995 Nov;4(11):2025-32 Genes involved and proteins ATM Location 11q22-q23.1 DNA/RNA Description: 66 exons spanning 184 kb of genomic DNA. Protein Description: 3056 amino acids; 350 kDa; contains a Pl 3-kinase-like domain. Localisation: Mostly in the nucleus in replicating cells, cytoplasm in differentiating cells. Function: Mediates cell cycle arrest in response to ionizing radiation through the phophorylation of targets including p53, cAbl, IkB-alpha and chk1. Mutations Germinal: Various types of mutations, dispersed throughout the gene, and therefore most patients are compound heterozygotes; however, most mutations appear to inactivate the ATM protein by truncation, large deletions, or annulation of initiation or termination. Zakian VA. ATM-related genes: what do they tell us about functions of the human gene? Cell. 1995 Sep 8;82(5):685-7 Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, WynshawBoris A. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996 Jul 12;86(1):159-71 Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood. 1996 Jan 15;87(2):423-38 Brown KD, Ziv Y, Sadanandan SN, Chessa L, Collins FS, Shiloh Y, Tagle DA. The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not upregulated following genome damage. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1840-5 Chen X, Yang L, Udar N, Liang T, Uhrhammer N, Xu S, Bay JO, Wang Z, Dandakar S, Chiplunkar S, Klisak I, Telatar M, Yang H, Concannon P, Gatti RA. CAND3: a ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 11q23.1. Mamm Genome. 1997 Feb;8(2):129-33 Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A. Ataxia-telangiectasia locus: sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene. Genome Res. 1997 Jun;7(6):592-605 To be noted Shiloh Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet. 1997;31:635-62 Note Heterozygote cancer risk: the relative risk of breast cancer in A-T heterozygote women has been estimated through epidemiological studies to be 3.9 (CI 2.1-7.1), and through haplotype analysis to be 3.32 (CI 1.756.38); since the A-T heterozygote frequency is about 1%, 2-4% of breast cancer cases may be due to ATM heterozygosity; the risk of other types of cancer in A-T heterozygotes is low. The A-T variant Nijmegen breakage syndrome does not involve the same gene. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, Döhner H. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med. 1997 Oct;3(10):1155-9 Vorechovský I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarström L, Webster AD, Yuille MA. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet. 1997 Sep;17(1):96-9 210 Ataxia telangiectasia Uhrhammer N et al. Westphal CH. Cell-cycle signaling: Atm displays its many talents. Curr Biol. 1997 Dec 1;7(12):R789-92 Xie G, Habbersett RC, Jia Y, Peterson SR, Lehnert BE, Bradbury EM, D'Anna JA. Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpoints. Oncogene. 1998 Feb 12;16(6):721-36 Ziv Y, Bar-Shira A, Pecker I, Russell P, Jorgensen TJ, Tsarfati I, Shiloh Y. Recombinant ATM protein complements the cellular A-T phenotype. Oncogene. 1997 Jul 10;15(2):159-67 Janin N, Andrieu N, Ossian K, Laugé A, Croquette MF, Griscelli C, Debré M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families. Br J Cancer. 1999 Jun;80(7):1042-5 Gatti RA.. Ataxia-telangiectasia. B Vogelstein and K W Kinzler, Editors, The Genetic Basis of Human Cancer, McGraw-Hill, Inc., New York. 1998: 275-300. Telatar M, Teraoka S, Wang Z, Chun HH, Liang T, CastellviBel S, Udar N, Borresen-Dale AL, Chessa L, BernatowskaMatuszkiewicz E, Porras O, Watanabe M, Junker A, Concannon P, Gatti RA. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet. 1998 Jan;62(1):86-97 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) This article should be referenced as such: Uhrhammer N, Bay JO, Gatti RA. Ataxia telangiectasia. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):209-211. 211 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Dysplastic nevus syndrome (DNS) Claude Viguié Service de Dermatologie, Hôpital Tarnier-Cochin, 89 rue d'Assas, 75006 Paris, France (CV) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Kprones/DysplNevusID10013.html DOI: 10.4267/2042/37570 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity of DNS is difficult to evaluate because a number of cases without malignant evolution are not recorded; DNS defines patients with numerous dysplastic nevi. FAMMM defines families where coexist numerous nevi with malignant melanoma (MM).Sporadic forms of dysplastic nevi are not considered as DNS. Alias: Familial atypical mole-malignant melanoma syndrome (FAMMM); B-K mole syndrome Inheritance: Autosomal dominant with high penetrance and variable expressivity; the frequency Multiple dysplastic naevi on the skin of the back, with (left) a surgically resected malignant melanoma on the scalp - Courtesy Daniel Wallach. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 212 Dysplastic nevus syndrome (DNS) Viguié C Clinics Cytogenetics Note The familial dysplastic nevus syndrome is a good example of a genetic disorder which leads to the practice of self prevention and prevention at the family level; the risk is the evolution towards MM. Inborn conditions A chromosome instability disorder was observed in cell cultures from the normal skin and dysplastic nevi over three-generations in DNS families, leading to translocations, duplications and deletions; in another study on MM, translocations involving bands 11q24, 1q25 and Xq13 were observed in patients with DNS, in dysplastic nevi and in the normal skin as well; a loss of chromosome 9 was found in 2 out of 4 DN, suggesting that deletion / inactivation of a gene on 9p may be a primary event in melanocyte transformation; loss of heterozygocity (LOH) for markers flanking the CDKN2A on 9p was described in primary MM and in a metastasis; other putative tumor suppressor genes which could be involved in the process are located in 1p13, 10p, 10q, 11q and 6q15-q23. DNS is characterized cytogeneticaly by an UV-induced elevated level of sister chromatid exchange (SCE); the post-UV plasmid hypermutability test is a laboratory marker for FAMMM patients, suggesting a defective repair mechanism of UV-induced DNA damage; deficient DNA repair in lymphocyte studies also characterizes some patients with sporadic dysplastic nevi or non familial MM. Phenotype and clinics Predominant in patients with a clear complexion, blue eyes and/or presence of numerous nevi; the dysplastic nevus or "nevus of Clark" or "atypical melanocytic nevus" is a large mole with a variable size (5 to 15 mm), an irregular border and a color varying from dark brown to depigmentation; lesions are located mainly on the upper trunk, back, limbs, abdomen and arms; the number of moles is variable, from 10 to up to 100. Histologic studies show the dysplastic nature of these nevi: junctional hyperplasia with isolated or clustered melanocytes, cells with large, irregular, hyperchromatic, and non mitotic nucleus; this aspect is intermediate between benign nevus and MM. Neoplastic risk The main risk is to develop a MM but there is also a possible increased incidence of pancreatic cancer, breast cancer, and myeloma; MM usually arises from a dysplastic nevus (DN) but it can also appear de novo or from a benign nevus; it occurs most often in the skin but it may also involve other sites, mainly the eye or the central nervous system; the risk of MM depends on three factors: 1- The number of nevi: MM occurs in 2 to 7% of the population; without DN the risk is multiplied by 2 if the total number of nevi is higher than 25; the risk is multiplied by 4 if they are more than 5 nevi with a diameter higher than 5 cm; the risk is multiplied by 2 with one DN and by 12 with 10 DN; 40% of MM occur on dysplastic nevi, more frequently in superficial than nodular forms. 2- The existence of at least one case of MM in the family (risk x 2); the risk of MM is 100% in case of FAMMM; the patients with DNS who develop MM are notably younger than patients with sporadic forms; the age of onset in FAMMM regresses from generation to generation. 3- The role of UV as a promoting factor is discussed; the number of DN increases with sun exposure. Genes involved and proteins Still unknown Location Locus in 1p36 (called CMM1 for cutaneous malignant melanoma): this locus segregates with MM and DNS, but no gene is yet cloned. CDKN2C/p18 (cyclin-dependent kinase inhibitor 2) Location Locus in 1p32; this locus has been found mutated in the germline from patients with MM and other tumors. CDKN2A/p16/MTS1/CDK4 inhibitor (cyclin-dependent kinase inhibitor 2A) Location Locus in 9p21; this locus has been designated as CMM2; germline mutations were found in this locus in 30 to 40% of patients with FAMMM, and in some patients with two cutaneous and/or mucous MM; P16 is a candidate gene for MM susceptibility; there is a p16 mutation in 10 to 14% of patients suffering from sporadic multifocal MM; P16 is also involved in several other types of cancers; other tumor suppressor genes located at 9p are hypothetically involved in MM progression. Treatment Clinical vigilance and tumour exeresis. Evolution The number of DN can increase during life with an increase in MM risk. Prognosis CDK4 (cyclin dependent kinase) According to the tumour expansion at the time of exeresis. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Location Locus in 12q14; 2 germline mutations found in 3 FAMMM families. 213 Dysplastic nevus syndrome (DNS) Viguié C Goldstein AM, Dracopoli NC, Engelstein M, Fraser MC, Clark WH Jr, Tucker MA. Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity. Am J Hum Genet. 1994 Mar;54(3):48996 Still unknown Location Locus in 6q: a 6q allelic loss was identified in 21 of 53 informative loci; the chromosomal region bearing the highest frequency of 6q allelic loss was defined by the markers MYB and ESR located at 6q22-q23 and 6q24q27, respectively; this may indicate genetic heterogeneity. Levin DB, Wilson K, Valadares de Amorim G, Webber J, Kenny P, Kusser W. Detection of p53 mutations in benign and dysplastic nevi. Cancer Res. 1995 Oct 1;55(19):4278-82 Novakovic B, Clark WH Jr, Fears TR, Fraser MC, Tucker MA. Melanocytic nevi, dysplastic nevi, and malignant melanoma in children from melanoma-prone families. J Am Acad Dermatol. 