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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 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 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 4, Number 1, January - March 2000 Table of contents Gene Section EP300 (E1A binding protein p300) Jean-Loup Huret 1 EXT1 (exostoses (multiple) 1) Judith VMG Bovée 3 EXT2 (exostoses (multiple) 2) Judith VMG Bovée 5 NUMA1 (nuclear mitotic apparatus protein 1) Jean-Loup Huret 7 ABL2 (Abelson homolog 2) Jean-Loup Huret 9 AMP-19 (AML1 partner from chromosome 19) Jean-Loup Huret 10 GMPS (guanine monphosphate synthetase) Jean-Loup Huret 11 AF3p21 (ALL1 fused gene from chromosome 3p21) Jean-Loup Huret 13 NUP98 (nucleoporin 98 kDa) Jean-Loup Huret 14 Leukaemia Section t(11;22)(q23;q13) Jean-Loup Huret 16 t(2;11)(p21;q23) Elena W Fleischman 17 +22 or trisomy 22 (solely?) Jean-Loup Huret 19 12p rearrangements in ALL Nyla A Heerema 20 Classification of B-cell chronic lymphoproliferative disorders (CLD) Antonio Cuneo 22 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Classification of B-cell non-Hodgkin lymphomas (NHL) Antonio Cuneo 24 i(17q) in myeloid malignancies Chrystèle Bilhou-Nabera 27 t(1;12)(q25;p13) Jean-Loup Huret 29 t(1;16)(q12;q24) Jean-Loup Huret 30 t(1;2)(q12;q37) Jean-Loup Huret 31 t(1;21)(p36;q22) Jean-Loup Huret 32 t(11;12)(p15;q13) Jean-Loup Huret 33 t(11;22)(q23;q11.2) Jean-Loup Huret 35 t(17;21)(q11.2;q22) Jean-Loup Huret 37 t(18;21)(q21;q22) Jean-Loup Huret 38 t(19;21)(q13.4;q22) Jean-Loup Huret 39 t(3;11)(p21;q23) Jean-Loup Huret 40 t(3;11)(q25;q23) Jean-Loup Huret 41 Solid Tumour Section Bone: Chondrosarcoma Judith VMG Bovée 42 Cancer Prone Disease Section Hereditary multiple exostoses (HME) Judith VMG Bovée 46 Rhabdoid predisposition syndrome Jean-Loup Huret 49 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review EP300 (E1A binding protein p300) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/P300ID97.html DOI: 10.4267/2042/37578 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology functions during differentiation; there is embryonic lethality of mice nullizygous for p300 (with defects in neurulation and heart development), and as well of mice double heterozygous for p300 and CBP, underlining their essential and associated role. Identity Other names: P300; E1A binding protein p300 HGNC (Hugo): EP300 Location: 22q13.2 Homology DNA/RNA CBP Transcription Implicated in 9046 bp mRNA; coding sequence: 7244 bp. t(11;22)(q23;q13) Protein Note Very rare. Disease Therapy related acute non lymphocytic leukemia. Hybrid/Mutated gene 5 MLL-3 P300. Abnormal protein N-term MLL fused to C-term P300. Oncogenesis Likely to be driven by the MLL part. Description 2414 amino acids; 264 kDa. Expression Widely expressed ; also expressed in the whole embryo; possesses from N term to C term: a nuclear localization signal, a poly-serine, a bromodomain, a poly-glu, a binding region for E1A adenovirus, and a poly-gln. Localisation Gastric and colorectal carcinomas Nucleus. Oncogenesis Mutations in both alleles. Function p300 and CBP are highly related proteins implicated in transcriptional responses to various extracellular and intracellular signals with chromatin remodeling; they are non-DNA-binding transcriptional coactivators; they interact with transcriptional activators as well as repressors; p300 and CBP are involved in most cellular programs, including growth, terminal differentiation, and P53-mediated apoptosis (with MDM2 interaction) processes; p300 and CBP appear to have distinct Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) References Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Lawrence JB, Livingston DM.. Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev. 1994 Apr 15;8(8):869-84. Eckner R. p300 and CBP as transcriptional regulators and targets of oncogenic events. Biol Chem. 1996 Nov;377(11):685-8 1 EP300 (E1A binding protein p300) Huret JL Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood. 1997 Dec 15;90(12):4699-704 Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, Newsome D, Bronson RT, Li E, Livingston DM, Eckner R. Gene dosagedependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell. 1998 May 1;93(3):361-72 Giles RH, Peters DJ, Breuning MH. Conjunction dysfunction: CBP/p300 in human disease. Trends Genet. 1998 May;14(5):178-83 Giordano A, Avantaggiati ML. p300 and CBP: partners for life and death. J Cell Physiol. 1999 Nov;181(2):218-30 Grossman SR, Perez M, Kung AL, Joseph M, Mansur C, Xiao ZX, Kumar S, Howley PM, Livingston DM. p300/MDM2 complexes participate in MDM2-mediated p53 degradation. Mol Cell. 1998 Oct;2(4):405-15 Ugai H, Uchida K, Kawasaki H, Yokoyama KK. The coactivators p300 and CBP have different functions during the differentiation of F9 cells. J Mol Med. 1999 Jun;77(6):481-94 This article should be referenced as such: Snowden AW, Perkins ND. Cell cycle regulation of the transcriptional coactivators p300 and CREB binding protein. Biochem Pharmacol. 1998 Jun 15;55(12):1947-54 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Huret JL. EP300 (E1A binding protein p300). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):1-2. 2 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review EXT1 (exostoses (multiple) 1) Judith VMG Bovée Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html DOI: 10.4267/2042/37575 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Homology Location : 8q24.11 Human EXT2, EXTL1, EXTL2 and EXTL3, mouse Ext1, Drosophila tout velu. DNA/RNA Mutations Description Germinal 11 exons, spans approximately 350 kb of genomic DNA. Germline mutations in EXT1 are causative for hereditary multiple exostoses, a genetically heterogeneous autosomal dominant disorder; mutations include nucleotide substitutions (54%), small deletions (27%) and small insertions (16%), of which the majority is predicted to result in a truncated or nonfunctional protein. Transcription 3.4 kb. Protein Description Somatic 746 amino acids, 86.304 kDa. No somatic mutations were found in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas tested. Expression mRNA is ubiquitously expressed (also chondrocytes), highest level of expression in liver. in Implicated in Localisation Hereditary multiple exostoses Endoplasmic reticulum. Prognosis The main complication in hereditary multiple exostoses is malignant transformation of an osteochondroma (exostosis) into chondrosarcoma, which is estimated to occur in 1-5% of the HME cases. Cytogenetics Clonal aberrations were found at band 8q24.1 in sporadic and hereditary osteochondromas using cytogenetic analysis; loss of heterozygosity was almost exclusively found at the EXT1 locus in 5 out of 14 osteochondromas. Function A tumour suppressor function is suggested; EXT1 is an endoplasmic reticulum (ER) resident type II transmembrane glycoprotein whose expression in cells alters the synthesis and display of cell surface heparan sulfate, and EXT1 was suggested to be involved in chain polymerization of heparan sulphate; an EXT1 homologue in Drosophila melanogaster (tout-velu, Ttv) was demonstrated to be involved in heparan sulphate proteoglycan biosynthesis controlling diffusion of an important segment polarity protein called Hedgehog (Hh). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 3 EXT1 (exostoses (multiple) 1) Bovée JVMG Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer. 1998 May 1;82(9):1657-63 Oncogenesis Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild type allele in three osteochondromas, supporting the Knudson's two hit model for tumour suppressor genes in osteochondroma development; these results indicate that in cartilaginous cells of the growth plate inactivation of both copies of the EXT1-gene is required for osteochondroma formation in hereditary cases. Lin X, Gan L, Klein WH, Wells D. Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene. Biochem Biophys Res Commun. 1998 Jul 30;248(3):738-43 Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem. 1998 Oct 9;273(41):26265-8 References McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet. 1998 Jun;19(2):158-61 Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G. Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet. 1993 Jul;53(1):71-9 Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Genes Chromosomes Cancer. 1999 Nov;26(3):237-46 Mertens F, Rydholm A, Kreicbergs A, Willén H, Jonsson K, Heim S, Mitelman F, Mandahl N. Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Genes Chromosomes Cancer. 1994 Jan;9(1):8-12 Ahn J, Lüdecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet. 1995 Oct;11(2):137-43 Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 1999 Sep;65(3):689-98 Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXTlinked markers on chromosomes II and 8. Am J Hum Genet. 1995 May;56(5):1125-31 Kitagawa H, Shimakawa H, Sugahara K. The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-Nacetylhexosaminyltransferase that transfers Nacetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. The key enzyme for the chain initiation of heparan sulfate. J Biol Chem. 1999 May 14;274(20):13933-7 Raskind WH, Conrad EU, Chansky H, Matsushita M. Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Am J Hum Genet. 1995 May;56(5):1132-9 McCormick C, Duncan G, Tufaro F. New perspectives on the molecular basis of hereditary bone tumours. Mol Med Today. 1999 Nov;5(11):481-6 Lin X, Wells D. Isolation of the mouse cDNA homologous to the human EXT1 gene responsible for Hereditary Multiple Exostoses. DNA Seq. 1997;7(3-4):199-202 Simmons AD, Musy MM, Lopes CS, Hwang LY, Yang YP, Lovett M. A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Hum Mol Genet. 1999 Nov;8(12):2155-64 Lohmann DR, Buiting K, Lüdecke HJ, Horsthemke B. The murine Ext1 gene shows a high level of sequence similarity with its human homologue and is part of a conserved linkage group on chromosome 15. Cytogenet Cell Genet. 1997;76(34):164-6 The I, Bellaiche Y, Perrimon N. Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol Cell. 1999 Oct;4(4):633-9 Lüdecke HJ, Ahn J, Lin X, Hill A, Wagner MJ, Schomburg L, Horsthemke B, Wells DE. Genomic organization and promoter structure of the human EXT1 gene. Genomics. 1997 Mar 1;40(2):351-4 This article should be referenced as such: Bovée JVMG. EXT1 (exostoses (multiple) 1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):3-4. Bellaiche Y, The I, Perrimon N. Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature. 1998 Jul 2;394(6688):85-8 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 4 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review EXT2 (exostoses (multiple) 2) Judith VMG Bovée Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/EXT2ID213.html DOI: 10.4267/2042/37576 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology nucleotide substitutions (57%), small deletions (19%) and small insertions (24%), of which the majority is predicted to result in a truncated or non-functional protein. Identity Location: 11p11-p12 DNA/RNA Somatic No somatic mutations were found in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas tested. Description Sixteen exons across the EXT2 locus were identified, two of which (1a and 1b) are alternatively spliced; spans approximately 108 kb of genomic DNA. Implicated in Transcription Hereditary multiple exostoses 3.5 and 3.7 kb. Endoplasmic reticulum. Prognosis The main complication in hereditary multiple exostoses is malignant transformation of an osteochondroma (exostosis) into chondrosarcoma, which is estimated to occur in 1-5% of the HME cases. Cytogenetics 11p rearrangement was found in 1 sporadic osteochondroma (exostosis) using cytogenetic analysis; loss of heterozygosity at the EXT2 locus was absent in 14 osteochondromas. Function References Protein Description 718 amino acids; 82.2 kDa. Expression mRNA is ubiquitously expressed. Localisation A tumour suppressor function is suggested; EXT2 is a glycosyltransferase, suggested to be involved in chain polymerization of heparan sulphate. Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G. Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet. 1993 Jul;53(1):71-9 Homology Human EXT1, EXTL1, EXTL2 and EXTL3, mouse Ext2. Wu YQ, Heutink P, de Vries BB, Sandkuijl LA, van den Ouweland AM, Niermeijer MF, Galjaard H, Reyniers E, Willems PJ, Halley DJ. Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Hum Mol Genet. 1994 Jan;3(1):167-71 Mutations Germinal Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXTlinked markers on chromosomes II and 8. Am J Hum Genet. 