in oncology and haematology

PTCH1 (patched homolog 1 (Drosophila)) Huret JL

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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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 2 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. 1997; 1(1)



Editor

Jean-Loup Huret (Poitiers, France)

Volume 1, Number 1, May-September 1997

Table of contents

Gene Section

PTCH (patched homolog) 1 Jean-Loup Huret

TAL1 (T-cell acute leukemia 1) 3 Jean-Loup Huret, Marie-Claude Labastie

ALK (anaplastic lymphoma kinase) 4 Jean-Loup Huret

NF1 (neurofibromin 1) 5 Jean-Loup Huret

Leukaemia Section

Childhood myelodysplastic syndromes 7 Jean-Loup Huret, Claude Léonard

idic(X)(q13) 9 Franck Viguié

Polycythemia vera (PV) 11 Jean-Loup Huret, Nicole Smadja

+11 or trisomy 11 (solely) 12 François Desangles

Chronic lymphocytic leukaemia (CLL) 13 Hossein Mossafa, Jean-Loup Huret

dic(9;12)(p11-13;p11-12) 15 Jean-Loup Huret

t(1;3)(p36;q21) 16 Jean-Loup Huret

t(1;22)(p13;q13) 17 Jean-Loup Huret

t(3;5)(q25;q34) 18 Jean-Loup Huret

t(12;21)(p12;q22) 19 Jean-Loup Huret, Alain Bernheim





+14 or trisomy 14 (solely) 21 Jean-Loup Huret

t(3;12)(q26;p13) 22 François Desangles

t(8;21)(q22;q22) 23 Jean-Loup Huret

t(9;22)(q34;q11) in ALL 26 Jean-Loup Huret

t(9;22)(q34;q11) in ANLL 29 Jean-Loup Huret

Solid Tumour Section

Bladder cancer 32 Jean-Loup Huret, Claude Léonard

Cancer Prone Disease Section

Naevoid basal cell carcinoma syndrome (NBCS) 34 Jean-Loup Huret

Neurofibromatosis type 1 (NF1) 36 Jean-Loup Huret

Neurofibromatosis type 2 (NF2) 38 Jean-Loup Huret


Gene Section Short Communication

Atlas Genet Cytogenet Oncol Haematol. 1997; 1(1) 1



PTCH (patched homolog) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Published in Atlas Database: May 1997

Online version is available at: http://AtlasGeneticsOncology.org/Genes/PTCH100.html DOI: 10.4267/2042/32018 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: PTC, but this term was confusing with PTC/PKA. Location: 9q22.3 Local order: between FACC and XPAC.

DNA/RNA Description 23 exons, 2 of which are non-coding; 34 kb.

Transcription Alternate splicing: 3 different 5' termini.

Protein Description Glycoprotein; 12 transmembrane domains, 2 extra cellular loops and intracellular N-term and C-term.

Localisation Transmembrane protein.

Function Part of a signalling pathway; opposed by the hedgehog gene's product; transmembrane protein, with a probable cell to cell adhesion role; is thought to have a repressive activity on cell proliferation; the recent demonstration of NBCS syndrome (see below) as a chromosome instability syndrome suggests that this protein has a role in DNA maintenance, repair and/or replication.

Homology Patched (drosophila segment polarity gene).

Mutations Germinal Germ-line mutations lead to protein truncation in naevoid basal cell carcinoma syndrome (NBCS) patients (see below).

Somatic Mutation and allele loss events in basal cell carcinoma, in NBCS and in sporadic basal cell carcinoma are, so far, in accordance with the two-hit model for neoplasia, as is found in retinoblastoma.

Implicated in Naevoid basal cell carcinoma syndrome (NBCS) or Gorlin syndrome Disease Autosomal dominant condition; cancer prone disease (multiple basal cell carcinomas); it is also a chromosome instability syndrome.

Cytogenetics Spontaneous and induced chromosome instability.

Sporadic basal cell carcinoma

References Tabata T, Eaton S, Kornberg TB. The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Genes Dev 1992 Dec;6(12B):2635-45.

Basler K, Struhl G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 1994 Mar 17; 368(6468):208-14.

Capdevila J, Estrada MP, Sánchez-Herrero E, Guerrero I. The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development. EMBO J 1994 Jan 1; 13(1):71-82.

PTCH (patched homolog) Huret JL


Gailani MR, Stǻhle-Bäckdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Undén AB, Dean M, Brash DE, Bale AE, Toftgǻrd R. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 1996 Sep; 14(1):78-81.

Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, Dean M, Wainwright B. A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J Biol Chem 1996 May 24; 271(21):12125-8.

Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB,Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996 Jun 14; 85(6):841-51.

Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP. Human homolog of patched, a candidate gene for

the basal cell nevus syndrome. Science 1996 Jun 14; 272(5268):1668-71.

Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S, Suthers G, Haites N, Edwards M, Wainwright B, Chenevix-Trench G. Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. Am J Hum Genet 1997 Jan; 60(1):21-6.

Shafei-Benaissa E, Savage JR, Babin P, Larregue M, Papworth D, Tanzer J, Bonnetblanc JM, Huret JL. The naevoid basal-cell carcinoma syndrome (Gorlin syndrome) is a chromosomal instability syndrome. Mutat Res 1998 Feb 2; 397(2):287-92.

This article should be referenced as such:

Huret JL. PTCH (patched homolog). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):1-2.





TAL1 (T-cell acute leukemia 1) Jean-Loup Huret, Marie-Claude Labastie

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Institut d'Embryologie Cellulaire et Moléculaire-CNRS UPR 9064, Nogent-sur-Marne, France (MCL)

Published in Atlas Database: August 1997

Online version is available at: http://AtlasGeneticsOncology.org/Genes/TAL1.html DOI: 10.4267/2042/32019 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: SCL (stem cell leukaemia), TCL5 (T cell leukaemia 5). Location: 1p32

DNA/RNA

SILTAL1

61b 4 51a 2b 2a 3

DNA diagram

Description 8 exons; 16 kb.

Transcription (Complex) alternate splicing of: 1A with 2A, or 3, or 5, vs 1B, 2B, 3 and 5.

Protein Description 331 amino acids and other; 42, 40, 34 kDa; domains: prolin rich in N-term; basic Helix-Loop-Helix from the exon 6.

Expression In erythroblastes, megakaryoblastes, mastocytes, basophils, and in the nervous system; role in haematopoietic cell differentiation.

Function Transcription factor; exhibits sequence-specific DNA binding activity when in dimers with another bHLH protein such as E2A.

Homology - TAL2 in 9q32; - LYL1 in 19p13.