1995 Oct;33(4):631-6 MC1R (melanocortin receptor) Location Locus in 16q24.3; defined as possible susceptibility gene. Pavarino EC, Antonio JR, Pozzeti EM, Larranãga HJ, Tajara EH. Cytogenetic study of neoplastic and nonneoplastic cells of the skin. Cancer Genet Cytogenet. 1995 Nov;85(1):16-9 P53 Cannon-Albright LA, Kamb A, Skolnick M. A review of inherited predisposition to melanoma. Semin Oncol. 1996 Dec;23(6):667-72 Location 17p13; P53 mutations were found in benign and dysplastic nevi from patients with previous personal or familial history of MM; however, these mutations are considered to be late events and cannot be used as a marker to identify patients at high risk of MM. Harland M, Meloni R, Gruis N, Pinney E, Brookes S, Spurr NK, Frischauf AM, Bataille V, Peters G, Cuzick J, Selby P, Bishop DT, Bishop JN. Germline mutations of the CDKN2 gene in UK melanoma families. Hum Mol Genet. 1997 Nov;6(12):2061-7 Moriwaki SI, Tarone RE, Tucker MA, Goldstein AM, Kraemer KH. Hypermutability of UV-treated plasmids in dysplastic nevus/familial melanoma cell lines. Cancer Res. 1997 Oct 15;57(20):4637-41 References Greene MH, Clark WH Jr, Tucker MA, Elder DE, Kraemer KH, Guerry D 4th, Witmer WK, Thompson J, Matozzo I, Fraser MC. Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome. N Engl J Med. 1985 Jan 10;312(2):91-7 Puig S, Ruiz A, Castel T, Volpini V, Malvehy J, Cardellach F, Lynch M, Mascaro JM, Estivill X. Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene. Hum Genet. 1997 Dec;101(3):359-64 Hecht F, Hecht BK. Chromosome rearrangements in dysplastic nevus syndrome predisposing to malignant melanoma. Cancer Genet Cytogenet. 1988 Oct 1;35(1):73-8 Sanford KK, Parshad R, Price FM, Tarone RE, Thompson J, Guerry D. Radiation-induced chromatid breaks and DNA repair in blood lymphocytes of patients with dysplastic nevi and/or cutaneous melanoma. J Invest Dermatol. 1997 Oct;109(4):5469 Cowan JM, Francke U. Cytogenetic analysis in melanoma and nevi. Cancer Treat Res. 1991;54:3-16 Hürlimann AF, Bohnert E, Schnyder UW, Jung EG. Dysplastic nevus syndrome: intrafamilial identification of carriers by cytogenetics. Dermatology. 1992;184(3):223-5 Ang CG, Kelly JW, Fritschi L, Dowling JP. Characteristics of familial and non-familial melanoma in Australia. Melanoma Res. 1998 Oct;8(5):459-64 Lassam NJ, From L, Kahn HJ. Overexpression of p53 is a late event in the development of malignant melanoma. Cancer Res. 1993 May 15;53(10 Suppl):2235-8 Platz A, Hansson J, Ringborg U. Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study. Int J Cancer. 1998 Sep 25;78(1):13-5 Titus-Ernstoff L, Barnhill RL, Duray PH, Ernstoff MS, Kirkwood JM. Dysplastic nevi in relation to superficial spreading melanoma. Cancer Epidemiol Biomarkers Prev. 1993 MarApr;2(2):99-101 Lefkowitz A, Schwartz RA, Janniger CK. Melanoma precursors in children. Cutis. 1999 Jun;63(6):321-4 Carey WP Jr, Thompson CJ, Synnestvedt M, Guerry D 4th, Halpern A, Schultz D, Elder DE. Dysplastic nevi as a melanoma risk factor in patients with familial melanoma. Cancer. 1994 Dec 15;74(12):3118-25 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) This article should be referenced as such: Viguié C. Dysplastic nevus syndrome (DNS). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):212-214. 214 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Nijmegen breakage syndrome Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France (NU, JOB, RAG) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Kprones/NijmegenID10020.html DOI: 10.4267/2042/37571 This article is an update of: Couturier J. Nijmegen breakage syndrome. Atlas Genet Cytogenet Oncol Haematol.1999;3(1):46-47. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology though the mental retardation appears to be progressive; cerebellar ataxia is absent; alphafoetoprotein levels are normal, in contrast to AT patients. - Craniofacial dysmorphy: progressive and severe microcephaly, "bird-like" face with prominent midface, long nose and receding mandible. - Immunodeficiency: severe combined deficiency with agammaglobulinemia, IgA, IgG2 and IgG4 deficiencies, decreased CD3+ and CD4+ lymphocytes, and decreased CD4+/CD8+ ratio; these disturbances are responsible of frequent respiratory, gastrointestinal and urinary infections. Identity Alias: Ataxia-telangiectasia, variant VI; Seemanova syndrome II; Microcephaly with normal intelligence, immunodeficiency, lymphoreticular malignancies; Immunodeficiency, microcephaly, chromosomal instability Note: Belongs to the group of inherited chromosomal instability syndromes: - Bloom's syndrome, - Fanconi's disease, - Ataxia telangiectasia (AT); see also, in Deep Insight section: Ataxia-Telangiectasia and variants. Inheritance: Autosomal recessive disease; since the recognition of the Nijmegen breakage syndrome (NBS) in 1981, about 50 patients are included in the NBS Registry in Nijmegen; the disease appears to have originated in central Europe, in the Slavic population, and to have spread through a founder effect. Neoplastic risk High frequency and early development of lymphomas, more often involving B-cells, in contrast with those found in AT; other forms of cancer may also be at higher risk. Cytogenetics Clinics Inborn conditions Note The condition is characterised by growth and mental retardation, craniofacial dysmorphy, ovarian failure, immunodeficiency, chromosome instability, predisposition to lymphoid malignancies, and radiosensitivity. - Lymphocyte cultures often show low mitotic index. - Structural chromosome aberrations are observed in 10-30% of metaphases; most of the rearrangements occur in or between chromosomes 7 and 14, at bands 7p13, 7q35, 14q11, and 14q32, as in AT; these bands contain immunoglobulin and T-cell receptor genes; the most frequent rearrangement is the inv(7)(p13q35). Phenotype and clinics Other findings - Growth and mental development: 30% of children have low birth weight and short stature, and 75% a head circumference at birth below the 3rd percentile; all patients develop a severe microcephaly during the first months of life; mental development is normal in 35% of the patients, moderately retarded in the others, Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Note Radiosensitivity: increased sensitivity of both lymphocytes and fibroblasts to ionising radiations and radiomimetics, radio-resistant DNA synthesis. 215 Nijmegen breakage syndrome Uhrhammer N, et al. Maser RS, Monsen KJ, Nelms BE, Petrini JH. hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks. Mol Cell Biol. 1997 Oct;17(10):6087-96 Genes involved and proteins NBS1 Location 8q21 DNA/RNA Description: 16 exons. Protein Function: The product of NBS1, nibrin (p95), should have a role in the control of double-strand DNA breaks involved, for example, in VDJ joining in immunoglobulin and T-cell receptor genes recombination process, in meiotic recombination, and in radio-induced DNA lesions; this suggests that nibrin and the product of ATM could act in a common pathway of detection or repair of double-strand breaks; nibrin/p95 is found associated with Rad50 and Mre11 at sites of DNA double-strand breaks. Mutations Germinal: All Nijmegen patients show truncating mutations. Shiloh Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu Rev Genet. 1997;31:635-62 References Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD, Lee WH. Association of BRCA1 with the hRad50hMre11-p95 complex and the DNA damage response. Science. 1999 Jul 30;285(5428):747-50 Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S, Endo S, Smeets D, Solder B, Belohradsky BH, Der Kaloustian VM, Oshimura M, Isomura M, Nakamura Y, Komatsu K. Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet. 1998 Jun;19(2):179-81 Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, Wilson RK, Digweed M, Rosenthal A, Sperling K, Concannon P, Reis A. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 1998 May 1;93(3):467-76 Yamazaki V, Wegner RD, Kirchgessner CU. Characterization of cell cycle checkpoint responses after ionizing radiation in Nijmegen breakage syndrome cells. Cancer Res. 1998 Jun 1;58(11):2316-22 Dong Z, Zhong Q, Chen PL. The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage. J Biol Chem. 1999 Jul 9;274(28):19513-6 van der Burgt I, Chrzanowska KH, Smeets D, Weemaes C. Nijmegen breakage syndrome. J Med Genet. 1996 Feb;33(2):153-6 This article should be referenced as such: Jongmans W, Vuillaume M, Chrzanowska K, Smeets D, Sperling K, Hall J. Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation. Mol Cell Biol. 1997 Sep;17(9):5016-22 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Uhrhammer N, Bay JO, Gatti RA. Nijmegen breakage syndrome. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):215-216. 216 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Short Communication WAGR (Wilms' tumor/aniridia/genitourinary anomalies/mental retardation syndrome) Manfred Gessler Theodor-Boveri-Institut fuer Biowissenschaften, Lehrstuhl Physiol. Chemie I, Am Hubland, D-97074 Wuerzburg, Germany (MG) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Kprones/WAGRID10032.html DOI: 10.4267/2042/37572 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Genes involved and proteins Inheritance: Generally sporadic, a few inherited cases sometimes with milder phenotype were reported; occurrence: rare Note Contiguous gene syndrome: - Wilms' tumor: WT1 Wilms' tumor suppressor gene, - Genitourinary anomalies: WT1 haplo-insufficiency, - Mental retardation: unknown, - Aniridia: PAX6. Clinics Phenotype and clinics WT1 (Wilms' tumor suppressor gene) - High Wilms' tumor (WT) risk (can also manifest bilaterally), - Aniridia (AN), - Genitourinary anomalies (GU) (hypospadias and kryptorchism in males), - Mental retardation, - (Growth retardation). Various combinations of these features can be present, partly depending on