1995 May;56(5):1125-31 Germline mutations in EXT2 are causative for hereditary multiple exostoses, a heterogeneous autosomal dominant disorder; mutations include Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 5 EXT2 (exostoses (multiple) 2) Bovée JVMG Raskind WH, Conrad EU, Chansky H, Matsushita M. Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Am J Hum Genet. 1995 May;56(5):1132-9 Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Genes Chromosomes Cancer. 1999 Nov;26(3):237-46 Wuyts W, Ramlakhan S, Van Hul W, Hecht JT, van den Ouweland AM, Raskind WH, Hofstede FC, Reyniers E, Wells DE, de Vries B. Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11. Am J Hum Genet. 1995 Aug;57(2):382-7 Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 1999 Sep;65(3):689-98 Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet. 1996 Sep;14(1):25-32 Kitagawa H, Shimakawa H, Sugahara K. The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-Nacetylhexosaminyltransferase that transfers Nacetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. The key enzyme for the chain initiation of heparan sulfate. J Biol Chem. 1999 May 14;274(20):13933-7 Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul EV, De Boulle K, de Vries BB, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, van den Ouweland AM, McGaughran J, Halley DJ, Willems PJ. Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet. 1996 Oct;5(10):1547-57 McCormick C, Duncan G, Tufaro F. New perspectives on the molecular basis of hereditary bone tumours. Mol Med Today. 1999 Nov;5(11):481-6 Clines GA, Ashley JA, Shah S, Lovett M. The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans. Genome Res. 1997 Apr;7(4):359-67 Simmons AD, Musy MM, Lopes CS, Hwang LY, Yang YP, Lovett M. A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Hum Mol Genet. 1999 Nov;8(12):2155-64 Stickens D, Evans GA. Isolation and characterization of the murine homolog of the human EXT2 multiple exostoses gene. Biochem Mol Med. 1997 Jun;61(1):16-21 Stickens D, Brown D, Evans GA. EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis. Dev Dyn. 2000 Jul;218(3):452-64 Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR. Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer. 1998 May 1;82(9):1657-63 Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat. 2000;15(3):220-7 Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem. 1998 Oct 9;273(41):26265-8 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Bovée JVMG. EXT2 (exostoses (multiple) 2) (. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):5-6. 6 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review NUMA1 (nuclear mitotic apparatus protein 1) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/NUMAID119.html DOI: 10.4267/2042/37577 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Note Must not be confused with the t(11;17)(q23;q21), implicating PLZF and RARA, also in M3-ANLL (see below). Disease Atypical M3 acute non lyphoblastic leukemia (ANLL); only 1 case fully described. Hybrid/Mutated gene 5' exons of NuMA, fused to the exons encoding the retinoic acid and DNA-binding domains of RARA. Abnormal protein The NuMA-RARA fusion protein forms aggregates in the nucleus where the normal NuMA partly colocalizes. Identity HGNC (Hugo): NUMA1 Location: 11q13 DNA/RNA Transcription 7217 bp mRNA; coding sequence: 6305 bp. Protein Description 2101 amino acids; 239 kDa; the globular COOH tail domain contains a nuclear targeting sequence, a site for binding to the mitotic spindle and a site responsible for nuclear reformation; can build multiarm oligomers. References Price CM, Pettijohn DE. Redistribution of the nuclear mitotic apparatus protein (NuMA) during mitosis and nuclear assembly. Properties of purified NuMA protein. Exp Cell Res. 1986 Oct;166(2):295-311 Expression Widely expressed ; also expressed in the whole embryo. Compton DA, Szilak I, Cleveland DW. Primary structure of NuMA, an intranuclear protein that defines a novel pathway for segregation of proteins at mitosis. J Cell Biol. 1992 Mar;116(6):1395-408 Localisation Internal nuclear matrix protein in interphase which relocates to the spindle poles in mitotis. Yang CH, Lambie EJ, Snyder M. NuMA: an unusually long coiled-coil related protein in the mammalian nucleus. J Cell Biol. 1992 Mar;116(6):1303-17 Function Component of the mitotic spindle matrix: associates with microtubule motors during mitosis; essential role in organizing microtubule minus ends at spindle poles (anchors the microtubule ends); on the other hand, may not be essential in the nucleoskeleton structural architecture during interphase. Compton DA, Cleveland DW. NuMA is required for the proper completion of mitosis. J Cell Biol. 1993 Feb;120(4):947-57 Kempf T, Bischoff FR, Kalies I, Ponstingl H. Isolation of human NuMA protein. FEBS Lett. 1994 Nov 14;354(3):307-10 Gueth-Hallonet C, Weber K, Osborn M. NuMA: a bipartite nuclear location signal and other functional properties of the tail domain. Exp Cell Res. 1996 May 25;225(1):207-18 Implicated in Merdes A, Ramyar K, Vechio JD, Cleveland DW. A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell. 1996 Nov 1;87(3):447-58 t(11;17)(q13;q21) Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 7 NUMA1 (nuclear mitotic apparatus protein 1) Huret JL Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet. 1997 Sep;17(1):109-13 Harborth J, Wang J, Gueth-Hallonet C, Weber K, Osborn M. Self assembly of NuMA: multiarm oligomers as structural units of a nuclear lattice. EMBO J. 1999 Mar 15;18(6):1689-700 This article should be referenced as such: Merdes A, Cleveland DW. The role of NuMA in the interphase nucleus. J Cell Sci. 1998 Jan;111 ( Pt 1):71-9 Huret JL. NUMA1 (nuclear mitotic apparatus protein 1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):7-8. Dionne MA, Howard L, Compton DA. NuMA is a component of an insoluble matrix at mitotic spindle poles. Cell Motil Cytoskeleton. 1999;42(3):189-203 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 8 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication ABL2 (Abelson homolog 2) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/ABL2ID226.html DOI: 10.4267/2042/37579 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Homology Identity SRC homology; closely related to ABL1. Other names: ARG (Abelson related gene); ABLL HGNC (Hugo): ABL2 Location: 1q25 Implicated in t(1;12)(q25;p13) --> ABL2-ETV6 Disease Acute non lymphocytic leukemia. Abnormal protein The fusion protein is composed of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase domains of ABL2. References Kruh GD, King CR, Kraus MH, Popescu NC, Amsbaugh SC, McBride WO, Aaronson SA. A novel human gene closely related to the abl proto-oncogene. Science. 1986 Dec 19;234(4783):1545-8 ABL2 (1q25) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Seldin MF, Kruh GD. Mapping of Abll within a conserved linkage group on distal mouse chromosome 1 syntenic with human chromosome 1 using an interspecific cross. Genomics. 1989 Feb;4(2):221-3 DNA/RNA Transcription Kruh GD, Perego R, Miki T, Aaronson SA. The complete coding sequence of arg defines the Abelson subfamily of cytoplasmic tyrosine kinases. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5802-6 Alternate splicing in 5 prime; 3.8 kb mRNA; ORF: 3548 bp. Protein Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P, Kearney L, Biondi A. The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood. 1999 Dec 15;94(12):4370-3 Description 1182 amino acids; 128 kDa; comprises SH3 and SH2 domains, a protein tyrosine kinase domain, a nuclear localization domain. This article should be referenced as such: Huret JL. ABL2 (Abelson homolog 2). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):9. Function Cytoplasmic tyrosine kinase. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 9 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication AMP-19 (AML1 partner from chromosome 19) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/AMP19ID235.html DOI: 10.4267/2042/37581 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Implicated in Location : 19q13.4 t(19;21)(q13.4;q22) with AML1 involvement DNA/RNA 5.5 kB mRNA. Disease Acute non lymphocytic leukemia (ANLL) secondary to toxic exposure. Protein References Transcription Hromas R, Busse T, Carroll A, Mack D, Shopnick R, Zhang DE, Nakshatri H, Richkind K. Fusion AML1 transcript in a radiation-associated leukemia results in a truncated inhibitory AML1 protein. Blood. 2001 Apr 1;97(7):2168-70 Expression Wide; highest expression in heart. Homology This article should be referenced as such: None. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Huret JL. AMP-19 (AML1 partner from chromosome 19). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):10. 10 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review GMPS (guanine monphosphate synthetase) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/GMPSID229.html DOI: 10.4267/2042/37582 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Expression Other names: GMPS-PEN HGNC (Hugo): GMPS Location: 3q24 Higher in proliferating, transformed cells than in nontransformed cells; in normal cells, higher expression in fibroblasts, followed by bone marrow, leukocytes, erythrocytes, placenta, and liver. Localisation Cytoplasmic. Function Enzyme of the de novo synthesis of guanine nucleotides: amidotransferase that catalyzes the amination of xanthosine 5 prime monophosphate to form GMP in the presence of ATP and glutamine; GTP is also involved in many enzymatic reactions important for cell division. Implicated in Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. t(3;11)(q25;q23) DNA/RNA Protein Disease Treatment related acute non lymphoblastic leukemia (M4 ANLL). Hybrid/Mutated gene Fusion of MLL to GMPS. Description References 693 amino acids; 76 kDa; there are two variant forms of human GMP synthetase; homodimerization; GMP synthetase contains two functional domains: a glutamine amidotransferase (glutaminase domain, with a conserved Cys-His-Glu triad), responsible for glutamine hydrolysis, and a synthetase domain; responsible for ATP hydrolysis and GMP formation. Page T, Bakay B, Nyhan WL. Human GMP synthetase. Int J Biochem. 1984;16(1):117-20 Transcription 2212 bp mRNA; ORF: 2081 bp. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Hirst M, Haliday E, Nakamura J, Lou L. Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA. J Biol Chem. 1994 Sep 23;269(38):23830-7 11 GMPS (guanine monphosphate synthetase) Huret JL Lou L, Nakamura J, Tsing S, Nguyen B, Chow J, Straub K, Chan H, Barnett J. High-level production from a baculovirus expression system and biochemical characterization of human GMP synthetase. Protein Expr Purif. 1995 Aug;6(4):487-95 Fedorova L, Kost-Alimova M, Gizatullin RZ, Alimov A, Zabarovska VI, Szeles A, Protopopov AI, Vorobieva NV, Kashuba VI, Klein G, Zelenin AV, Sheer D, Zabarovsky ER. Assignment and ordering of twenty-three unique NotI-linking clones containing expressed genes including the guanosine 5'monophosphate synthetase gene to human chromosome 3. Eur J Hum Genet. 1997 Mar-Apr;5(2):110-6 Nakamura J, Lou L. Biochemical characterization of human GMP synthetase. J Biol Chem. 1995 Mar 31;270(13):7347-53 Nakamura J, Straub K, Wu J, Lou L. The glutamine hydrolysis function of human GMP synthetase. Identification of an essential active site cysteine. J Biol Chem. 1995 Oct 6;270(40):23450-5 Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rappaport EF, Felix CA. t(3;11)(q25;q23) fuses MLL with the GMPS (guanosine 5'-monophosphate synthetase) gene in treatmentrelated acute myeloid leukemia (AML). Blood 1999; 94 Suppl 1: Abst 2227 Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL. The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families. Nat Struct Biol. 1996 Jan;3(1):74-86 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Huret JL. GMPS (guanine monphosphate synthetase). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):11-12. 12 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication AF3p21 (ALL1 fused gene from chromosome 3p21) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/AF3p21ID228.html DOI: 10.4267/2042/37580 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Implicated in HGNC (Hugo): NCKIPSD Location: 3p21 t(3;11)(p21;q23) --> AF3p21-MLL Disease Treatment related acute non lymphoblastic leukemia (tANLL). Hybrid/Mutated gene 5 prime MLL - 3 prime AF3q21. Abnormal protein AT hooks and methyltransferase domains of MLL in the N-term fused to the proline-rich domain and nuclear localization signal of AF3p21. Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. DNA/RNA References Description Sano K, Hayakawa A, Jin-Hua P. A novel sh3 protein encoded by the AF3p21 gene is fused to MLL in a therapy-related leukemia with t(3; 11)(p21;q23). Blood 1999;94 Suppl 1:Abst 221 2990 bp cDNA. Protein Description This article should be referenced as such: 722 amino acids; N-term SH3 domain, proline-rich domain, and a nuclear localization signal in C-term. Huret JL. AF3p21 (ALL1 fused gene from chromosome 3p21). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):13. Expression Wide. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 13 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review NUP98 (nucleoporin 98 kDa) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Genes/NUP98.html DOI: 10.4267/2042/37583 This article is an update of: Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol.1999;3(1):15-16. Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol.1998;2(1):7. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Disease M2-M4 ANLL mostly; occasionally: CML-like cases. Prognosis Mean survival: 15 months. Cytogenetics Sole anomaly most often. Hybrid/Mutated gene 5' NUP98 - 3' HOXA9. Abnormal protein Fuses the GLFG repeat domains of NUP98 to the HOXA9 homeobox. Identity HGNC (Hugo): NUP98 Location: 11p15 DNA/RNA Transcription 3.6, 6.5, 7.0 kb mRNA. Protein Description inv (11)(p15q22)/MDS or ANLL --> NUP98/DDX10 920 amino acids; 97 kDa; contains repeated motifs (GLFG and FG) in N-term and a RNA binding motif in C-term. Disease Therapy related MDS and ANLL; de novo ANLL. Hybrid/Mutated gene 5' NUP98 - 3' DDX10. Abnormal protein Fuses the GLFG repeat domains of NUP98 to the acidic domain of DDX11. Expression Wide. Localisation Nuclear membrane localisation. Function t(1;11)(q23;p15) --> NUP98/PMX1 t(2;11)(q31;p15)/treatment related leukaemia --> NUP98/HOXD13 Nucleoporin: associated with the nuclear pore complex; role in nucleocytoplasmic transport processes. Homology Member of the GLFG nucleoporins. Disease So far, only 1 case of treatment related myelodysplasia evolving towards M6 acute non lymphocytic leukaemia. Implicated in t(7;11)(p15;p15)/ANLL --> NUP98/HOXA9 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 14 NUP98 (nucleoporin 98 kDa) Huret JL Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N, Kaneko Y, Ohki M. The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood. 1997 Jun 1;89(11):3936-44 Hybrid/Mutated gene 5' NUP98 - 3' HOXD13. Abnormal protein Fuses the GLFG repeat domains of NUP98 to the HOXD13 homeodomain. Powers MA, Forbes DJ, Dahlberg JE, Lund E. The vertebrate GLFG nucleoporin, Nup98, is an essential component of multiple RNA export pathways. J Cell Biol. 1997 Jan 27;136(2):241-50 t(11;12)(p15;q13)/treatment related leukemia Hybrid/Mutated gene 5' NUP98 - 3' unknown. Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD. NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia. Cancer Res. 1998 Oct 1;58(19):4269-73 References Kobzev YN, Rowley JD.. NUP98 gene rearrangements in leukemia detected by fluorescence in situ hybridization (FISH). Blood 1999; 94 Suppl 1: Abst 2221. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP, Jenkins NA, Copeland NG, Shaughnessy JD Jr. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet. 1996 Feb;12(2):154-8 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Huret JL. NUP98 (nucleoporin 98 kDa). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):14-15. 15 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(11;22)(q23;q13) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1122P300ID1121.html DOI: 10.4267/2042/37585 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Protein 264 kDa; widely expressed; possesses a nuclear localization signal, a poly-serine, a bromodomain, a poly-glu, a binding region for E1A adenovirus, and a poly-gln;. interact with transcriptional activators as well as repressors; involved (with CBP) in growth, differentiation, and apoptosis. Identity Note: Not to be confused with the t(11;22)(q23;q11), involving MLL and hCDCrel. Clinics and pathology Disease Result of the chromosomal anomaly A case of therapy related leukemia, 2.5 years after the treatment of a non Hodgkin lymphoma. Phenotype/cell stem origin Hybrid gene Acute non lymphocytic leukemia. Transcript Chimeric mRNAs from both derivative chromosomes are found. Prognosis Unknown (relapse at 20 months) but likely to be similar to the prognosis associated with other 11q23 therapy related leukemia. Fusion protein Description The MLL/p300 fusion transcript encodes a protein of about 3000 amino acids, the N-term half comprising the AT hook and DNA methyltransferase (exons 1 to 9) from MLL and the C-term half comprising the acetyltransferase domain and the TFIIB-binding domain of p300, excluding the nuclear localisation signal and the bromodomain. Genes involved and proteins MLL Location : In 11q23. DNA/RNA 13-15 kb mRNA. Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation. References Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood. 1997 Dec 15;90(12):4699-704 P300 Location : 22q13 DNA/RNA 9 kb mRNA. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Huret JL. t(11;22)(q23;q13). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):16. 16 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(2;11)(p21;q23) Elena W Fleischman Cancer Research Center, Moscow, Russia (EWF) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0211ID1109.html DOI: 10.4267/2042/37584 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity t(2;11)(p21;q23) G- banding (left) - Courtesy Eric Crawford, and R- banding (Editor). Clinics and pathology diagnosed: 4 ANLL, 2 ALL; ANLL FAB-types were: M0 evolving into M4, M1, M2 and atypical M3. Disease Epidemiology Myelodysplastic syndromes (MDS), acute non lymphocytic leukemia (ANLL) and acute lymphoblastic leukemia (ALL). Male predominance: 13 M:7 F; the majority of patients (16 out of 20) were over 50 years of age and 8 of them were over 60 years of age. Phenotype/cell stem origin Clinics 20 cases were documented, 14 of them were MDS; in three cases, type of MDS was not described; the remaining cases were: 2 AISA, 5 RA and 4 RAEB; in 6 patients, MDS has transformed into ANLL (M1, M5a, M6 and unidentified); in 6 cases acute leukemia was Variable. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Prognosis Due to heterogeneity of cases and lack of molecular data, the prognostic importance of t(2;11)(p21;q23) 17 t(2;11)(p21;q23) Fleischman EW hook and zinc fingers), a DNA methyl transferase motif. cannot be assessed; in 6 cases of MDS transformation into ANLL, MDS phase varied from 18 months to 5 years; in 4 out of 5 ANLL cases treated in 1986-1993, remission duration varied from 6 to 13 months. Cytogenetics Result of the chromosomal anomaly Cytogenetics morphological Hybrid gene A high variability of breakpoints on both chromosome 2 (2p16-2p21) and chromosome 11 (11q13-11q25) were found by conventional cytogenetics. Description Unknown. Cytogenetics molecular Description Unknown. Fusion protein MLL gene involvement was observed in 2 out of 3 cases studied. References Additional anomalies Feder M, Finan J, Besa E, Nowell P. A 2p;11q chromosome translocation in dysmyelopoietic preleukemia. Cancer Genet Cytogenet. 1985 Feb 1;15(1-2):143-50 Additional abnormalities were observed in 10 out of 20 cases; in 8 cases, del(5)(q13q33) is found; it is of note, that deletions of 5q usually are not seen in cases with MLL-associated translocations. de la Chapelle A, Knuutila S, Elonen E. Translocation (2;11) (p21;q23) in acute non-lymphocytic leukaemia: a non-random association. Scand J Haematol Suppl. 1986;45:91-7 Genes involved and proteins Thirman MJ, Gill HJ, Burnett RC, Mbangkollo D, McCabe NR, Kobayashi H, Ziemin-van der Poel S, Kaneko Y, Morgan R, Sandberg AA. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N Engl J Med. 1993 Sep 23;329(13):909-14 Note The gene involved in 2p is unknown. MLL Location 11q23 DNA/RNA 37 exons, spanning about 120 kb; 13-15 mRNA. Protein 431 kD; transcriptional regulatory factor, nuclear localization; Contains two DNA binding motifs (a AT Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Fleischman EW, Reshmi S, Frenkel MA, Konovalova WI, Guleva GP, Kulagina OE, Konstantinova LN, Tupitsyn NN, Rowley JD. MLL is involved in a t(2;11)(p21;q23) in a patient with acute myeloblastic leukemia. Genes Chromosomes Cancer. 1999 Feb;24(2):151-5 This article should be referenced as such: Fleischman EW. t(2;11)(p21;q23). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):17-18. 18 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication +22 or trisomy 22 (solely?) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/tri22ID1042.html DOI: 10.4267/2042/37601 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Cytogenetics molecular Identity Is appropriate to exclude or discover the presence of a hidden inv(16), inasmuch as inv(16) is associated with a relatively good prognosis. Note: +22 is often associated with inv(16)(p13q22) or its equivalents; the existence of trisomy 22 solely is debated. Additional anomalies Clinics and pathology Anomalies associated with +22 are del(7q) and/or +8, found in 15% of cases each; this percentage is similar in cases with or without inv(16). Disease Acute non lymphocytic leukemia (ANLL). Phenotype/cell stem origin References M4eo ANLL most often in cases associated with inv(16); M4 also, but only in 2/3 of cases, when +22 is apparently without inv(16); and eosinophilia may be missing in the latter case. Larson RA, Williams SF, Le Beau MM, Bitter MA, Vardiman JW, Rowley JD. Acute myelomonocytic leukemia with abnormal eosinophils and inv(16) or t(16;16) has a favorable prognosis. Blood. 1986 Dec;68(6):1242-9 Epidemiology Ohyashiki K, Ohyashiki JH, Iwabuchi A, Ito H, Toyama K. Central nervous system involvement in acute nonlymphocytic leukemia with inv(16)(p13q22). Leukemia. 1988 Jun;2(6):398-9 Young age, both in cases with or without inv(16). Clinics Grois N, Nowotny H, Tyl E, Krieger O, Kier P, Haas OA. Is trisomy 22 in acute myeloid leukemia a primary abnormality or only a secondary change associated with inversion 16? Cancer Genet Cytogenet. 1989 Nov;43(1):119-29 inv(16) may be at increased CNS relapse when +22 is also present. Prognosis Johansson B, Mertens F, Mitelman F. Secondary chromosomal abnormalities in acute leukemias. Leukemia. 1994 Jun;8(6):953-62 A fair prognosis is associated with +22 accompanying inv(16), and with +22 solely, comparable to the prognosis associated with inv(16). Langabeer SE, Grimwade D, Walker H, Rogers JR, Burnett AK, Goldstone AH, Linch DC. A study to determine whether trisomy 8, deleted 9q and trisomy 22 are markers of cryptic rearrangements of PML/RARalpha, AML1/ETO and CBFB/MYH11 respectively in acute myeloid leukaemia. MRC Adult Leukaemia Working Party. Medical Research Council. Br J Haematol. 1998 May;101(2):338-40 Cytogenetics Cytogenetics morphological +22 is a frequent anomaly additional to inv(16), but was not found associated with other anomalies recurrently found in de novo ANLL; +22 may also occur apparently in the absence of inv(16), but cryptic rearrangements of MYH11 (16p13) and CBFB (16q22) have been found in a number of cases; for some authors, +22 indicates the obligate existence of an inv(16); for others +22 solely is a true entity. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Wong KF, Kwong YL. Trisomy 22 in acute myeloid leukemia: a marker for myeloid leukemia with monocytic features and cytogenetically cryptic inversion 16. Cancer Genet Cytogenet. 1999 Mar;109(2):131-3 This article should be referenced as such: Huret JL. +22 or trisomy 22 (solely?). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):19. 