Implicated in t(1;14)(p32;q11)/T-ALL→ TAL1/TCRD

t(1;7)(p32;q34)/T-ALL→ TAL1/TCRB T-ALL with normal karyotype, Deletions at the DNA level (in the 5’ region) with a normal karyotype.

References Bash RO, Crist WM, Shuster JJ, Link MP, Amylon M, Pullen J, Carroll AJ, Buchanan GR, Smith RG, Baer R. Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study. Blood 1993 Apr 15; 81(8):2110-7. Wadman I, Li J, Bash RO, Forster A, Osada H, Rabbitts TH, Baer R. Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. EMBO J 1994 Oct 17; 13(20):4831-9. Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH. Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proc Natl Acad Sci USA 1995 Oct 10;92(21):9585-9. Hofmann TJ, Cole MD. The TAL1/Scl basic helix-loop-helix protein blocks myogenic differentiation and E-box dependent transactivation. Oncogene 1996 Aug 1; 13(3):617-24. Porcher C, Swat W, Rockwell K, Fujiwara Y, Alt FW, Orkin SH. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell 1996 Jul 12; 86(1):47-57. Ono Y, Fukuhara N, Yoshie O. Transcriptional activity of TAL1 in T cell acute lymphoblastic leukemia (T-ALL) requires RBTN1 or -2 and induces TALLA1, a highly specific tumor marker of T-ALL. J Biol Chem 1997 Feb 14; 272(7):4576-81.


Huret JL, Labastie MC. TAL1 (T-cell acute leukemia 1). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):3.





ALK (anaplastic lymphoma kinase) Jean-Loup Huret


Published in Atlas Database: September 1997

Online version is available at: http://AtlasGeneticsOncology.org/Genes/ALK.html DOI: 10.4267/2042/32020 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Location: 2p23

DNA/RNA Transcription 6.2 kb m RNA; coding sequence: 4.9 kb.

Protein Description 1620 amino acids; 177 kDa; after glycosylation, produces a 200 kDa mature glycoprotein.

Expression Tissue specific; mainly in: brain, gut and testis; not in the lymphocytes.

Localisation Cell membrane.

Function Membrane associated tyrosine kinase receptor; probable role in nervous system development and maintenance.

Homology Homologies with the insulin receptor super family: LTK (leucocyte tyrosine kinase), TRKA, ROS (homolog of the drosophila Sevenless), IGF1-R and IRbeta.

Implicated in t(2;5)(p23;q35)/CD30+ NHL → NPM1/ALK Disease High grade NHL; most often: CD30+ anaplastic large cell type.

Prognosis Nonetheless, a 80% five yr survival may be associated with this anomaly. Cytogenetics Additional anomalies are most often found. Hybrid/Mutated Gene 5' NPM1-3' ALK on der(5). Abnormal Protein 680 amino acids; N-term NPM1 is fused to the 563 C-term aminoacids of ALK (i.e. the entire cytoplasmic portion of ALK); no apparent expression of the ALK/NPM1 counterpart; localisation: both in the cytoplasm and in the nucleus. Oncogenesis Via the kinase function activated by oligomerization of NPM1-ALK mediated by the NPM1 part.

References Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994 Mar 4; 263(5151):1281-4. Erratum in Science 1995 Jan 20; 267(5196):316-7.

Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 1997 Jan 30; 14(4):439-49.

Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui X, Witte DP. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase. Oncogene 1997 May 8; 14(18):2175-88. Erratum in Oncogene 1997 Dec 4; 15(23):2883.

Bischof D, Pulford K, Mason DY, Morris SW. Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol Cell Biol 1997 Apr; 17(4):2312-25.


Huret JL. ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):4.





NF1 (neurofibromin 1) Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Genes/NF1ID134.html DOI: 10.4267/2042/32021 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Location: 17q11.2

DNA/RNA Description 60 exons; spans 350 kb; presence of 3 cryptic genes: OMGP, EVI2A, and EVI2B ('overlapping genes'), hidden within NF1 intron 27 with an opposite transcription direction.

Transcription At least 4 alternate splicings; 9.0 mRNA complete cds; coding sequence: CDS 198..8717.

Protein Description The protein has been called neurofibromin; 2839 amino acids.

Expression Is tissue and development stage specific.

Function GTPase activating protein (GAP) interacting with p21RAS →tumour suppressor.

Homology Other (GAP); IRA1 and 2, the yeast inhibitors of p21RAS.

Mutations Germinal Large deletions or insertions in 25% of cases, translocations and point mutations; widely dispersed, with no cluster: yielding difficulties in diagnosis; truncating effect in 2/3 of cases.

Somatic The second allele remains normal in benign tumours and is often lost in malignant tumours another process in tumourigenesis may involve RNA editing (for the second allele), which gives rise to a truncated neurofibromin having lost its GAP activity.

Implicated in Neurofibromatosis type 1 Disease Autosomal dominant cancer prone disease; neurofibromatosis type 1 (NF1: the same symbol is used for the disease neurofibromatosis type 1 and the gene neurofibromin 1) is an hamartoneoplastic syndrome.

Watson syndrome Disease Autosomal dominant disease with cardiac malformations, and, as is found in von Recklinghausen neurofibromatosis, low normal intelligence, café-au-lait spots, and neurofibromas but to a lesser extend.

Oncogenesis In accordance with the two-hit model for neoplasia, as is found in retinoblastoma.

References Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 1990 Jul 13; 62(1):193-201. Erratum in Cell 1990 Aug 10; 62(3):608.

Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and neck. Oxford Monogr Med Genet 1990; 19:392-399.

Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 1990 Jul 13; 62(1):187-192.

NF1 (neurofibromin 1) Huret JL


Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990 Jul 13; 249(4965):181-186. Erratum in Science 1990 Dec 21; 250(4988):1749.

Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet 1991 Nov; 28(11):752-756.

Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R, Thakker N. Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome. Am J Hum Genet 1993 Jul; 53(1):90-95.

Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, McCormick F. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 1994 Mar 3; 330(9):597-601.

Henry I. Médecine-sciences 1995; 11:93. (Review). French.

Li Y, O'Connell P, Breidenbach HH, Cawthon R, Stevens J, Xu G, Neil S, Robertson M, White R, Viskochil D. Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 1995 Jan 1; 25(1):9-18.

Metheny LJ, Cappione AJ, Skuse GR. Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I. J Neuropathol Exp Neurol 1995 Nov;54(6):753-760.

Cappione AJ, French BL, Skuse GR. A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors. Am J Hum Genet 1997 Feb; 60(2):305-312.

Hoffmeyer S, Nürnberg P, Ritter H, Fahsold R, Leistner W, Kaufmann D, Krone W. Nearby stop codons in exons of the neurofibromatosis type 1 gene are disparate splice effectors. Am J Hum Genet 1998 Feb; 62(2):269-77.