deletion extent. Location 11p13 DNA/RNA Description: 10 exons Transcription: 3 kb mRNA; four alternative splice forms. Protein Description: 429 to 449 amino acids, according to alternative splicings; zinc finger transcription factor. Localisation: Nuclear. Mutations Germinal: Various types of mutations, mostly affecting zinc fingers. Somatic: Biallelic inactivation in Wilms' tumors (<15%). Neoplastic risk High. Cytogenetics Inborn conditions del(11)(p13), contiguous gene syndrome with WT/GU and AN loci separated by about 700 kb; deletions may be cytogenetically invisible. PAX6 (paired-homeodomain protein) Location 11p13 DNA/RNA Description: http://www.hgu.mrc.ac.uk/Softdata/PAX6/About/pax6c dna.htm Cytogenetics of cancer Deletions of the second chromosome 11 copy are rare; Wilms' tumors of WAGR patients frequently show subtle mutations of the remaining WT1 allele. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 217 WAGR (Wilms' tumor/aniridia/genitourinary anomalies/mental retardation syndrome) Protein Description: Paired-homeobox transcription factor; see http://www.hgu.mrc.ac.uk/Softdata/PAX6/About/about .htm. Expression: Mainly eye, CNS and nasal development. Localisation:Nuclear. Function: Transcriptional regulator. Homology: Pax gene family. Mutations Germinal: Mostly nonsense mutations; see (The Human PAX6 Mutation Database). Somatic: Not known. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Gessler M References Riccardi VM, Sujansky E, Smith AC, Francke U. Chromosomal imbalance in the Aniridia-Wilms' tumor association: 11p interstitial deletion. Pediatrics. 1978 Apr;61(4):604-10 Ton CC, Hirvonen H, Miwa H, Weil MM, Monaghan P, Jordan T, van Heyningen V, Hastie ND, Meijers-Heijboer H, Drechsler M. Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell. 1991 Dec 20;67(6):1059-74 This article should be referenced as such: Gessler M. WAGR (Wilms' tumor/aniridia/genitourinary anomalies/mental retardation syndrome). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):217-218. 218 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) John A Martignetti Mount Sinai School of Medicine, Departments of Human Genetics and Pediatrics, 1425 Madison Ave, Box 1498, New York, NY 10029, USA (JAM) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Kprones/DiaphysStenosID10056.html DOI: 10.4267/2042/37573 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Phenotype and clinics Identity Main features include: - Bone dysplasia (100%) - Cortical growth abnormalities: diaphyseal medullary stenosis with overlying endosteal cortical thickening and scalloping, metaphyseal striations, scattered sclerotic areas symmetrically affecting the long bones; bilateral mandibular radiolucent and sclerotic lesions - Bone infarctions - Pathologic fractures: subsequent poor healing or nonunion - Progressive wasting or bowing of the lower extremities - bone pain - Pre-senile cataracts (25%) Alias: Bone dysplasia with medullary fibrosarcoma; Bone dysplasia with malignant fibrous histiocytoma; Hereditary bone dysplasia with malignant change Note: DMS-MFH is an hereditary bone dysplasia / cancer syndrome. Inheritance: Autosomal dominant; rare hereditary cancer syndrome with only four families identified worldwide; etiology unknown. Clinics Note Radiologic evidence of bone dysplasia not evident in childhood; X-ray findings become apparent during adolescence. Photograph A: Lateral X-ray view of the left tibia and fibula of an 18 year old male with DMS-MFH and MFH. Note the extensive diaphyseal cortical thickening, areas of resultant medullary stenosis, endosteal irregularities, overall permeative pattern in the medullary cavity, and metaphyseal striations. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 219 Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) Martignetti JA Photograph B: Tibia and MFH of patient shown in Photograph A. The MFH tumor was associated with the infarcted area in the proximal tibia. Hematoxylin and eosin preparation shows removed MFH tumor from infarcted area with typical storiform arrangement of spindle cells throughout the view. and symptoms may be evident in childhood; these include unexplained bone pain and pathologic fractures; in some, crippling pain and weakness of the lower extremities ensues following the sixth decade; malignancy occurs most frequently between the second to fifth decades and is particularly aggressive; only two long-term survivors, greater than five years, are known; pre-senile cataracts have been noted as early as in the third decade. - Bone malignant fibrous histiocytoma (MFH) (35%) Diagnosis: X-ray skeletal findings are unique; however, there may be some radiologic overlap with other diaphyseal dysplasias including Camurati-Engelman and Kenny-Caffey diseases and radiation osteitis; no hematologic or urinary markers of disease have been identified; 201Thallium chloride radionucleotide scans may offer discrimination between areas of increased metabolic bone activity found in DMS-MFH patients and malignant change. Neoplastic risk Other