19 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication 12p rearrangements in ALL Nyla A Heerema The Ohio State University, Division of Clinical Pathology, Department of Pathology, 167 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA (NAH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/12pALLID1074.html DOI: 10.4267/2042/37586 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity del(12)(p12) G-banding - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services. Clinics and pathology Cytogenetics Disease Cytogenetics morphological Various aberrations result in an abnormal 12p; these include morphological balanced translocations with 12p breakpoints, del(12p), add(12p), monosomy 12, der(12)t(V;12)(V;p), and dic(V;12)(V;p); an abnormal 12p usually occurs as part of a more complex karyotype, and occurs as the sole aberration in less than 20% of cases with an abnormal 12p; in greater than 10% of cases both 12p homologues are abnormal; few cases with an abnormal 12p have more than 50 chromosomes. Additional anomalies del(6q), del(13q) or monosomy 13, acquired +21; few recurring anomalies. Acute lyphocytic leukemia (ALL). Phenotype/cell stem origin Lack of specificity for particular immunophenotype, although more stem origin frequent in B-lineage cases. Epidemiology Approximately 10-15% of pediatric ALL cases, and 5% of adult ALL. Prognosis Recent data indicate no difference in overall outcome between childhood ALL cases with versus without 12p abnormalities, although there was an improved outcome for pseudodiploid patients with versus without a cytogenetic 12p abnormality; although a dic(9;12) has been reported to be associated with an excellent outcome, in a recent study, there was no difference in outcome between those patients with a dic(9;12) versus patients lacking an abnormal 12p. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Genes involved and proteins Note Approximately half of patients with an abnormal 12p have a rearranged TEL gene. 20 12p rearrangements in ALL Heerema NA Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A Collaborative Study of the Group Français de Cytogénétique Hématologique. Blood. 1996 Apr 15;87(8):3135-42 TEL (or ETV6) Location 12p13 Protein TEL proteins belong to the ETS family transcription factors; important in the vitelline angiogenesis and in the bone marrow hematopoiesis. Chessels JM, Swansbury GJ, Reeves B, Bailey CC, Richards SM. Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia. Br J Haematol. 1997 Oct;99(1):93-100 Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew S, Hancock M, Pui CH, Rivera GK, Grosveld GC, Behm FG. 12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia. Blood. 1997 Dec 1;90(11):4559-66 References Behrendt H, Charrin C, Gibbons B, Harrison CJ, Hawkins JM, Heerema NA, Horschler-Bötel B, Huret JL, Laï JL, Lampert F. Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group. Leukemia. 1995 Jan;9(1):102-6 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Heerema NA. 12p rearrangements in ALL. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):20-21. 21 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review Classification of B-cell chronic lymphoproliferative disorders (CLD) Antonio Cuneo Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BCLDClassifID2072.html DOI: 10.4267/2042/37587 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology immunoglobulins; cyIg: cytoplasmic Ig; IgV genes: genes encoding for the variable portion of the Ig. MTC and mTC1: major translocation cluster and minor translocation cluster 1 of BCL1 region, respectively. Identity Note: A classification of chronic (mature) B-cell lymphoproliferative disorders based on reproducible morphologic and immunologic criteria was proposed by the FAB group in 1989. Ever since a number of cytogenetic studies disclosed a remarkable degree of heterogeneity within each disease category. Herein, the main cytogenetic entities of chronic lymphocytic leukemia and related disorders, B-cell prolymphocytic leukemia, splenic lymphoma with villous lymphocytes are presented. Other disease subsets of B-cell CLD include the leukemic phase of follicle centre cell lymphoma, mantle cell lymphoma and lymphoplasmacytic lymphoma. The cytogenetic features of these forms of leukemic lymphoma are the described in the B-NHL classification. Comment: The incidence for each of these chromosome lesions (below) is higher when investigated by the more sensitive fluorescence in situ hybridization (FISH) technique: FISH detected 13q14 deletions in 40-50% of the cases, +12 in 15-20% of the cases; 11q22-23 deletions in 7-10% of the cases; 17p13 deletions in 15-20% of the cases. The prognostic significance for each of these anomalies, 11qexcluded, mainly derives from studies that used conventional cytogenetics and needs to be reassessed in the light of the more recent data provided by FISH analysis. Legend for immunophenotypes (below): +: positive in >90% of the cases; +/-: positive in more than 50% of the cases; -/+: positive in less than 50% of cases; -: positive in <10% of the cases; pan-B markers include CD19; CD20; CD79a R = rearranged; sIg: surface Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Clinics and pathology Disease Chronic lymphocytic leukemia CD5+ B cell that has encountered the antigen and harbours hypermutated IgV genes. Phenotype/cell stem origin CD5+; CD23+; CD38+/-; CD22 weak+; FMC7-; sIg+ weak. Cytogenetics del(13q) (10-15% of the cases): Typical morphology; indolent disease; favourable prognosis if present as the sole change (Note: typical morphology (FAB criteria): more than 90% of neoplastic cells are represented by small lymphocytes (diameter less than 14 m, i.e. < two red blood cells); atypical morphology: 10-55% of the lymphocytes are larger than 14 m with few prolymphocytes (CLL mixed-cell type); the cases are usually referred to as CLL/PL if prolymphocytes predominate among large lymphoid cells; PLL: more than 55%, and usually >70% of the cells are prolymphocytes.). Disease Chronic lymphocytic leukemia CD5+ virgin recirculating B-cell with germline IgV genes. Phenotype/cell stem origin CD5+; CD23+; CD38-/+; CD22 weak+; FMC7-; sIg+ weak. 22 Classification of B-cell chronic lymphoproliferative disorders (CLD) Cuneo A Cytogenetics +12 (10-15% of the cases): Frequent atypical morphology; relatively indolent disease; unfavourable prognosis as compared with other single chromosome aberrations, but not against complex karyotypes, 11qor 17p-. Cases with t(11;14) showed frequent CD5-positivity and featured an indolent course. Cytogenetics (20% of the cases) (breaks outside the MTC and mTC1 of BCL1). (20-40% of cases) with or without +3. Disease References Chronic lymphocytic leukemia CD5+ recirculating Bcell. Phenotype/cell stem origin CD5+; CD23+; CD22 weak+; FMC7-; sIg+ weak. Cytogenetics 11q22-23 deletion (ATM gene involved) (5-6% of the cases): Usually typical morphology with karyotype instability; Relatively aggressive disease, with development of multiple adenopathies; Unfavourable prognosis. del(17p) (p53 gene involved) (<5% of the cases): Morphology consistent with CLL/PL Advanced disease; Refractoriness to purine analougs; Unfavourable prognosis. t(11;14)(q13;q32) (BCL1 involved, mainly in the MTC and mTC1)(<5% of the cases): Rare cases of CLL/PL, transforming into prolymphocytic leukemia; Primary blood and marrow involvement, usually with splenomegaly, without adenopathy. 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 Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G, Mackie MJ, Parker AC, Castoldi GL, Guneo A, Knuutila S. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med. 1990 Sep 13;323(11):720-4 Döhner H, Fischer K, Bentz M, Hansen K, Benner A, Cabot G, Diehl D, Schlenk R, Coy J, Stilgenbauer S. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995 Mar 15;85(6):1580-9 Hernandez JM, Mecucci C, Criel A, Meeus P, Michaux I, Van Hoof A, Verhoef G, Louwagie A, Scheiff JM, Michaux JL. Cytogenetic analysis of B cell chronic lymphoid leukemias classified according to morphologic and immunophenotypic (FAB) criteria. Leukemia. 1995 Dec;9(12):2140-6 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 Disease Prolymphocytic leukemia (PLL). Phenotype/cell stem origin Peripheral B-lymphocyte that has encountered the antigen and harbours hypermutated IgV genes. Clinics Rare and aggressive disease with a majority of relatively large lymphocytes with round nucleus and a prominent central nucleolus. Cytogenetics t(11;14)(q13;q32) (BCL1 involved in the MTC and mTC1). 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 Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood. 1997 Apr 1;89(7):2516-22 Naylor M, Capra JD. Mutational status of Ig V(H) genes provides clinically valuable information in B-cell chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1837-9 Disease Splenic lymphoma with villous lymphocytes. Phenotype/cell stem origin Marginal zone lymphocytes harbouring hypermutated IgV genes. Pan-B+; CD5-/+; CD23-/+; CD11c+/-; CD25-/+; FMC7+/-; sIg+ bright. Clinics Indolent disease; There are not established correlations between chromosome lesions and hematologic features; Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 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 This article should be referenced as such: Cuneo A. Classification of B-cell chronic lymphoproliferative disorders (CLD). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):22-23. 23 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review Classification of B-cell non-Hodgkin lymphomas (NHL) Antonio Cuneo Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/BNHLClassifID2067.html DOI: 10.4267/2042/37588 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology cases may derive from post-germinal centre quiescent B-cells that harbour hypermutated IgV genes). Clinics Indolent disease; Leukemic involvement by lymphoid cells, including prolymphocytes and/or paraimmunoblasts Splenomegaly. Cytogenetics del(6)(q21-23) (20-30% of the cases). Identity Note: B-cell NHL include a number of clinicopathologic subsets of lymphoid neoplasms having heterogeneous features. This situation is reflected by variations in the classification systems that were proposed over the last decade. Cytogenetic findings were recognized to help defining a rationale biologic ground for the nosologic classification of lymphomas. An outlook of the salient cytogenetic entities in this spectrum of disorders is presented herein; a complete illustration of the cytogenetic profile of each disease is provided in specific cards. Unless otherwise specified the WHO classification system will be used. Legend for immunophenotypes (below): +: positive in >90% of the cases; +/-: positive in more than 50% of the cases; -/+: positive in less than 50% of cases; -: positive in <10% of the cases; pan-B markers include CD19; CD20; CD79a; R = rearranged; sIg: surface immunoglobulins; cyIg: cytoplasmic Ig; IgV genes: genes encoding for the variable portion of the Ig. Disease Lymphoplasmacytic lymphoma Phenotype/cell stem origin Histologic subset and Immunophenotype: Pan-B+; CD5-; CD10-; cyIgM+. Putative cell of origin: Peripheral B-lymphocyte transforming into plasma cell with mutated IgV genes and ongoing mutations. Clinics Indolent low-grade disease, with possible clinical and/or histologic progression. Cytogenetics t(9;14)(p13;q32) PAX5/IgH (50% of cases). Clinics and pathology Disease Disease Small lymphocytic lymphoma (SLL) Phenotype/cell stem origin Histologic subset and Immunophenotype: Pan-B+; CD5+; CD23+; CD10-; sIgM+ faint. Putative cell of origin: CD5+ virgin B-cell with germline IgV genes (as was recently demonstrated to be the case with chronic lymphocytic leukemia, the leukemic counterpart of SLL, it is likely that part of the Follicle centre cell lymphoma Phenotype/cell stem origin Histologic subset and Immunophenotype: Pan-B+; CD10+/-; CD5-; sIg+. Putative cell of origin: Centrocytes / centroblasts of germinal centre origin with somatic hypermutation of the IgV genes and ongoing mutations (antigen driven stimulation). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 24 Classification of B-cell non-Hodgkin lymphomas (NHL) Cuneo A Clinics Indolent. Advanced stages predominate. Conflicting data as to the prognostic significance of the t(14;18)/BCL2. Cytogenetics t(14;18)(q32;q21) / BCL2 Rearr (70-80% of cases). Cases with dual 8;14 and 14;18 translocations have a worse outcome (data requiring confirmation -1 study only). Cytogenetics t(8;14) or variants (25% of cases). t(8;14)+ t(14;18) (30% of cases). Disease Disease Diffuse large cell lymphoma Phenotype/cell stem origin Histologic subset and Immunophenotype: CD19+; CD22+; CD10-/+; SIg+. Putative cell of origin: Large transformed B-cells harbouring somatic hypermutation of the Ig genes (ongoing mutations in some cases). Clinics Usually aggressive. Immunoblastic lymphoma (Kiel classification) do worse than centroblastic lymphomas. No convincing demonstration that any "primary" cytogenetic / molecular defect has prognostic significance; complex karyotype confers a shorter survival. Cytogenetics t(14;18) and p53 mutations (20% of the cases). t(3;V)(q27;V)/ BCL6 Rearr (6-30% of cases (% variations depending on detection methods: molecular genetics and FISH more sensitive that conventional cytogenetics)). Or variants c-MYC Rearr (7-10% of cases). Mantle cell lymphoma Phenotype/cell stem origin Histologic subset and Immunophenotype: Pan-B +; CD5+; CD23-; CD10-/+; sIgM+ bright. Putative cell of origin: CD5+ B-cells of the follicle mantle having germline IgV gene sequences. Clinics Advanced stages predominate. Response to chemotherapy often unsatisfactory. Short survival. Complex karyotype carries an unfavourable prognostic significance. Cytogenetics t(11;14)(q13;q32)/BCL1 Rearr (50-90%) (molecular genetic methods have limited application due to variability of breakpoints; FISH is the most sensitive technique). Disease Marginal zone B-cell lymphoma (MZBCL) Phenotype/cell stem origin Histologic subset and Immunophenotype: pan-B+; CD5-/+; CD10-; CD23-; CD11c+/-; cyIg + (40% of the cells), sIgM+ bright; sIgD-). Putative cell of origin: Marginal zone lymphocytes harbouring hypermutated IgV genes. Cytogenetics t(11;18)(q21;q21) PI2/MLT fusion (30-50% of the lowgrade MALT): Extra-nodal low-grade MALT lymphoma; indolent disease. t(1;14)(p21;q32): Extra-nodal MALT lymphoma. del(7)(q22-31) (40% of the cases): Splenic MZBCL. +3/+3q (30-70% of the cases): Nodal, extra-nodal and splenic MZBCL. Disease Burkitt's lymphoma Phenotype/cell stem origin Histologic subset and Immunophenotype: Pan-B+; TdT-; CD10+; CD5-; sIgM+. Putative cell of origin: Peripheral B-cells that have encountered the antigen and harbours somatic hypermutation of the Ig genes. Clinics Extremely aggressive disease. Specific treatment mandatory. Cytogenetics Or variants / c-MYC R earr (80% of the cases). References Offit K, Parsa NZ, Filippa D, Jhanwar SC, Chaganti RS. t(9;14)(p13;q32) denotes a subset of low-grade non-Hodgkin's lymphoma with plasmacytoid differentiation. Blood. 1992 Nov 15;80(10):2594-9 Disease Burkitt-like lymphoma Phenotype/cell stem origin Histologic subset and Immunophenotype: Pan-B+; TdT-; CD10-/+ CD5-; sIg+. Putative cell of origin: Peripheral B-cells that have encountered the antigen. Clinics Aggressive disease. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, Monconduit M, Bastard C. Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood. 1994 Aug 15;84(4):1043-9 Kramer MH, Hermans J, Wijburg E, Philippo K, Geelen E, van Krieken JH, de Jong D, Maartense E, Schuuring E, Kluin PM. Clinical relevance of BCL2, BCL6, and MYC rearrangements in 25 Classification of B-cell non-Hodgkin lymphomas (NHL) Cuneo A diffuse large B-cell lymphoma. Blood. 1998 Nov 1;92(9):315262 Macpherson N, Lesack D, Klasa R, Horsman D, Connors JM, Barnett M, Gascoyne RD. Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation. J Clin Oncol. 1999 May;17(5):1558-67 Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Piva N, Milani R, Bullrich F, Veronese ML, Croce C, Birg F, Döhner H, Hagemeijer A, Castoldi G. Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features. Blood. 1999 Feb 15;93(4):1372-80 Panayiotidis P, Kotsi P. Genetics of small lymphocyte disorders. Semin Hematol. 1999 Apr;36(2):171-7 Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood. 1999 Jun 1;93(11):3601-9 Richardson MA. Research of complementary/alternative medicine therapies in oncology: promising but challenging. J Clin Oncol. 1999 Nov;17(11 Suppl):38-43 Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M, Price H, Karran L, Majekodunmi O, Wlodarska I, Pan L, Crook T, Hamoudi R, Isaacson PG, Dyer MJ. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell. 1999 Jan 8;96(1):35-45 Küppers R, Klein U, Hansmann ML, Rajewsky K. Cellular origin of human B-cell lymphomas. N Engl J Med. 1999 Nov 11;341(20):1520-9 This article should be referenced as such: López-Guillermo A, Cabanillas F, McDonnell TI, McLaughlin P, Smith T, Pugh W, Hagemeister F, Rodríguez MA, Romaguera JE, Younes A, Sarris AH, Preti HA, Lee MS. Correlation of bcl2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood. 1999 May 1;93(9):3081-7 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Cuneo A. Classification of B-cell non-Hodgkin lymphomas (NHL). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):2426. 26 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Mini Review i(17q) in myeloid malignancies Chrystèle Bilhou-Nabera Laboratoire d'Hématologie, Hôpital du Haut-Lévêque, CHU de Bordeaux, Ave de Magellan, 33 604 Pessac, France (CBN) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/i17qID1038.html DOI: 10.4267/2042/37589 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology lymphoid leukemias, and Hodgkin and non-Hodgkin lymphomas. In chronic myeloid leukemia, i(17q) is a frequent and well known secondary anomaly, either solely in 10% of cases, or with other additional anomalies, in at least another 10% of cases, in particular with +8. Identity Clinics and pathology Disease Myeloproliferative (MPD/MDS). / myelodysplastic diseases Phenotype/cell stem origin Previous studies on isolated i(17q) have suggested this aberration was associated with chronic myeloid abnormalities with a high rate of progression to ANLL; a new clinico-pathological entity in which i(17q) is the sole abnormality has been reported in a mixed myeloproliferative disorder / myelodysplastic syndrome with an aggressive course; if teen patients were included in this study classified as chronic myeloid malignancy at initial presentation: these features were not confirmed after a negative molecular BCR-ABL analysis in all cases studied (eleven patients). i(17q) G- banding (left) - Courtesy Jean-Luc Lai (top) and Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services (middle and bottom); and R- banding (right) - top: Editor, bottom: Courtesy Jacques Boyer. Etiology i(17q) as sole cytogenetic aberration represents only 1% of cases in myeloid malignancies. Note: An isochromosome 17 results in a loss of the short arm (17p) and duplication of the long arm (17q) leading to a single copy of 17p and three copies of 17q. An i(17q), usually observed in a complex karyotype, has been reported in solid tumors and in various types of hematological diseases: acute and chronic myeloid leukemias, acute lymphoid leukemiasand chronic Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Cytology A severe hyposegmentation of neutrophil nuclei (pseudo-Pelger Huet neutrophils (PHH)) and a prominence of the monocyte/macrophage lineage has been noted; other studies have identified an association between hyposegmented neutrophils and loss of 17p 27 i(17q) in myeloid malignancies Bilhou-Nabera C (called 17p- syndrome), always included in complex karyotypes; the i(17q) appeared to be a part of the malignant clone as demonstrated in cases available for a FISH analysis: all myeloid cell lines observed contained the abnormal i(17q), whereas none of the lymphocytes were affected. References Borgström GH, Vuopio P, de la Chapelle A. Abnormalities of chromosome No. 17 in myeloproliferative disorders. Cancer Genet Cytogenet. 1982 Feb;5(2):123-35 Testa JR, Cohen BC. Dicentric chromosome 17 in patients with leukemia. Cancer Genet Cytogenet. 1986 Sep;23(1):47-52 Prognosis Becher R, Carbonell F, Bartram CR. Isochromosome 17q in Ph1-negative leukemia: a clinical, cytogenetic, and molecular study. Blood. 1990 Apr 15;75(8):1679-83 By standard Kaplan-Meier analysis, the median survival was 2.5 years (range 0.85-5.25 years). Weh HJ, Fiedler W, Hossfeld DK. Cytogenetics in multiple myeloma: are we studying the 'right' cells? Eur J Haematol. 1990 Oct;45(4):236-7 Genes involved and proteins Note The underlying molecular defect that produces the isolated i(17q) is unknown: breakage of the proximal p arm (17p11.2) with rejoining of both centromerecontaining chromatids and subsequent inactivation of one centromere; breakpoints could involve important genetic material whose disruption could result in oncogene or tumor suppression gene deregulation. In understanding the specific i(17q) phenotype, loss of genes localized on 17p were suggested as p53 (17p13.1); a direct correlation between p53 loss and PHH neutrophils was found in a series of MDS and ANLL with 17p- syndrome. 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 Fugazza G, Bruzzone R, Puppo L, Sessarego M. Granulocytes with segmented nucleus retain normal chromosomes 17 in Philadelphia chromosome-positive chronic myeloid leukemia with i(17q) and pseudo-Pelger anomaly. A case report studied with fluorescence in situ hybridization. Cancer Genet Cytogenet. 1996 Sep;90(2):166-70 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: Bilhou-Nabera C. i(17q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):27-28. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 28 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(1;12)(q25;p13) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0112ID1147.html DOI: 10.4267/2042/37591 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Protein Belong to the ETS transcription factors family characterized by the ETS domain, domain which is responsible for the sequence specific DNA-binding activity. Clinics and pathology Disease Acute non lymphocytic leukemia (ANLL). Phenotype/cell stem origin Result of the chromosomal anomaly M4Eo ANLL. Epidemiology Only one case available. Hybrid gene Cytogenetics Transcript Both reciprocal transcripts are detected. Cytogenetics morphological Fusion protein A cryptic inv(16) was present, ascertained by a CBFb/MYH11 rearrangement; there fore, the t(1;12) may be a secondary anomaly. Description The fusion protein is composed of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase domains of ABL2. Genes involved and proteins ABL2 References Location 1q25 Protein Tyrosine kinase; closely related to ABL1. Cazzaniga G, Tosi S, Aloisi A, Giudici G, Daniotti M, Pioltelli P, Kearney L, Biondi A. The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood. 1999 Dec 15;94(12):4370-3 ETV6 Cazzaniga G, Tosi S, Aloisi A, Giudici G, Pioltelli P, Kearney L, Biondi A. The tyrosine kinase ABL-related gene 'ARG' is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood 1999;94 Suppl 1:Abst 233 Location 12p13 DNA/RNA Alternative transcripts. This article should be referenced as such: Huret JL. t(1;12)(q25;p13). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):29. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 29 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(1;16)(q12;q24) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0116q12q24ID1318.html DOI: 10.4267/2042/37592 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics and pathology Cytogenetics Disease Cytogenetics morphological Acute non lymphocytic leukemia (ANLL). Note Poorly known: only 2 cases to date. The t(1;16) presented as a der(16)t(1;16) in the 2 cases, resulting in trisomy 1q. The t(1;16) was the sole anomaly in each case. Phenotype/cell stem origin References A case of Fanconi anemia and a case of M1-ANLL. Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, Berger R. Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations. Leukemia. 1999 Dec;13(12):1975-81 Epidemiology The Fanconi anemia patient was a 9 yr old girl, and the ANLL case was a 22 yr old male patient. Prognosis Unknown. This article should be referenced as such: Huret JL. t(1;16)(q12;q24). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):30. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 30 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(1;2)(q12;q37) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0102q12q37ID1317.html DOI: 10.4267/2042/37590 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics and pathology Cytogenetics Disease Cytogenetics morphological Acute leukemias. Note Poorly known: only 3 cases to date. The t(1;2) presented as a der(2)t(1;2) in at least 2 of the 3 cases, resulting in trisomy 1q. The t(1;2) was associated with a t(9;22) in 1 ANLL case and in the ALL case; +8 was found in 1 ANLL case and del(7q) in the ALL case. The karyotypes were complex in 2 cases. The t(1;2) is likely to be a secondary anomaly. Phenotype/cell stem origin 1 case of M0 acute non lymphocytic leukemia (ANLL), 1 case of M4 ANLL, and 1 case of acute lymphoblastic leukemia (ALL). References Epidemiology Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, Berger R. Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations. Leukemia. 1999 Dec;13(12):1975-81 A 76 yr old female patient, a 81 yr old male patient, and a 69 yr old male patient. Prognosis Unknown. This article should be referenced as such: Huret JL. t(1;2)(q12;q37). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):31. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 31 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(1;21)(p36;q22) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0121ID1186.html DOI: 10.4267/2042/37593 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology The gene involved in 1p36 is unknown. Identity AML1 Note: Only two cases, one with features identical to a case of t(18;21)(q21;q22), and a case of t(19;21)(q13.4;q22). Location 21q22 DNA/RNA Transcription is from telomere to centromere. Protein Contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes. Clinics and pathology Disease Acute non lymphocytic leukemia (ANLL) secondary to toxic exposure. Etiology ANLL occurred about 50 years after radiation exposure from nuclear explosion in one case, 5 years after treatment with antitopoisomerase II for lung cancer in the other case. References Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD. CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Blood. 1998 Oct 15;92(8):2879-85 Evolution Complete remission in the two patients; relapse in the one documented case. Prognosis Hromas RA, Busse TM, Shopnick R, Jumean H, Bowers C, Richkind K. Cloning of an AML1 translocation in a novel syndrome of radiation-induced acute myeloid leukemia. Blood 1999; 94 suppl 1: Abst 3056 Unknown. This article should be referenced as such: Genes involved and proteins Huret JL. t(1;21)(p36;q22). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):32. Note Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 32 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(11;12)(p15;q13) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1112ID1185.html DOI: 10.4267/2042/37595 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity t(11;12)(p15;q13) G- banding - Courtesy Melanie Zenger and Claudia Haferlach. DNA/RNA Alternate splicing. Protein Contains repeated motifs and a RNA binding motif; nucleoporin: role in nucleo-cytoplasmic transport. Clinics and pathology Disease Treatment related acute non lymphoblastic leukemia (tANLL) so far. Epidemiology Result of the chromosomal anomaly Only one case; a female patient aged 39 yrs and treated with antitopoisomerase II for Hodgkin disease. Hybrid gene Cytogenetics Description 5 prime NUP98 - 3 prime unknown. Cytogenetics morphological Showed also rearrangement. a t(17;21)(q11;q22) with AML1 Fusion protein Genes involved and proteins Description Fuses the N-term domains undetermined sequence. Note The gene involved in 12q13 is unknown. References NUP98 NUP98 to an Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD. CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Blood. 1998 Oct 15;92(8):2879-85 Location : 11p15 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) of 33 t(11;12)(p15;q13) Huret JL Kobzev YN, Rowley JD. NUP98 gene rearrangements in leukemia detected by fluorescence in situ hybridization (FISH). Blood. 1999 ; 94 (numero Suppl 1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Huret JL. t(11;12)(p15;q13). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):33-34. 34 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(11;22)(q23;q11.2) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1122hCDCrelID1183.html DOI: 10.4267/2042/37596 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation. Identity Note: Not to be confused with the t(11;22)(q23;q13), involving MLL and P300. hCDCRel Clinics and pathology Location 22q11 DNA/RNA 2 kb mRNA Protein hCDCRel (human cell division cycle related) is a septin (family of filament forming proteins, involved in cytosqueletal organization). Disease De novo acute non lymphocytic leukemia (ANLL), so far. Phenotype/cell stem origin 2 cases of M4, one M2, and one M1. Epidemiology Yet poorly known; 2 young adults (22 and 34 yrs) and 2 infant twins; 2M/2F. Result of the chromosomal anomaly Prognosis Documented in only 2 cases (dead at 10 and 21 mths); likely to be comparable with that of other entities with 11q23/MLL11q23/MLL involvement. Hybrid gene Cytogenetics Description 5 prime MLL - 3 prime hCDCRel, with fusion of MLL exon 7 to hCDCRel exon 3. Cytogenetics morphological References Sole anomaly in 3 of 3 cases. Marukawa O, Akao Y, Inazawa J, Ariyama T, Abe T, Naoe T, Tanimoto M, Saito H, Otsuki Y, Tsujimoto Y. Molecular cloning of the breakpoint of t(11;22) (q23;q11) chromosome translocation in an adult acute myelomonocytic leukaemia. Br J Haematol. 1996 Mar;92(3):687-91 Genes involved and proteins MLL Baer MR, Stewart CC, Lawrence D, Arthur DC, Mrózek K, Strout MP, Davey FR, Schiffer CA, Bloomfield CD. Acute myeloid leukemia with 11q23 translocations: myelomonocytic immunophenotype by multiparameter flow cytometry. Leukemia. 1998 Mar;12(3):317-25 Location In 11q23. DNA/RNA 13-15 kb mRNA. Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett BD, Kelly KM, Lerou PH, Moulton T, Budarf ML, Felix CA. Protein Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 35 t(11;22)(q23;q11.2) Huret JL t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6413-8 Yagi M, Zieger B, Roth GJ, Ware J. Structure and expression of the human septin gene HCDCREL-1. Gene. 1998 Jun 8;212(2):229-36 This article should be referenced as such: Huret JL. t(11;22)(q23;q11.2). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):35-36. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 36 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(17;21)(q11.2;q22) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1721ID1181.html DOI: 10.4267/2042/37597 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Protein Contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes. Clinics and pathology Disease Acute non lymphoblastic leukemia (ANLL) and myelodysplastic syndromes (MDS); de novo ANLL and treatment related leukemias (t-ANLL). Result of the chromosomal anomaly Phenotype/cell stem origin One M2, one treatment related RAEBt/M4, one tANLL. Hybrid gene Etiology Description 5 prime AML1-3 prime unknown; breakpoint in intron 5 or 6 of AML1. Two cases are secondary to treatment with topoisomerase II inhibitors for Hodgkin disease and neuroblastoma. Fusion protein Epidemiology Description The N-term is provided by AML1, as in the t(3;21) and in the t(8;21) associated with ANLLs, whereas, in the ALL with t(12;21), the fusion protein comprises the Cterm part of AML1. 3 cases to date; 1M/2F, aged 2yrs, 39 yrs and 76 yrs. Prognosis Unknown. Cytogenetics References Additional anomalies Sole anomaly in one case; one case was also -7, +8, one case showed also a t(11;12)(p15;q13) with NUP98 rearrangement. Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD. CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Blood. 1998 Oct 15;92(8):2879-85 Genes involved and proteins Kobzev YN, Rowley JD. NUP98 gene rearrangements in leukemia detected by fluorescence in situ hybridization (FISH). Blood. 1999 ; 94 (numero Suppl 1). Note The gene involved in 17q11 is unknown; the breakpoint on chromosome 17 is between the loci for NF1 and RARA. LySunnaram B, Gandemer V, Le Mee F, Cayuela JM, Edan C, Le Gall E, Goasguen JE. Secondary raeb-t associated with t(17;21) in a child treated by VP16 for neuroblastoma. Blood. 1999 ; 94 (numero Suppl 1). AML1 This article should be referenced as such: Location 21q22 DNA/RNA Transcription is from telomere to centromere. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Huret JL. t(17;21)(q11.2;q22). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):37. 37 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(18;21)(q21;q22) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1821ID1187.html DOI: 10.4267/2042/37598 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics and pathology Genes involved and proteins Disease Note The gene involved in 18q21 is unknown. Acute non lymphocytic leukemia (ANLL) secondary to toxic exposure. Note Only one case, but with features identical to 2 other cases: one case of t(1;21)(p36;q22), and one case of t(19;21)(q13.4;q22). AML1 Location 21q22 DNA/RNA Transcription is from telomere to centromere. Protein Contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes. Phenotype/cell stem origin M2-ANLL Etiology About 50 years after radiation exposure from nuclear explosion. Clinics References Pancytopenia preceeded leukemia. Hromas RA, Busse TM, Shopnick R, Jumean H, Bowers C, Richkind K. Cloning of an AML1 translocation in a novel syndrome of radiation-induced acute myeloid leukemia. Blood. 1999; 94 (suppl1). Evolution Complete remission was obtained and the patient returned to the previous pancytopenia; subsequent relapse occurred. This article should be referenced as such: Huret JL. t(18;21)(q21;q22). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):38. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 38 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(19;21)(q13.4;q22) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1921ID1182.html DOI: 10.4267/2042/37599 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology DNA/RNA Transcription is from telomere to centromere. Protein Contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes. Clinics and pathology Disease Acute non lymphocytic leukemia (ANLL) secondary to toxic exposure. Note Only one case, but with features identical to 2 other cases: one case of t(1;21)(p36;q22), and one case of t(18;21)(q21;q22). Phenotype/cell stem origin Result of the chromosomal anomaly M2-ANLL Hybrid gene Etiology Description AMP-19 is fused to AML1 out of frame. About 50 years after radiation exposure from nuclear explosion. Fusion protein Clinics Description Truncated AML1 with the DNA binding domain, but not a transcriptional activation region. Oncogenesis Could function as a dominant negative inhibitor of normal AML1. Pancytopenia preceeded leukemia. Evolution Complete remission was obtained and the patient returned to the previous pancytopenia; subsequent relapse occurred. References Genes involved and proteins Hromas RA, Busse TM, Shopnick R, Jumean H, Bowers C, Richkind K. Cloning of an AML1 translocation in a novel syndrome of radiation-induced acute myeloid leukemia. Blood. 1999; 94 (suppl1). AMP19 Location 19q13.4 This article should be referenced as such: AML1 Huret JL. t(19;21)(q13.4;q22). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):39. Location 21q22 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 39 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(3;11)(p21;q23) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0311ID1165.html DOI: 10.4267/2042/37594 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation. Clinics and pathology Disease AF3p21 Treatment related acute non lymphoblastic leukemia (tANLL). Location 3p21 Phenotype/cell stem origin M5b ANLL. Result of the chromosomal anomaly Epidemiology Only one case; a female patient aged 23 yrs and treated 9 years ago for T-ALL. Hybrid gene Prognosis Description Breakpoints of MLL between exons 9 and 10 and upstream of exon 1 of the AF3p21 gene. Unknown; likely to be poor, both as it carries a MLL rearrangements and as occurs in t-ANLL. Fusion protein Cytogenetics Description AT hooks and methyltransferase domains of MLL in the N-term fused to the proline-rich domain and nuclear localization signal of AF3p21. Cytogenetics morphological Sole anormaly. Genes involved and proteins References MLL Sano K, Hayakawa A, JinHua P. A novel sh3 protein encoded by the AF3p21 gene is fused to MLL in a therapy-related leukemia with t(3; 11)(p21;q23). Blood. 1999 ; 94 (numero Suppl 1). Location In 11q23 DNA/RNA 13-15 kb mRNA. Protein 431 kDa; contains two DNA binding motifs (a AT Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Huret JL. t(3;11)(p21;q23). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):40. 