Huret JL. NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):5-6.

Leukaemia Section Mini Review




Childhood myelodysplastic syndromes Jean-Loup Huret, Claude Léonard

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Cytogénétique, Laboratoire d'Anatomo Pathologie, CHU Bicêtre, 78 r Leclerc, F94270 Le Kremlin-Bicêtre, France (CL)

Published in Atlas Database: July 1997

Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/childMDS.html DOI: 10.4267/2042/32022 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease Very heterogeneous: I. idiopathic MDS II. secondary MDS: to previous chemo- and/or radio-therapy. III. 'genetic MDS': cases associated with a congenital genetic disease, such as: - Neurofibromatosis type 1 (Von Recklinhausen)(MIM 16220): an hamartoneoplastic syndrome, - Kostmann syndrome (MIM 20270): also called congenital neutropenia, - Bloom syndrome (MIM 21090): a chromosome instability syndrome, - Dubowitz syndrome (MIM 22337): mimicks Bloom's, but without chromosome instability, - Fanconi anaemia (MIM 22765): a chromosome instability syndrome, - Schwachman syndrome (MIM 26040): with pancreatic insufficiency, and risk of leukaemia, - Pearson disease (MIM 26056) and other mitochondrial diseases: they often share pancreatic insufficiency, bone marrow pancytopenia with myelodysplastic features but maintained polyclonality, muscular and other ubiquitous manifestations, - Familial monosomy 7, - Familial platelet storage pool deficiency, - Unbalanced constitutional karyotypes, including +21, +8, del(11q), del(21q) miscellaneous conditions.

Phenotype / cell stem origin RA, RARS (very rare), RAEB, RAEBT, CMML, 'Juvenile CML', 'Infantile Monosomy 7', 'non classifiable cases according to the FAB'; with variable proportions according to the studies.

Epidemiology 10% of haematological malignancies in children; median age: 2 to 5 yrs; sex ratio: balanced for some, male predominance (in RAEB±T or CMML) for others.

Prognosis CR is obtained; however, median survival is about 3 yrs, while 1/3 of the cases may be considered as cured; good prognostic features are: young age, female sex, normal karyotype, and some of the genetic predisposing factors; worse prognosis is found in secondary MDS, RAEB and RAEBT, cases with +8, +19, t(1;7).

Cytogenetics Cytogenetics, morphological A normal karyotype or a monosomy 7 (intermediate prognosis) are found in 30% -or more- of cases each; others are: +8, +21, t(1;7), del(6q).

References Creutzig U, Cantù-Rajnoldi A, Ritter J, Romitti L, Odenwald E, Conter V, Riehm H, Masera G. Myelodysplastic syndromes in childhood. Report of 21 patients from Italy and West Germany. Am J Pediatr Hematol Oncol 1987; 9(4):324-30.

Brandwein JM, Horsman DE, Eaves AC, Eaves CJ, Massing BG, Wadsworth LD, Rogers PC, Kalousek DK. Childhood myelodysplasia: suggested classification as myelodysplastic syndromes based on laboratory and clinical findings. Am J Pediatr Hematol Oncol 1990; 12(1):63-70.

Tuncer MA, Pagliuca A, Hicsonmez G, Yetgin S, Ozsoylu S, Mufti GJ. Primary myelodysplastic syndrome in children: the clinical experience in 33 cases. Br J Haematol 1992 Oct; 82(2):347-53.

Childhood myelodysplastic syndromes Huret JL, Léonard C


Hasle H, Jacobsen BB, Pedersen NT. Myelodysplastic syndromes in childhood: a population based study of nine cases. Br J Haematol 1992 Aug; 81(4):495-8.

Mansoor AM, Bharadwaj TP, Sethuraman S, Chandy M, Pushpa V, Kamada N, Murthy PB. Analysis of karyotype, SCE, and point mutation of RAS oncogene in Indian MDS patients. Cancer Genet Cytogenet 1993 Jan; 65(1):12-20.

Hasle H. Myelodysplastic syndromes in childhood classification, epidemiology, and treatment. Leuk Lymphoma 1994 Mar; 13(1-2):11-26. (Review).

Zipursky A, Thorner P, De Harven E, Christensen H, Doyle J. Myelodysplasia and acute megakaryoblastic leukemia in Down's syndrome. Leuk Res 1994 Mar; 18(3):163-71.

Hasle H, Kerndrup G, Jacobsen BB. Childhood myelodysplastic syndrome in Denmark: incidence and predisposing conditions. Leukemia 1995 Sep; 9(9):1569-72.

Passmore SJ, Hann IM, Stiller CA, Ramani P, Swansbury GJ, Gibbons B, Reeves BR, Chessells JM. Pediatric

myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 1995 Apr 1; 85(7):1742-50.

Barnard DR, Kalousek DK, Wiersma SR, Lange BJ, Benjamin DR, Arthur DC, Buckley JD, Kobrinsky N, Neudorf S, Sanders J, Miller LP, Shina DC, Hammond GD, Woods WG. Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Childrens Cancer Group. Leukemia 1996 Jan; 10(1):5-12.

[No authors listed]. Forty-four cases of childhood myelodysplasia with cytogenetics, documented by the Groupe Français de Cytogénétique Hématologique. Leukemia 1997 Sep; 11(9):1478-85.


Huret JL, Léonard C. Childhood myelodysplastic syndromes. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):7-8.

Leukaemia Section Short Communication




idic(X)(q13) Franck Viguié

Laboratoire de Cytogénétique - Service d'Hématologie Biologique, Hôpital Hôtel-Dieu, 75181 Paris Cedex 04, France


Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/idicX.html DOI: 10.4267/2042/32023

This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

idic(X)(q13) G- banding and FISH; top - Courtesy Melanie Zenger and Claudia Haferlach; bottom - Courtesy Jean Luc Lai

Childhood myelodysplastic síndromes Huret JL, Léonard C


Clinics and pathology Disease Acute non lymphocytic leukaemia (ANLL), Myelodysplastic syndromes (MDS), Chronic myeloproliferative diseases (MPS).

Phenotype / cell stem origin M1, M2, M4 ANLL, often with preceding MDS; MDS: often RARS; an early progenitor cell is involved.

Epidemiology Rare finding; only found in female patients aged 47-86 yrs; as one normal X chromosome seems to be needed, it is not that surprising that male cases are not found.

Clinics No history of toxic exposure.

Cytology Bone marrow iron accumulation, ringed sideroblasts are often found.

Prognosis Variable.

Genetics Note: The gene(s) involved are unknown; breakpoint located within a 450kb region proximal from XIST and containing an inverted repeat.