findings Thirteen cases of osseous MFH; thirty-five per cent of DMS-MFH patients develop MFH; the age distribution has been from the second to fifth decades; no sex predilection; in its sporadic form, MFH represents approximately 6% of all bone cancers and is the most frequently occurring adult soft-tissue sarcoma. Note Collagen fibrils from the endosteal surface of bones appear frayed and unraveled (npublished results); chemical crosslink analysis of bone biopsy samples reveal altered hydroxylysylpyridinolin (HP) / lysylpyridinoline (LP) ratios (unpublished results). Treatment Genes involved and proteins No known treatment for the dysplasia; the tumors are highly aggressive - treated with surgical ablation and the same chemotherapeutic regimens as osteosarcoma; it is believed that preoperative chemotherapy improves surgical outcome. Note The gene has been mapped by linkage analysis to a 3 cM region on chromosome 9p21-22; all families used in the study generated positive LOD scores in this region and all affecteds had similar phenotypic findings consistent with the syndrome being genetically homogeneous; a number of genes in the region, Evolution The disease becomes radiologically apparent only in adolescence: however, retrospectively, clinical signs Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 220 Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) Norton KI, Wagreich JM, Granowetter L, Martignetti JA. Diaphyseal medullary stenosis (sclerosis) with bone malignancy (malignant fibrous histiocytoma): Hardcastle syndrome. Pediatr Radiol. 1996 Sep;26(9):675-7 including p15 and p16, have been excluded as the DMS-MFH gene by DNA sequencing analysis; under the hypothesis that hereditary and sporadic MFH tumors are genetically identical, the DMS-MFH tumorsuppressor gene region has been further narrowed to 1.5 cM using loss of heterozygosity analysis; the continued search for the common minimally deleted region in MFH tumors should provide the most powerful method for gene identification. Martignetti JA, Desnick RJ, Aliprandis E, Norton KI, Hardcastle P, Nade S, Gelb BD. Diaphyseal medullary stenosis with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer syndrome maps to 9p21-22. Am J Hum Genet. 1999 Mar;64(3):801-7 Martignetti JA, Gelb BD, Pierce H, Picci P, Desnick RJ. Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22evidence for a common genetic defect. Genes Chromosomes Cancer. 2000 Feb;27(2):191-5 References Arnold WH. Hereditary bone dysplasia with sarcomatous degeneration. Study of a family. Ann Intern Med. 1973 Jun;78(6):902-6 This article should be referenced as such: Martignetti JA. Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):219-221. Hardcastle P, Nade S, Arnold W. Hereditary bone dysplasia with malignant change. Report of three families. J Bone Joint Surg Am. 1986 Sep;68(7):1079-89 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Martignetti JA 221 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Deep Insight Section Review Familial chronic lymphocytic leukaemia Martin Yuille Academic Department of Haematology and Cytogenetics Institute of Cancer Research, 15 Cotswold Road, SUTTON Surrey SM2 5NG, UK (MY) Published in Atlas Database: October 1999 Online updated version : http://AtlasGeneticsOncology.org/Deep/FamilCLLID20009.html DOI: 10.4267/2042/37574 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology suppressor genes including those associated with the mutator phenotype and p53. A putative tumour suppressor locus has been identified on chromosome 13q14. A number of case-control and cohort studies have examined the cancer risks associated with a family history of lymphoproliferative disorders, including CLL (Table 1). These studies showed an elevated risk of lymphoproliferative disorders in relatives. Although no study has systematically examined the incidence of leukaemia by specific subtype in cases and relatives, there is evidence suggesting that the familial risk of leukaemia is greater than the risk of all lymphoproliferative disorders. In the cohort study reported by Goldgar et al using the Utah population database, a 6-fold increase in risk was seen in relatives of patients with lymphocytic leukaemia. This database comprises over 1.4 million records on a population with normal levels of inbreeding that is genetically representative of a Northern European population. Abstract Literature reports on chronic lymphocytic leukaemia (CLL) that show both an elevated familial relative risk and familial clustering suggest there is value in conducting a genome-wide linkage search on CLL families. Our current aim is to ascertain families with CLL and to collect blood samples in order to perform a genetic linkage study. Background Approximately 1.3% of males and 1% of females in Europe and North America develop leukaemia. CLL is the most common of its subtypes, constituting about 30% of all cases. Its incidence rate increases logarithmically from age 35 and has a median age of onset of 64 years. No single cytogenetic