40 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Leukaemia Section Short Communication t(3;11)(q25;q23) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: February 2000 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t311GMPSID1173.html DOI: 10.4267/2042/37600 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation. Clinics and pathology Disease Treatment related acute non lymphoblastic leukemia. Phenotype/cell stem origin Result of the chromosomal anomaly M4 ANLL. Etiology One case, a 13 yr old boy; occurred 9 yrs after treatment for neuroblastoma with antitopoisomerase II. Hybrid gene Genes involved and proteins Description Fusion of MLL exon 7 to GMPS. GMPS References Location 3q24 DNA/RNA 2.2 kb mRNA. Protein 76 kDa; enzyme of the de novo synthesis of guanine nucleotides: amidotransferase that catalyzes the amination of xanthosine 5 prime monophosphate to form GMP. Hirst M, Haliday E, Nakamura J, Lou L. Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA. J Biol Chem. 1994 Sep 23;269(38):23830-7 Nakamura J, Straub K, Wu J, Lou L. The glutamine hydrolysis function of human GMP synthetase. Identification of an essential active site cysteine. J Biol Chem. 1995 Oct 6;270(40):23450-5 Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rappaport EF, Felix CA. t(3;11)(q25;q23) fuses MLL with the GMPS (guanosine 5'-monophosphate synthetase) gene in treatmentrelated acute myeloid leukemia (AML). Blood. 1999 ; 94 (numero Suppl 1). MLL Location In 11q23. DNA/RNA 13-15 kb mRNA. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Huret JL. t(3;11)(q25;q23). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):41. 41 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Solid Tumour Section Mini Review Bone: Chondrosarcoma Judith VMG Bovée Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Tumors/chondrosarcID5063.html DOI: 10.4267/2042/37602 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology chondrosarcoma (2%) and extra-skeletal myxoid chondrosarcoma (5%). Furthermore, dedifferentiated chondrosarcoma is a relatively rare high grade sarcoma next to a low-grade conventional malignant cartilageforming tumor, comprising 6-10% of all chondrosarcomas. Conventional chondrosarcoma can be categorized according to their location in bone. Identity Figure 1: En bloc resection specimen of the proximal fibula of a 43 year old female, containing a lobulated bluish white, translucent tumour (4.5 x 2 x 1.9 cm) located centrally within the medullary cavity, consistent with central chondrosarcoma. Classification Note: Approximately 90% of chondrosarcomas are histologically of the conventional type; in addition to conventional chondrosarcoma, some rare variants with distinctive microscopic and clinical features are discerned: clear cell chondrosarcoma (1%), mesenchymal chondrosarcoma (2%), juxtacortical Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) Figure 2: Corresponding macro-slice showing a lobular architecture, and endosteal cortical thinning. Cytonuclear appearance can be more readily appreciated in figure 3. 42 Bone: Chondrosarcoma Bovée JVMG Figure 3: Micrograph displaying low cellularity with limited cytonuclear atypia, and a high amount of chondroid matrix surrounding tumor cells consistent with a grade I chondrosarcoma. Note the presence of a binucleated cell. The majority of chondrosarcomas (75%) are located centrally within the medullary cavity (central chondrosarcoma), whereas a minority (15%) develops from the surface of bone (peripheral chondrosarcoma) as a result of malignant transformation within the cartilaginous cap of a solitary or hereditary pre-existent osteochondroma. Clinics and pathology mainly chondroid matrix and the absence of mitoses; In contrast, grade III chondrosarcomas are highly cellular, with nuclear polymorphism, mitoses and a mostly myxoid matrix; Increasing histological grade is correlated with higher metastatic potential; it is considered difficult to assess the histological grade of cartilaginous tumours and to reliably distinguish between benign tumours and those of low-grade malignancy. Epidemiology Treatment Primary malignant bone tumours occur 1/100,000, of which 17-24% consists of chondrosarcoma; the majority of patients are between 35 and 60 years old with equal sex distribution. Because chondrosarcoma is highly resistant to chemotherapy and radiotherapy, surgical treatment is the only option for curative treatment. Clinics The majority of central chondrosarcomas are considered to arise de novo and malignant transformation of solitary enchondroma is extremely rare (<1%); in patients demonstrating multiple enchondromas, such as Ollier's disease, the incidence of secondary central chondrosarcoma is much higher (30-35%); peripheral chondrosarcomas usually originate from the cartilaginous cap of an osteochondroma; malignant transformation is low in solitary osteochondromas (<1%) but is estimated to occur in 1-5% of cases of hereditary multiple exostoses; furthermore, an occasional recurrent chondrosarcoma may exhibit a higher grade of Evolution Compared to benign cartilaginous tumours, chondrosarcomas more frequently present with pain and tenderness; they usually develop in the trunk, pelvis and long bones. Pathology There are no apparent cytonuclear differences between central and peripheral conventional chondrosarcomas and both are histologically classified into three grades using the criteria of Evans et al. Grade I chondrosarcomas demonstrate low cellularity, limited cytonuclear atypia, few multinucleated cells, a Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 43 Bone: Chondrosarcoma Bovée JVMG malignancy than the original neoplasm, suggesting that tumours may additionally progress from low to high grade. chondrosarcoma, an identical somatic 6 bp deletion in exon 7 of p53 and loss of the same copy of chromosome 13 provided compelling evidence for a common origin instead of the 'collision tumor' theory; in addition, many different genetic alterations were found, indicating that the separation of the two clones is a relatively early event in the histogenesis of dedifferentiated chondrosarcoma. Unfortunately, most other genetic analyses on chondrosarcoma were performed on a heterogeneous group including all different subtypes of chondrosarcoma; ploidy-analysis of chondrosarcomas has been described and aneuploidy is more frequently found in high-grade chondrosarcomas; two series of chondrosarcomas (n=23 and n=50) studied by CGH revealed extensive genetic aberrations; the majority of these changes were gains of whole chromosomes or whole chromosome arms, most frequent at 20q (3238%), 20p (24-31%), and 14q23-qter (24-28%); a correlation between gain at 8q24.1 and shorter overall survival was reported; amplification of the c-myc proto-oncogene, located at 8q24, was found in four of 12 chondrosarcomas, and was not associated with any clinicopathological features; the only recurrent highlevel amplification, seen in two tumours (7%), affected the minimal common region 12cen-q15; although both cytogenetic analysis and CGH point at 12cen-q15, CDK4, MDM2 and SAS were not frequently amplified in chondrosarcoma. Partial allelotypings of a heterogeneous group of chondrosarcoma revealed that in addition to LOH at the EXT-loci on chromosomes 8 (4/17) and 11 (7/17), LOH was found at 10q11 (12/18), the Rb - (9/25) and p53-locus (7/28). Overexpression of the p53 protein and TP53 mutations have been observed mainly in high-grade chondrosarcomas, suggesting that the p53 gene could play a role in the progression of chondrosarcoma. Prognosis Metastasis in chondrosarcoma highly depends on the histological grade of malignancy; grade I chondrosarcomas demonstrate local recurrence, but seldom metastasize; grade II chondrosarcomas demonstrate metastases in 10-30% of the cases, whereas grade III chondrosarcomas demonstrate metasases in the majority of cases; in contrast to chondrosarcomas located elsewhere in the skeleton, those located in the phalanx behave as a locally aggressive lesion with minimal metastatic potential. Cytogenetics Cytogenetics Morphological Extra-skeletal myxoid chondrosarcoma, comprising 5% of all chondrosarcomas, is characterized by a reciprocal translocation t(9;22)(q22;q12), fusing the EWS to the CHN gene. Cytogenetic analysis on a heterogeneous group of chondrosarcomas revealed that structural aberrations of chromosomes 1, 6, 9, 12 and 15 and numerical aberrations of chromosomes 5, 7, 8 and 18 were most frequent; abnormalities of chromosome 1 and 7 were confined to malignant cartilaginous tumours; like in other mesenchymal neoplasms, band 12q13-15 is prominently involved in the aberrations; the presence of chromosome aberrations was found to strongly correlate with increasing histological grade; complex aberrations were mainly seen in the high-grade chondrosarcomas. Cytogenetics Molecular In a comparative study of central and peripheral chondrosarcomas, 19 of 20 peripheral chondrosarcomas showed LOH at all loci (EXT, EXTL, 13q14, 17p13, 9p21 and chromosome 10) tested while only 3 of 12 central chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14 and 17p13. DNA-flow-cytometry demonstrated a wide variation in the ploidy status in peripheral chondrosarcomas (DNA-indices 0.56 - 2.01), whereas central chondrosarcomas were predominantly peridiploid; these results indicate that peripheral chondrosarcomas, arising secondarily to an exostosis, may obtain genetic alterations during malignant transformation, with subsequent genetic instability as demonstrated by a high percentage of LOH and a wide variation in ploidy status; in contrast, peridiploidy and a low percentage of LOH in central tumors suggest that a different oncogenic molecular mechanism may be operative; no mutations in the EXT1 and EXT2 genes were found in secondary peripheral chondrosarcoma. Investigating both the cartilaginous as well as the highgrade malignant component of dedifferentiated Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) References Cuvelier CA, Roels HJ. Cytophotometric studies of the nuclear DNA content in cartilaginous tumors. Cancer. 1979 Oct;44(4):1363-74 Kreicbergs A, Boquist L, Borssén B, Larsson SE. Prognostic factors in chondrosarcoma: a comparative study of cellular DNA content and clinicopathologic features. Cancer. 1982 Aug 1;50(3):577-83 Kreicbergs A, Silvferswärd C, Tribukait B. Flow DNA analysis of primary bone tumors. Relationship between cellular DNA content and histopathologic classification. Cancer. 1984 Jan 1;53(1):129-36 Xiang JH, Spanier SS, Benson NA, Braylan RC. Flow cytometric analysis of DNA in bone and soft-tissue tumors using nuclear suspensions. Cancer. 1987 Jun 1;59(11):1951-8 Castresana JS, Barrios C, Gómez L, Kreicbergs A. Amplification of the c-myc proto-oncogene in human chondrosarcoma. Diagn Mol Pathol. 1992 Dec;1(4):235-8 44 Bone: Chondrosarcoma Bovée JVMG Barrios C, Castresana JS, Ruiz J, Kreicbergs A. Amplification of c-myc oncogene and absence of c-Ha-ras point mutation in human bone sarcoma. J Orthop Res. 1993 Jul;11(4):556-63 Brody RI, Ueda T, Hamelin A, Jhanwar SC, Bridge JA, Healey JH, Huvos AG, Gerald WL, Ladanyi M. Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma. Am J Pathol. 1997 Mar;150(3):1049-58 Bridge JA, Bhatia PS, Anderson JR, Neff JR. Biologic and clinical significance of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions. Cancer Genet Cytogenet. 1993 Sep;69(2):79-90 Larramendy ML, Tarkkanen M, Valle J, Kivioja AH, Ervasti H, Karaharju E, Salmivalli T, Elomaa I, Knuutila S. Gains, losses, and amplifications of DNA sequences evaluated by comparative genomic hybridization in chondrosarcomas. Am J Pathol. 1997 Feb;150(2):685-91 Wadayama B, Toguchida J, Yamaguchi T, Sasaki MS, Yamamuro T. p53 expression and its relationship to DNA alterations in bone and soft tissue sarcomas. Br J Cancer. 1993 Dec;68(6):1134-9 Oshiro Y, Chaturvedi V, Hayden D, Nazeer T, Johnson M, Johnston DA, Ordóñez NG, Ayala AG, Czerniak B. Altered p53 is associated with aggressive behavior of chondrosarcoma: a long term follow-up study. Cancer. 1998 Dec 1;83(11):2324-34 Coughlan B, Feliz A, Ishida T, Czerniak B, Dorfman HD. p53 expression and DNA ploidy of cartilage lesions. Hum Pathol. 1995 Jun;26(6):620-4 Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Genes Chromosomes Cancer. 1999 Nov;26(3):237-46 Hasegawa T, Seki K, Yang P, Hirose T, Hizawa K, Wada T, Wakabayashi J. Differentiation and proliferative activity in benign and malignant cartilage tumors of bone. Hum Pathol. 1995 Aug;26(8):838-45 Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXTlinked markers on chromosomes II and 8. Am J Hum Genet. 1995 May;56(5):1125-31 Bovée JV, Cleton-Jansen AM, Rosenberg C, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis. J Pathol. 1999 Dec;189(4):454-62 Heliö H, Karaharju E, Böhling T, Kivioja A, Nordling S. Chondrosarcoma of bone. A clinical and DNA flow cytometric study. Eur J Surg Oncol. 