Cytogenetics Cytogenetics, morphological Both the 2 centromeres appear to be active.

Cytogenetics, molecular Breakpoint at or near the X inactivation center at Xq13. The XIST (X inactive specific transcript) gene is deleted. In 2 cases studied with BrDU, idic(X) was late-replicating.

Additional anomalies + idic(X)(or more copies) in 2/3 of cases; other known anomalies in MDS/ANLL; rings.

References Dewald GW, Brecher M, Travis LB, Stupca PJ. Twenty-six patients with hematologic disorders and X chromosome abnormalities. Frequent idic(X)(q13) chromosomes and Xq13 anomalies associated with pathologic ringed sideroblasts. Cancer Genet Cytogenet 1989; 42:173-185.

Rack KA, Chelly J, Gibbons RJ, Rider S, Benjamin D, Lafreniére RG, Oscier D, Hendriks RW, Craig IW, Willard HF, et al. Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukemia. Hum Mol Genet 1994; 3:1053-1059.

Dierlamm J, Michaux L, Criel A, Wlodarska I, Zeller W, Louwagie A, Michaux JL, Mecucci C, Van den Berghe H. Isodicentric (X)(q13) in haematological malignancies: presentation of five new cases, application of fluorescence in situ hybridization (FISH) and review of the literature. Br J Haematol 1995; 91:885-891.


Viguié F. idic(X)(q13). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):9-10.





Polycythemia vera (PV) Jean-Loup Huret, Nicole Smadja

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Laboratoire de Recherche en Cytogénétique Hématologique, Hôpital Saint Antoine, Paris, France (NS)


Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/PV.html DOI: 10.4267/2042/32024 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease Chronic myeloproliferative syndrome

Phenotype / cell stem origin Pluripotent -non lymphoid- stem cell is involved.

Epidemiology Annual incidence: 10/106; sex ratio: 1M/1F; median age 60 yrs.

Clinics Asymptomatic for a long time, revealed by symptoms related to blood hyperviscosity (headache, vertigo...), or by asthenia, pruritus, skin erythrosis, or various other symptoms; splenomegaly is frequent: 70%; hepatomegaly in 40%; blood data: red cell mass of > 36 ml/kg in males, > 32 ml/kg in females; arterial oxygen saturation > 92%; high haemoglobin; WBC and platelets counts may be high.

Prognosis Chronic disease, with, however, risks of thrombosis and haemorrhages in various tissues, including central nervous system; bone marrow evolution towards: 1- myelofibrosis with myeloid metaplasia (MMM) in 20% of cases; 2- acute leukaemia in 10%, either as an acute transformation, or as a therapy related ANLL; prognosis: median survival is 14 yrs with blood-letting, 12 yrs with 32P, less than 10 yrs with standard chemotherapy.

Cytogenetics Cytogenetics, morphological Normal karyotype is found in > 80% of cases at diagnosis, abnormal karyotype occurs with evolution, but the appearance of a clonal anomaly does not

indicate progression of the disease, and may also occur during evolution to MMM; finally, up to 100% of cases with acute transformation have chromosome anomalies; these are: del(20q), +8, +9 may be seen solely or simultaneously in 20% of cases with chromosome anomalies, del(13q) and a partial duplication dup(1q)(sometimes in the form of t(1;7)(q10;p10) in 10%, other anomalies in 30%; none of them has prognostic significance; del(5q) and del(7q), hypodiploidy are seen in cases evolving towards therapy related ANLL: they confirm the diagnosis and indicate an adverse prognosis.

Genes involved and Proteins Note: genes involved are unkown.

References Berlin NI. Diagnosis and classification of the polycythemias. Semin Hematol 1975 Oct; 12(4):339-51.

Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI, Wasserman LR. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 1986 Apr; 23(2):132-43.

Landaw SA. Acute leukemia in polycythemia vera. Semin Hematol 1986 Apr; 23(2):156-65.

Rege-Cambrin G, Mecucci C, Tricot G, Michaux JL, Louwagie A, Van Hove W, Francart H, Van den Berghe H. A chromosomal profile of polycythemia vera. Cancer Genet Cytogenet 1987; 25:233-45.

No authors listed. Cytogenetics of acutely transformed chronic myeloproliferative syndromes without a Philadelphia chromosome. A multicenter study of 55 patients. Groupe Français de Cytogénétique Hématologique. Cancer Genet Cytogenet 1988 Jun; 32(2):157-68.


Huret JL, Smadja N. Polycythemia vera (PV). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):11.





+11 or trisomy 11 (solely) François Desangles

Laboratoire de Biologie, Hôpital du Val de Grâce, 75230 Paris, France


Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/tri11.html DOI: 10.4267/2042/32025 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease Myeloid lineage: (ANLL, MDS) Phenotype / cell stem origin M1, M2, and M4 ANLL; therapy related ANLL; MDS evolving towards ANLL; stem cell immunophenotype (DR+, CD34+, and CD15, 33 and/or 13 positive); trilineage dysplasia may be present. To be noted that M1 and M2 subtypes of ANLL have rarely been found associated with the classical MLL rearrangements. Epidemiology Frequency: 1% of ANLL and MDS as well; balanced sex ratio; found in adults; med age: 60 yrs. Prognosis Short CR; poor prognosis.

Cytogenetics Cytogenetics, morphological +11

Cytogenetics, molecular Partial tandem duplication (in situ) of MLL gene located in 11q23.

Probes Oncor, Inc.

Additional anomalies None (by that very fact).

Genes involved and Proteins MLL Location: 11q23 DNA / RNA 21 exons, spanning over 100 kb; 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; wide expression; nuclear localisation; transcriptional regulatory factor.

Results of the chromosomal anomaly Hybrid gene Description Exons 1 to 6 or 8 fused to a nearly entire MLL gene, starting at exon 2 (i.e. the duplicated segment is E2 to E6 or 8).

Fusion protein Description AT hook and DNA methyltransferase from MLL in N-term fused to a quite entire MLL in C-term. Expression localisation Nuclear localisation. Oncogenesis Probable altered transcriptional regulation.

To be noted Such a tandem duplication of MLL may also be found in cases with a normal karyotype.

References Ingram L, Raimondi SC, Mirro J Jr, Rivera GK, Ragsdale ST, Behm F. Characteristics of trisomy 11 in childhood acute leukemia with review of the literature. Leukemia 1989 Oct; 3(10):695-8. (Review). Chichman SA, Canaani E, Croce CM. Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia. JAMA 1995 Feb 15; 273(7):571-6. (Review).

This article should be referenced as such: Desangles F. +11 or trisomy 11 (solely). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):12.