abnormality or gene mutation is found in all CLL cases. However, activation of each of the oncogenes BCL1, BCL2 and BCL3 has been reported in some cases after detection of cytogenetic abnormalities, as has mutation in tumour Study Radovanovic et al., 1994 Pottern et al., 1991 Linet et al., 1989 Cartwright et al., 1987 Giles et al., 1984 Gunz et al., 1975 Goldgar et al., 1994 Cases Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia Lymphoproliferative disorders Leukaemia Lymphocytic leukaemia Relatives Leukaemia - First and second degree Obs 7/130 Exp 0/130 Leukaemia - Parents and siblings 13/237 30/1207 Leukaemia - Parents and siblings 25/342 10/342 Lymphocytic leukaemia - All blood 5/330 2/559 Lympho-proliferative disorders - First degree Leukaemia - First degree Lymphocytic leukaemia - First degree 35 10.3 16 18 6.61 3.6 Table 1: Familial leukaemia risks Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 222 Familial chronic lymphocytic leukaemia Yuille M offspring. Anticipation is now known to arise in a dozen instances from single gene defects associated, variously, with dominant or recessive modes of inheritance. Identification of a familial CLL gene would significantly help research into the molecular pathology and aetiology of CLL. Earlier diagnosis of CLL and new approaches to therapy should also follow identification of a gene or genes. Case reports There is no doubt from literature reports over 7 decades that multiple cases of CLL do occur in families. Two of these are illustrated in Figures 1 and 2. Both are consistent explicitly or implicitly with vertical transmission of an autosomal trait over three generations. In Figure 1, the absence of recorded CLL in the first two generations is consistent with incomplete penetrance. Although early reports on familial CLL were published before B-cells had been described, most of the diagnoses are likely to be accurate. This is because the specific morphology of mature B-cell CLL makes diagnosis comparatively easy and the generally indolent course of the disease contrasts markedly with the other leukaemias. We have identified reports that describe over 80 pedigrees which show clustering of CLL and, sometimes, other lymphoproliferative disorders. Some of this literature has been reviewed . Of these 80 pedigrees, over a quarter are multigenerational CLL families with up to four generations, thus illustrating vertical transmission of CLL consistent with an autosomal dominant mode of inheritance. The majority of families comprise sibs. This is not surprising: CLL usually has an indolent course and may be asymptomatic for many years, yet it also has a late onset. It has been suggested that even striking clusters of common cancers could be due to ascertainment bias. This is, however, statistical fallacy. For example, we have identified reports of 10 sibships with three of more affecteds, yet a family with 3 affected sibs would be expected to occur by chance about every 1,000 years. Analysis of these reports has also indicated a mean decline in age of onset of 21 years (SE = 4.1y) (P = 0.001) between the affected in the parental generation and the affected offspring as well as a reduced cumulative disease-free survival period for the Current progress In 1996 we began collecting detailed family histories from 130 patients with CLL registered at the Royal Marsden Hospital under the care of D.C. In order to extend the study, the MRC Adult Leukaemia Working Party gave us permission to identify CLL patients in MRC trials and contact their consultants (DC is the MRC trials co-ordinator). Of the 1402 patients with CLL registered in the CLL trials, we have contacted and collected family history information on 250 (June 1997). We have identified 20 families with at least two CLL cases. In most of the potentially informative families, the affecteds are siblings. We are pursuing a further 39 families. We initiated this spring an International Co-operative Group on Familial CLL under the auspices of the International Workshop on CLL with a successful satellite meeting of IWCLL. All members of IWCLL in 32 nations overseas have been contacted and many have expressed an interest in contributing. So far, around 20 overseas CLL families have been identified and blood samples are being collected. We have confirmed the finding of anticipation in our families and we have published data that does not support the claim that germline mutations in the Ataxia Telangiectasia confer a particular risk of CLL. Figure 1. Adapted from McPhedran et al - filled symbols indicate a diagnosis of CLL Figure 2. Adapted from Furbetta et al - filled symbols indicate a diagnosis of CLL Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 223 Familial chronic lymphocytic leukaemia Yuille M Cartwright RA, Bernard SM, Bird CC, Darwin CM, O'Brien C, Richards ID, Roberts B, McKinney PA. Chronic lymphocytic leukaemia: case control epidemiological study in Yorkshire. Br J Cancer. 