1995 Aug;21(4):408-13 Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 1999 Sep;65(3):689-98 Raskind WH, Conrad EU, Chansky H, Matsushita M. Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Am J Hum Genet. 1995 May;56(5):1132-9 Bovée JV, van der Heul RO, Taminiau AH, Hogendoorn PC. Chondrosarcoma of the phalanx: a locally aggressive lesion with minimal metastatic potential: a report of 35 cases and a review of the literature. Cancer. 1999 Nov 1;86(9):1724-32 Simms WW, Ordóñez NG, Johnston D, Ayala AG, Czerniak B. p53 expression in dedifferentiated chondrosarcoma. Cancer. 1995 Jul 15;76(2):223-7 Raskind WH, Conrad EU, Matsushita M. Frequent loss of heterozygosity for markers on chromosome arm 10q in chondrosarcomas. Genes Chromosomes Cancer. 1996 Jun;16(2):138-43 Larramendy ML, Mandahl N, Mertens F, Blomqvist C, Kivioja AH, Karaharju E, Valle J, Böhling T, Tarkkanen M, Rydholm A, Akerman M, Bauer HC, Anttila JP, Elomaa I, Knuutila S. Clinical significance of genetic imbalances revealed by comparative genomic hybridization in chondrosarcomas. Hum Pathol. 1999 Oct;30(10):1247-53 Yamaguchi T, Toguchida J, Wadayama B, Kanoe H, Nakayama T, Ishizaki K, Ikenaga M, Kotoura Y, Sasaki MS. Loss of heterozygosity and tumor suppressor gene mutations in chondrosarcomas. Anticancer Res. 1996 JulAug;16(4A):2009-15 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Bovée JVMG. Bone: Chondrosarcoma. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):42-45. 45 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Hereditary multiple exostoses (HME) Judith VMG Bovée Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands (JVMGB) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Kprones/HeredMultExostosID10061.html DOI: 10.4267/2042/37603 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology representing approximately 50% of all primary benign tumours of bone; they gradually develop and increase in size in the first decade of life; the stratified zones of chondrocytes that are normally found in the growth plate can still be recognised on the interface of cartilage and bone in osteochondroma; consequently, osteochondromas cease growing as the growth plates close during puberty; the majority is asymptomatic and is located in bones that developed from cartilage, especially the long bones in the extremities. Identity Alias: Diaphyseal aclasis Inheritance: Autosomal dominant disorder, genetically heterogeneous; males are more often affected, possibly partly due to an incomplete penetrance in females; approximately 62% of the patients have a positive family history. Clinics Neoplastic risk Phenotype and clinics Malignant transformation is low in solitary osteochondromas (<1%) but is estimated to occur in 15% of cases of hereditary multiple exostoses. Presence of multiple osteochondromas (osteocartilaginous exostosis), bony protrusions covered by a cartilaginous cap on the outer surface of bone, resulting in a variety of orthopaedic deformities such as disproportionate short stature and bowing of the forearm; osteochondromas are the most common benign bone tumours, Treatment Osteochondromas can be surgically removed for cosmetic or functional reasons. Figure 1: X-ray of the upper arm of a patient coming from a family with hereditary multiple exostoses (HME), demonstrating multiple osteochondromas (exostoses). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 46 Hereditary multiple exostoses (HME) Bovée JVMG Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G. Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet. 1993 Jul;53(1):71-9 Cytogenetics Cytogenetics of cancer Clonal karyotypic abnormalities in the cartilaginous cap of osteochondroma involving 8q22-24.1 were found in ten out of 30 sporadic and in 1 out of 13 hereditary osteochondromas, supporting a neoplastic origin; this was confirmed since aneuploidy was found in 4 out of 10 osteochondromas and LOH was almost exclusively found at the EXT1 locus in 5 out of 14 osteochondromas; no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. Le Merrer M, Legeai-Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H, Toutain A, Achard F, Munnich A, Maroteaux P. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet. 1994 May;3(5):717-22 Ahn J, Lüdecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet. 1995 Oct;11(2):137-43 Wicklund CL, Pauli RM, Johnston D, Hecht JT. Natural history study of hereditary multiple exostoses. Am J Med Genet. 1995 Jan 2;55(1):43-6 Genes involved and proteins Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet. 1996 Sep;14(1):25-32 EXT1 and EXT2 Location 8q24 and 11p11-p12. Note HME is a genetically heterogeneous disorder for which at present, two genes, EXT1 and EXT2 located respectively on 8q24 and 11p11-p12, have been isolated; the EXT1 gene was reported to show linkage in 44%-66% of the HME families, whereas EXT2 would be involved in 27%; additional linkage to chromosome 19p has been found, suggesting the existence of an EXT3 -gene, although loss of heterozygosity studies could not confirm this; two patients with multiple osteochondromas demonstrated a germline mutation in EXT1 combined with loss of the remaining wild type allele in three osteochondromas, confirming the tumour suppressor function of the EXT genes and indicating that in cartilaginous cells of the growth plate inactivation of both copies of the EXT1gene is required for osteochondroma formation in hereditary cases. Protein Function: A tumour suppressor function is suggested for the EXT genes, which was confirmed by the combination of EXT1 germline mutations with loss of the remaining wildtype allele in osteochondroma; the EXT gene products were shown to be involved in heparan sulphate biosynthesis. Mutations Germinal: Germline mutations of EXT1 and EXT2 in HME patients have been studied extensively in Caucasian as well as Asian populations. Somatic: No somatic mutations were found in the EXT1 and EXT2 gene in 34 sporadic and hereditary osteochondromas and chondrosarcomas tested. Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul EV, De Boulle K, de Vries BB, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, van den Ouweland AM, McGaughran J, Halley DJ, Willems PJ. Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet. 1996 Oct;5(10):1547-57 Hecht JT, Hogue D, Wang Y, Blanton SH, Wagner M, Strong LC, Raskind W, Hansen MF, Wells D. Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Am J Hum Genet. 1997 Jan;60(1):80-6 Legeai-Mallet L, Margaritte-Jeannin P, Lemdani M, Le Merrer M, Plauchu H, Maroteaux P, Munnich A, Clerget-Darpoux F. An extension of the admixture test for the study of genetic heterogeneity in hereditary multiple exostoses. Hum Genet. 1997 Mar;99(3):298-302 Legeai-Mallet L, Munnich A, Maroteaux P, Le Merrer M. Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet. 1997 Jul;52(1):12-6 Philippe C, Porter DE, Emerton ME, Wells DE, Simpson AH, Monaco AP. Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Am J Hum Genet. 1997 Sep;61(3):520-8 Raskind WH, Conrad EU 3rd, Matsushita M, Wijsman EM, Wells DE, Chapman N, Sandell LJ, Wagner M, Houck J. Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum Mutat. 1998;11(3):231-9 Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, Mollica F, Lüdecke HJ, Sayli BS, Pazzaglia UE, Mortier G, Hamel B, Conrad EU, Matsushita M, Raskind WH, Willems PJ. Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet. 1998 Feb;62(2):346-54 Bovée JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 1999 Sep;65(3):689-98 References Crandall BF, Field LL, Sparkes RS, Spence MA. Hereditary multiple exostoses. Report of a family. Clin Orthop Relat Res. 1984 Nov;(190):217-9 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) 47 Hereditary multiple exostoses (HME) Bovée JVMG Park KJ, Shin KH, Ku JL, Cho TJ, Lee SH, Choi IH, Phillipe C, Monaco AP, Porter DE, Park JG. Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses. J Hum Genet. 1999;44(4):230-4 Legeai-Mallet L, Rossi A, Benoist-Lasselin C, Piazza R, Mallet JF, Delezoide AL, Munnich A, Bonaventure J, Zylberberg L. EXT 1 gene mutation induces chondrocyte cytoskeletal abnormalities and defective collagen expression in the exostoses. J Bone Miner Res. 2000 Aug;15(8):1489-500 Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, Pan Q, Long Z, Fan C, Deng HX. Mutation analysis of hereditary multiple exostoses in the Chinese. Hum Genet. 1999 Jul-Aug;105(12):45-50 Porter DE, Emerton ME, Villanueva-Lopez F, Simpson AH. Clinical and radiographic analysis of osteochondromas and growth disturbance in hereditary multiple exostoses. J Pediatr Orthop. 2000 Mar-Apr;20(2):246-50 Bernard MA, Hogue DA, Cole WG, Sanford T, Snuggs MB, Montufar-Solis D, Duke PJ, Carson DD, Scott A, Van Winkle WB, Hecht JT. Cytoskeletal abnormalities in chondrocytes with EXT1 and EXT2 mutations. J Bone Miner Res. 2000 Mar;15(3):442-50 Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs MB, Clines GA, Lüdecke HJ, Lovett M, Van Winkle WB, Hecht JT. Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Cell Motil Cytoskeleton. 2001 Feb;48(2):149-62 Bovée JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC. Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest. 2000 Dec;80(12):1925-34 Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Bovée JVMG. Hereditary multiple exostoses (HME). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):46-48. 48 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Rhabdoid predisposition syndrome Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: January 2000 Online updated version : http://AtlasGeneticsOncology.org/Kprones/rhabdKpronID10051.html DOI: 10.4267/2042/37604 This article is an update of: Huret JL. Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol.1999;3(2).107 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinics Genes involved and proteins Note The following observations have suggested that a new cancer-prone disease, related to the gene hSNF5/INI, could be delineated: - Two siblings with a paravertebral malignant rhabdoid tumor in the first year of life and a poor outcome; no family history; - renal rhabdoid tumors associated with tumors of the central nervous system in a given patient; - germ-line mutations of INI1 identified in four children, three with renal rhabdoid tumors and one with an atypical teratoid tumor of the brain (out of 18 atypical teratoid and rhabdoid tumors studied); - and 4 recent pedigrees with - malignant rhabdoid tumor, choroid plexus carcinoma, atypical teratoid tumor, medulloblastoma, and/or primitive neuroectodermal tumor, - either occurring in sibs or in a given patient, - with a INI1 point mutation in the tumor DNA and loss of wild type allele and/or heterozygosity for the mutation in constitutional DNA. hSNF5/INI1 Location 22q11.2 Mutations Germinal: Are found in this syndrome. Somatic: Mutation and allele loss events in sporadic rhabdoid tumors are in accordance with the two-hit model for neoplasia, as is found in retinoblastoma. References Lynch HT, Shurin SB, Dahms BB, Izant RJ Jr, Lynch J, Danes BS. Paravertebral malignant rhabdoid tumor in infancy. In vitro studies of a familial tumor. Cancer. 1983 Jul 15;52(2):290-6 Fort DW, Tonk VS, Tomlinson GE, Timmons CF, Schneider NR. Rhabdoid tumor of the kidney with primitive neuroectodermal tumor of the central nervous system: associated tumors with different histologic, cytogenetic, and molecular findings. Genes Chromosomes Cancer. 1994 Nov;11(3):146-52 Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999 Jan 1;59(1):74-9 Phenotype and clinics No apparent stigmata. Neoplastic risk Sévenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet. 1999 Nov;65(5):1342-8 Malignant rhabdoid tumors and atypical teratoid tumors, choroid plexus carcinomas, medulloblastomas, and primitive neuroectodermal tumors; highly aggressive tumors; very early onset in children or infants, and, apparently, high penetrance. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1) This article should be referenced as such: Huret JL. Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(1):49. 49 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Instructions to Authors Manuscripts submitted to the Atlas must be submitted solely to the Atlas. Iconography is most welcome: there is no space restriction. The Atlas publishes "cards", "deep insights", "case reports", and "educational items". Cards are structured review articles. 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