Chronic lymphocytic leukaemia (CLL) Hossein Mossafa, Jean-Loup Huret

Laboratoire Pasteur-Cerba, 95066, Cergy-Pontoise, France (HM) Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)


Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/CLL.html DOI: 10.4267/2042/32026 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease Chronic lymphoproliferation

Phenotype / cell stem origin B-cell disease; the existence of rare cases of T-CLL has been debated.

Epidemiology Annual incidence 30/106; represents 70% of lymphoid leukaemias, 1/4 of all leukaemias; median age: 60-80 yrs, 2M/1F.

Clinics Diagnosis is often delayed, due to the lack of symptoms (therefore, median survival from the begining of the disease may be much more than med. surv. from diagnosis); enlarged lymph nodes; splenomegaly; blood data: lymphocytosis > 4 X 109/l; hypogammaglobulinemia in 60%.

Cytology Typically, proliferation of mature small lymphocytes of normal morphology; lymphocytes with more abundant cytoplasm can be present; prolymphocytes must represent less than 10% of the lymphocytes (otherwise, the diagnosis of 'chronic lymphocytic leukaemia-prolymphocytic leukaemia' should be made); expression of sIg with monotypy (monoclonality); CD19+, CD20+, and CD5+ most often.

Treatment None in early stage; chemotherapy afterwards.

Evolution

Unrelated causes and disease-related infections are the 2 major causes of death.

Other: autoimmune hemolytic anaemia and thrombocytopenia; transformation into Richter's disease or into prolymphocytic leukaemia (in 10%).

Prognosis According to the staging: A (less than 3 lymph nodes, Hb < 10g/dl, platelets < 100 X 109/l): survival not reduced compared to age matched population; B (3 or more lymph nodes; Hb and platelets maintained): median survival of 5 yrs; C (Hb < 10g/dl and/or platelets < 100 X 109/l): median survival of 2 yrs; according to the karyotype: survival is better in cases with a normal karyotype (median: 15 yrs vs 8 yrs with an abnormal karyotype), worse in the 10% of cases where a complex karyotype is found (median: 6 yrs); specific chromosome anomalies have specific prognoses (see below).

Cytogenetics Cytogenetics, morphological Clonal anomaly is found in about 50% of cases; complex karyotypes are found in 10%; unrelated clones demonstrating the existence of cells subpopulations are frequent findings in this disease. +12: is found in 15-20% of cases, depending on the use of interphase cytogenetics methods (FISH) and the cell morphology of the cases under study (trisomy 12 is typically found in atypical lymphocyte morphology and CD5- cases, often with an increased number of prolymphocytes, in advanced stages, and is associated with disease progression); trisomy 12 is an adverse prognostic factor (median survival: 5 yrs); found either as the sole anomaly, as an anomaly accompanied by others, or even as an accompanying (secondary) anomaly; present only in a subset of the malignant cell population; region q13-q22 might be of particular pathogenetic importance;

Chronic lymphocytic leukaemia (CLL) Mossafa H, Huret JL


del(13q) and t(13;Var): found in 10-20% of cases; q14 and Rb gene and also DNA sequences telomeric and centromeric to Rb are often involved; deletion may be hetero- or homozygous; good prognostic feature (median survival > 15 yrs); 14q32 involvement: is frequent in CLL, as in other B-cell chronic leukaemias or lymphomas; t(11;14)(q13;q32), typical of mantle cell lymphoma, with BCL1/IgH rearrangement, may occasionally be found in CLL; t(14;19)(q32;q13), with BCL3/IgH rearrangement, may be associated with short survival; t(2;14)(p13;q32), exceptional; Other t(14; var) have been found; del(6q), del(11q), +3, +18: are the most frequent other anomalies.

Genes involved and Proteins Note: Genes involved as a primary event are still unknown. P53 has been found mutated in 10-15% of cases; adverse prognostic indicator.

References [No authors listed]. Prognostic and therapeutic advances in CLL management: the experience of the French Cooperative Group. French Cooperative Group on Chronic Lymphocytic Leukemia. Semin Hematol 1987 Oct; 24(4):275-90.

Huret JL, Mossafa H, Brizard A, Dreyfus B, Guilhot F, Xue XQ, Babin P, Tanzer J. Karyotypes of 33 patients with clonal aberrations in chronic lymphocytic leukemia. Review of 216 abnormal karyotypes in chronic lymphocytic leukemia. Ann Genet 1989; 32(3):155-159.

Escudier SM, Pereira-Leahy JM, Drach JW, Weier HU, Goodacre AM, Cork MA, Trujillo JM, Keating MJ, Andreeff M.

Fluorescent in situ hybridization and cytogenetic studies of trisomy 12 in chronic lymphocytic leukemia. Blood 1993 May 15; 81(10):2702-2707.

Que TH, Marco JG, Ellis J, Matutes E, Babapulle VB, Boyle S, Catovsky D Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridization: analysis by stage, immunophenotype, and morphology. Blood. 1993 ; 82 (2) : 571-575.

Criel A, Wlodarska I, Meeus P, Stul M, Louwagie A, Van Hoof A, Hidajat M, Mecucci C, Van den Berghe H. Trisomy 12 is uncommon in typical chronic lymphocytic leukemias. Br J Haematol 1994 Jul; 87(3):523-528.

Matutes E. Trisomy 12 in chronic lymphocytic leukemia. Leuk Res 1996 May; 20(5):375-377.

Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R, Hamblin T, Lens D, Swansbury GJ, Catovsky D. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol 1996 Feb; 92(2):382-388.

Woessner S, Solé F, Pérez-Losada A, Florensa L, Vilá RM. Trisomy 12 is a rare cytogenetic finding in typical chronic lymphocytic leukemia. Leuk Res 1996 May;20(5):369-374.

Crossen PE. Genes and chromosomes in chronic B-cell leukemia. Cancer Genet Cytogenet 1997 Mar; 94(1):44-51. (Review).

Dierlamm J, Michaux L, Criel A, Wlodarska I, Van den Berghe H, Hossfeld DK. Genetic abnormalities in chronic lymphocytic leukemia and their clinical and prognostic implications. Cancer Genet Cytogenet 1997 Mar; 94(1):27-35. (Review).

Garcia-Marco JA, Price CM, Catovsky D. Interphase cytogenetics in chronic lymphocytic leukemia. Cancer Genet Cytogenet 1997 Mar; 94(1):52-58.


Mossafa H, Huret JL. Chronic lymphocytic leukaemia (CLL). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):13-14.





dic(9;12)(p11-13;p11-12) Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/dic0912.html DOI: 10.4267/2042/32027 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Note: dic(9;12) is mainly found in ALL, and that is the clinical entity which is described below.