1987 Jul;56(1):79-82 International effort The identification of sufficient CLL families to be able successfully to perform a genetic linkage study to find the CLL gene is a major task. With support from the Medical Research Council in the UK and from the International Workshop on CLL, the Co-ordinating Centre based at the Institute of Cancer Research and the Royal Mrsden NHS Trust Hospital in London has been able to accrue families from around the world on a collaborrative basis. For example, haematologists from 9 countries contributed families to a paper testing a candidate gene, ATM. More detailed genetic approaches will become possible as the numbers of families contributed increases. Clinicians who identify CLL families (i.e. families with more than one affected individual) are encouraged to advise the Co-ordinating Centre. Gale RP, Foon KA. Biology of chronic lymphocytic leukemia. Semin Hematol. 1987 Oct;24(4):209-29 Linet MS, WA Blattner. The epidemiology of Chronic Lymphocytic Leukemia. In: Chronic Lymphocytic Leukaemia eds. Polliack A and D. Catovsky. Harwood Academic Publishers Chur, Switzerland.1988 Linet MS, Van Natta ML, Brookmeyer R, Khoury MJ, McCaffrey LD, Humphrey RL, Szklo M. Familial cancer history and chronic lymphocytic leukemia. A case-control study. Am J Epidemiol. 1989 Oct;130(4):655-64 Pottern LM, Linet M, Blair A, Dick F, Burmeister LF, Gibson R, Schuman LM, Fraumeni JF Jr. Familial cancers associated with subtypes of leukemia and non-Hodgkin's lymphoma. Leuk Res. 1991;15(5):305-14 Hawthorn LA, Chapman R, Oscier D, Cowell JK. The consistent 13q14 translocation breakpoint seen in chronic Bcell leukaemia (BCLL) involves deletion of the D13S25 locus which lies distal to the retinoblastoma predisposition gene. Oncogene. 1993 Jun;8(6):1415-9 Contact: M. R. Yuille MA PhD. Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, 15 Cotswold Road, SUTTON Surrey SM2 5NG UK OR Prof Daniel Catovsky DSc(Med) FRCPath FRCP FmedSci. Academic Department of Haematology and Cytogenetics, Royal Marsden NHS Trust Hospital, Fulham road, London SW3 6JJ Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in firstdegree relatives of cancer probands. J Natl Cancer Inst. 1994 Nov 2;86(21):1600-8 Oscier DG. Cytogenetic and molecular abnormalities in chronic lymphocytic leukaemia. Blood Rev. 1994 Jun;8(2):88-97 Radovanovic Z, Markovic-Denic L, Jankovic S. Cancer mortality of family members of patients with chronic lymphocytic leukemia. Eur J Epidemiol. 1994 Apr;10(2):211-3 References Gartenhaus R, Johns MM 3rd, Wang P, Rai K, Sidransky D. Mutator phenotype in a subset of chronic lymphocytic leukemia. Blood. 1996 Jan 1;87(1):38-41 Jorde LB, MH Skolnick. Demographic and genetic application of computerized record linking: the Utah Mormon genealogy Information et Sciences Humaines, 56-57,105-117 Horwitz M, Goode EL, Jarvik GP. Anticipation in familial leukemia. Am J Hum Genet. 1996 Nov;59(5):990-8 Miller BA, Ries LAG, Hankey BF, Kosary CL Harras A, SS. Cancer Statistics Review 1973-90. National Cancer Institute, NIH Pub No. 93-2789. Taylor GM, JM Birch. The Hereditary Basis of Human Leukemia. In: Leukemia (6th edition) edited by Henderson E.S., Lister T.A. and M.F. Greaves. W.B. Saunders Co. London 1996 GUASCH J. Not Available Sang. 1954;25(4):384-421 Furbetta D, P Solinas. Hereditary chronic lymphatic leukemia Proc. Sec Intern. Congr Hum Genet 1961; 2:1078-1079 . Yuille MR, Houlston RS, Catovsky D. Anticipation in familial chronic lymphocytic leukaemia. Leukemia. 1998 Nov;12(11):1696-8 McPhedran P, Heath CW Jr, Lee J. Patterns of familial leukemia. Ten cases of leukemia in two interrelated families. Cancer. 1969 Aug;24(2):403-7 Bevan S, Catovsky D, Marossy A, Matutes E, Popat S, et al. Linkage analysis for ATM in familial B cell chronic lymphocytic leukaemia. Leukemia. 1999 Oct;13(10):1497-500 Gunz FW, Gunz JP, Veale AM, Chapman CJ, Houston IB. Familial leukaemia: a study of 909 families. Scand J Haematol. 1975 Sep;15(2):117-31 Bevan S, Yuille MR, Marossy A, Catovsky D, Houlston RS. Ataxia telangiectasia gene mutations and chronic lymphocytic leukaemia. Lancet. 1999 Feb 27;353(9154):753 Conley CL, Misiti J, Laster AJ. Genetic factors predisposing to chronic lymphocytic leukemia and to autoimmune disease. Medicine (Baltimore). 1980 Sep;59(5):323-34 Stankovic T, Weber P, Stewart G, Bedenham T, Murray J, Byrd PJ, Moss PA, Taylor AM. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet. 1999 Jan 2;353(9146):26-9 Giles GG, Lickiss JN, Baikie MJ, Lowenthal RM, Panton J. Myeloproliferative and lymphoproliferative disorders in Tasmania, 1972-80: occupational and familial aspects. J Natl Cancer Inst. 1984 Jun;72(6):1233-40 This article should be referenced as such: McLellan T, Jorde LB, Skolnick MH. Genetic distances between the Utah Mormons and related populations. Am J Hum Genet. 1984 Jul;36(4):836-57 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Yuille M. Familial chronic lymphocytic leukaemia. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):222-224. 224 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. 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