Clinics and pathology Disease ALL most often; rarely: CML in blast crisis, T-cell leukaemia or lymphoma.

Phenotype / cell stem origin Of dic(9;12)/ALL: L1/L2 CD10+ most often, may be CIg+ ALL.

Epidemiology 1% of paediatric ALL; sex ratio: 2M/1F; children and young adults (> 1 yr, < 25 yrs); no infant case.

Clinics Moderate organomegaly; bood data: moderate WBC.

Treatment No BMT; no high risk protocol.

Prognosis CR in all cases; 5 yrs survival > 95%.

Cytogenetics Cytogenetics, morphological Dicentric with loss of parts of 9p and 12p → ploidy: 45 chromosomes.

Additional anomalies +8, +21.

To be noted Bone marrow transplantation should not be performed, as the prognosis of the dic(9;12)/ALL is excellent.

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

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


Huret JL. dic(9;12)(p11-13;p11-12). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):15.





t(1;3)(p36;q21) Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0103.html DOI: 10.4267/2042/32028 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease Myeloid lineage (MDS, ANLL, therapy related ANLL, BC-CML)

Phenotype / cell stem origin MDS (RA: 3 cases; RAEB: 4 cases; CMML: 2 cases; RAEBT: 1 case); ANLL (M1, M4...), often (13/16 cases) with preceding MDS, according to cases herein reviewed; seem to involve a myeloid stem cell, t(1;3) being absent from B or T lymphocytes; may be secondary to toxic exposure.

Epidemiology Median age: 49 yrs; sex ratio: 7M/9F.

Clinics Blood data: frequent thrombocytosis.

Cytology Dysmegakaryocytopoiesis.

Prognosis Very poor so far: median survival is 6 mths in ANLL, 20 mths in MDS.

Cytogenetics Additional anomalies del (5q) in 3 of 16 cases.

To be noted This translocation share commun features with inv(3)(q21q26), t(3;3)(q21;q26), and t(3;5)(q21-25;q31-35).

References Welborn JL, Lewis JP, Jenks H, Walling P. Diagnostic and prognostic significance of t(1;3)(p36;q21) in the disorders of hematopoiesis. Cancer Genet Cytogenet 1987; 28:277-285.

Grigg AP, Gascoyne RD, Phillips GL, Horsman DE. Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3. Br J Haematol 1993; 83:158-165.


Huret JL. t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):16.





t(1;22)(p13;q13) Jean-Loup Huret




Identity

t(1;22)(p13;q13) G- and R- banding

Clinics and pathology Disease Only found so far in M7 ANLL (acute megakaryocytic leukaemia); not found in Down syndrome (DS), and yet, DS is a disease with highly elevated risk of M7.

Phenotype / cell stem origin M7 (CD 41).

Epidemiology 30% of paediatric M7; 70 to 100% of infants M7; age: infants (17/18); sex ratio: 5M/13F herein reviewed.

Clinics Organomegaly; bood data: moderate WBC; Thrombocytopenia; myelofibrosis.

Prognosis CR: 11/18; poor survival is probable.

Cytogenetics Additional anomalies Often none; otherwise: +der(1), +19, +6…

References Lion T, Haas OA, Harbott J, Bannier E, Ritterbach J, Jankovic M, Fink FM, Stojimirovic A, Herrmann J, Riehm HJ, et al. The translocation t(1;22)(p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children. Blood 1992 Jun 15; 79(12):3325-30.

Lion T, Haas OA. Acute megakaryocytic leukemia with the t(1;22)(p13;q13). Leuk Lymphoma 1993 Sep; 11(1-2):15-20. (Review).


Huret JL. t(1;22)(p13;q13). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):17.





t(3;5)(q25;q34) Jean-Loup Huret




Clinics and pathology Disease ANLL; may be preceded by MDS; BC-CML

Phenotype / cell stem origin M2, M4, M6 (although a rare subtype) ANLL; trilineage involvement.

Epidemiology Med. age: 35 yrs; balanced sex ratio.

Prognosis CR: 8/12, but median survival is less than 1 yr.

Cytogenetics Cytogenetics, morphological Location of breakpoints is difficult to ascertain.

Additional anomalies Most often none; +8.

Genes involved and Proteins MLF1 Location: 3q25

Protein 31 kDa; do not contain known functional motifs; widely expressed; cytoplasmic localisation.

NPM1 Location: 5q34

Protein Nuclear localisation; binds to single and double strand nucleic acids; phosphoprotein that may transport ribonucleoproteins; may also have a role in DNA replication.

Results of the chromosomal anomaly Hybrid gene Description 5' NPM-3' MLF1 on der(5).

Fusion protein Expression localisation 54 kDa with the 175 N-term amino acids from NPM; localization: nucleus, mainly in the nucleolus.

To be noted Specific comments: this translocation share some (but not all) common features with t(1;3)(p36;q21), inv(3)(q21q26)..., although the genes involved on chromosome 3 are different.

References De Braekeleer M, Vekemans M. A t(3;5) in blastic phase of a Philadelphia chromosome-negative chronic myeloid leukemia. Cancer Genet Cytogenet 1989 Feb; 37(2):163-8. (Review).

Grigg AP, Gascoyne RD, Phillips GL, Horsman DE. Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3. Br J Haematol 1993; 83:158-65.

Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB, Raimondi SC, Cohen KJ, Carroll AJ, Morris SW. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 1996; 12:265-275.


Huret JL. t(3;5)(q25;q34). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):18.





t(12;21)(p12;q22) Jean-Loup Huret, Alain Bernheim

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH); Laboratoire de Cytogénétique, UMR 1599 CNRS, Institut Gustave Roussy, 94805 Villejuif, France (AB)



Clinics and pathology Disease B cell ALL

Phenotype / cell stem origin L1 and L2, CD10+.

Epidemiology 15 to 35% of paediatric B-lineage ALL: so far the most frequent translocation in this group; rare or absent in adults and in infants; age: children; no case > 20 yrs so far; male and female equally represented.

Clinics Standard ALL.

Prognosis CR in all cases; prognosis seems good.

Cytogenetics Cytogenetics, morphological t(12;21) often remained undetected.

Cytogenetics, molecular Easily detected by chromosomes 12 and 21 painting or specific probes.

Additional anomalies Frequent del(12)(p12) on the other chromosome; in rare cases duplication of der(21)t(12;21); looks like a +21.

Variants t(6;12;21), t(3;12;21)

Genes involved and Proteins ETV6 Location: 12p13

DNA / RNA 9 exons; alternate splicing.

Protein Contains a HLH domain and a ETS-DNA binding domain; wide expression; nuclear localisation; ETS-related transcription factor.

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.

Results of the chromosomal anomaly Hybrid gene Description TEL-AML1 chimaeric gene; 5' centromere to 3' telomere orientation.

Transcript The fusion transcript on chromosome 21 TEL-AML1 is the crucial one; the AML1-TEL transcript is absent in some cases; the other TEL allele is often deleted.

t(12;21)(p12;q22) Huret JL, Bernheim A


Detection protocol RT-PCR of the fusion transcript.

Fusion protein Description Helix loop helix of TEL fused to the nearly entire AML1 protein, comprising the Runt domain and the transactivation domain.

References Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994 Apr 22; 77(2):307-16.

Romana SP, Poirel H, Leconiat M, Flexor MA, Mauchauffé M, Jonveaux P, Macintyre EA, Berger R, Bernard OA. High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood 1995 Dec 1; 86(11):4263-9.

Raynaud S, Cave H, Baens M, Bastard C, Cacheux V, Grosgeorge J, Guidal-Giroux C, Guo C, Vilmer E, Marynen P, Grandchamp B. The 12; 21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood 1996 Apr 1; 87(7):2891-9.


Huret JL, Bernheim A. t(12;21)(p12;q22). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):19-20.





+14 or trisomy 14 (solely) Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/tri_14.html DOI: 10.4267/2042/32032 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease Myeloid disorders: MDS in more than half cases, ANLL in 1/4 of cases, chronic myeloproliferative syndrome (atypical CML); exceptionally: lymphoproliferations; therefore, only trisomy 14 solely in myeloid malignancies is herein described.

Phenotype / cell stem origin MDS: RA, RAEB±T mainly; ANLL: M1, M2, M4; atypical CML: with dysplastic features.

Epidemiology Median age 60-65 yrs (range: 4-89 yrs); sex ratio: 4M/3F.

Clinics No history of carcinogen exposure of note; blood data: platelets count: 130 X 109/l; monocytosis in half cases.

Cytology All FAB subtypes of MDS can be found; atypical CML cases present with dysplastic features; non-lobulated megakaryocytes are often found.

Prognosis Survival < 2 yrs in most cases; +14 do not seem to bear a distinct prognosis.

Cytogenetics Cytogenetics, morphological Most often (90% of cases) in mosaic with normal cells.

Cytogenetics, molecular Chromosome painting (although +14 detection attempts are, so far, not relevant).

Additional anomalies None, at least in the sub-clone with '+14 solely', by that very fact; most often none in karyotype follow-up.

Variants May be found as i(14q).

Genes involved and Proteins Note: genes involved are unknown.

References Brizard A, Guilhot F, Babin P, Burucoa C, Tanzer J, Huret JL. Four additional cases of trisomy 14 as the sole anomaly in various haematological malignancies. Leuk Res 1992; 16(5):537-40. (Review).

Toze CL, Barnett MJ, Naiman SC, Horsman DE. Trisomy 14 is a non-random karyotypic abnormality associated with myeloi malignancies. Br J Haematol 1997 Jul;98(1):177-85.


Huret JL. +14 or trisomy 14 (solely). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):21.





t(3;12)(q26;p13) François Desangles

Laboratoire de Biologie, Hôpital du Val de Grâce, 75230 Paris, France



Identity

t(3;12)(q26;p13) G-banding - Courtesy Jean-Luc Lai and Alain Vanderhaegen.

Clinics and pathology Disease Myeloid lineage: MDS in transformation, ANLL, BC-CML. Phenotype / cell stem origin Multilineage involvement; RAEB → M2, M7 and others ANLL subtypes. Epidemiology Only 8 cases described so far; sex ratio: 3M/1F; age: 3-87 yrs (med: 40 yrs). Cytology Megakaryocytes dysplasia Prognosis Very poor; survival often below 1 yr.

Cytogenetics Cytogenetics, molecular Heterogenous breakpoints. Probes

- EVI1: ly2 and l3 E Parganas, St Jude Children's Reseach Hospital, Memphis, TN;

- MDS1: P856 G Nucifora, Univ. of Chicago, IL; - TEL: YAC 958b8 CEPHII Mega-YAC library

Paris, France;

- TEL: cDNA c50F4, c163E7, c148B6 Lawrence Livermore National Laboratories, Livermore, CA.

Additional anomalies del(7q) or -7.

Genes involved and Proteins MDS1 EVI1 Location: 3q26

ETV6 Location: 12p13

DNA / RNA 9 exons; alternate splicing. Protein Contains a Helix-Loop-Helix and ETS DNA binding domains; wide expression; nuclear localisation; ETS-related transcription factor.

References Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994 Apr 22; 77(2):307-16.

Secker-Walker LM, Mehta A, Bain B. Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study. Br J Haematol 1995 Oct; 91(2):490-501.

Raynaud SD, Baens M, Grosgeorge J, Rodgers K, Reid CD, Dainton M, Dyer M, Fuzibet JG, Gratecos N, Taillan B, Ayraud N, Marynen P. Fluorescence in situ hybridization analysis of t(3; 12)(q26; p13): a recurring chromosomal abnormality involving the TEL gene (ETV6) in myelodysplastic syndromes. Blood 1996 Jul 15; 88(2):682-9.


Desangles F. t(3;12)(q26;p13). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):22.





t(8;21)(q22;q22) Jean-Loup Huret




Identity

t(8;21)(q22;q22) G-banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (top) and Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at the Waisman Center (middle and below); R-banding (right) - above: Editor; 2nd row: - Courtesy Christiane Charrin; 3rd and 4th row: - Courtesy Roland Berger.

Clinics and pathology Disease ANLL

Phenotype / cell stem origin M2 mostly, rarely: M1 or M4.

Epidemiology Annual incidence: 1/106; 10% of ANLL, 40% of M2

t(8;21)(q22;q22) Huret JL


ANLL; the most frequent anomaly in chilhood ANLL; Seen in children and adults: mean age 30 yrs, rare in elderly patients; male excess (4M/3F) is much less than sometimes claimed.

Clinics Chloromas

Cytology Numerous and thin Auer rods; eosinophilia of the bone marrow; CD19 (early B) and CD56 (natural killer) may be expressed: the cell involved may be an early progenitor.

Prognosis CR in most cases (90%); but relapse is frequent, and median survival -1.5 yrs (adults) to 2 yrs (children)- in the range with other ANLL in some series, relatively long median survival, especially in the adults for others; no adverse effect of additional chromosome anomalies.

Cytogenetics Cytogenetics, molecular Cases with cryptic molecular translocation have been detected (similar to Ph negative CML with positive BCR-ABL) → FISH use may be relevant.

Additional anomalies Sole anomaly in only 20%; additional anomalies: numerical in 2/3, structural in 1/3; loss of Y or X chromosome in half cases (1 X must be present), del(7q) or -7, +8, del(9q): 10% each.

Variants Complex t(8;21;Var) involving a (variable) third chromosome have been described in 3%; part from chromosome 21 goes on der(8), part of the 8 on der (Var), and part of Var on der(21); therefore, the crucial event lies on der(8).

Translocation t(8;21) is found in 5-12% of AML. Among the non-random chromosomal aberrations observed in AML, t(8;21)(q22;q22) is one of the best known and usually correlates with AML M2, with well defined and specific morphological features. The common morphological features include the presence of large blast cells with abundant basophilic cytoplasm, often containing numerous azurophilic granulations; few blasts in some cases show very large granules (pseudo-Chediak-Higashi granules), suggesting abnormal fusion. Auer rods are frequently found. In addition to the large blast cells, there are also some smaller blasts, predominantly found in the peripheral blood. Promyelocytes, myelocytes and mature granulocytes with variable dysplasia are seen in the bone marrow. These cells may show abnormal nuclear segmentation and/or cytoplasmic staining defects including homogeneous pink colored cytoplasm - Courtesy Georges Flandrin, CD-ROM AML/MDS G. Flandrin/ICG. TRIBVN.

t(8;21)(q22;q22) Huret JL


t(8;21)(q22;q22): cohybridization experiments using dJ155L8 (ETO) and dJ1107L6 (AML1); note the splitting of AML1 and colocalization on der(8) with ETO - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome: contact M Rocchi.

Genes involved and Proteins ETO Location: 8q22


Protein 3 proline rich domains, 2 Zn fingers, and in C-term, a PEST region; tissue restricted expression; nuclear localisation; putative transcription factor.

AML1 Location: 21q22


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.

Results of the chromosomal anomaly Hybrid gene Description 5' AML1 - 3' ETO; breakpoints: at the very 5' end of ETO, between exons 5 and 6 in AML1.

Detection protocol RT-PCR in cases: 1- of typical cell morphology, but apparently without the t(8;21); 2- for minimal residual disease detection.

Fusion protein Description The N-term runt domain from AML1 is fused to the 577 C-term residues from ETO; reciprocal product not detected; probable DNA binding role; the fusion protein retains the ability to recognize the AML1 concensus binding site → negative dominant competitor with the normal AML1) and to dimerize with the CBFb subunit.

Oncogenesis Probable altered transcriptional regulation of normal AML1 target genes.

References Berger R, Bernheim A, Daniel MT, Valensi F, Sigaux F, Flandrin G. Cytologic characterization and significance of normal karyotypes in t(8;21) acute myeloblastic leukemia. Blood 1982 Jan; 59(1):171-8.

[No authors listed]. Acute myelogenous leukemia with an 8;21 translocation. A report on 148 cases from the Groupe Français de Cytogénétique Hématologique. Cancer Genet Cytogenet 1990 Feb; 44(2):169-79.

Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai M, Kaneko Y. The 8;21 chromosome translocation in acute myeloid leukemia is always detectable by molecular analysis using AML1. Blood 1993 Mar 15; 81(6):1573-9.

Ohki M. Molecular basis of the t(8;21) translocation in acute myeloidleukemia. Semin Cancer Biol 1993 Dec; 4(6):369-75. (Review).

Nucifora G, Rowley JD. AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 1995 Jul 1; 86(1):1-14. (Review).


Huret JL. t(8;21)(q22;q22). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):23-25.





t(9;22)(q34;q11) in ALL Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0922ALL.html DOI: 10.4267/2042/32035

This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Note: Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this translocation may be seen in the following diseases: CML, ANLL, and ALL, and will therefore be described in the 3 different situations: t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL. t(9;22)(q34;q11) in ALL is herein described.

t(9;22)(q34;q11) G-banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (3 top) and Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services (2 bottom); R-banding (right) top: Editor; 2 others Courtesy Jean-Luc Lai and Alain Vanderhaegen); diagram and breakpoints (Editor).

t(9;22)(q34;q11) in ALL Huret JL


Clinics and Pathology Disease ALL

Phenotype / cell stem origin L1 or L2 ALL; most often with B-cell phenotype, rare T-cell cases; heterogeneity of lineage involvement: may either be a multipotent stem cell, or a lymphoid-committed progenitor.

Epidemiology 20% of adult ALL, 2-5% of children ALL.

Clinics Frequent CNS involvement, even at diagnosis; blood data: high WBC (50-150 X 109/l).

Cytology CD10+ in most cases, sometimes CD19+ CD10-.

Treatment BMT is indicated.

Prognosis Is very poor, especially in lymphoid-committed progenitor cases; the breakpoint in M-bcr or in m-bcr (see below) does not seem to have impact on prognosis.

Cytogenetics Cytogenetics, morphological The chromosomal anomaly disappears during remission, in contrast with BC-CML cases when treated with conventional therapies.

Cytogenetics, molecular Is useful to uncover a 'masked Philadelphia' chromosome, where chromosomes 9 and 22 all appear to be normal, but where cryptic insertion of 3' ABL within a chromosome 22 can be demonstrated.

Additional anomalies Found in 50 to 80% of cases: +der(22), -7, del(7q) most often, +8, but not an i(17q), in contrast with CML and ANLL cases; complex karyotypes, often hyperploid, are frequent.

Variants t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, may be found, as in CML.

Genes involved and Proteins ABL Location: 9q34

DNA / RNA Alternate splicing (1a and 1b) in 5'.

Protein Giving rise to 2 proteins of 145 kDa; contains SH (SRC homology) domains; N-term SH3 and SH2 - SH1 (tyrosine kinase) - DNA binding motif - actin binding domain C-term; widely expressed; localisation is mainly nuclear; inhibits cell growth.

BCR Location: 22q11

DNA / RNA Various splicings.

Protein Main form: 160 kDa; N-term Serine-Threonine kinase domain, SH2 binding, and C-term domain which functions as a GTPase activating protein for p21rac; widely expressed; cytoplasmic localisation; protein kinase; probable role in signal transduction.

Results of the chromosomal anomaly Hybrid gene Description The crucial event lies on der(22), id est 5' BCR/3' ABL hybrid gene is pathogenic, while ABL/BCR may or may not be expressed; - breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2; - breakpoint in BCR is either: 1- in the same region as in CML, called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4; transcript is 8.5 kb long; this results in a 210 kDa chimeric protein (P210), with the first 902 or 927 amino acids from BCR; 2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), → 7 kb mRNA, resulting in a 190 kDa protein (P190), with the 427 N-terminal amino acids from BCR.

Transcript 7 or 8.5 kb.

t(9;22)(q34;q11) in ALL Huret JL


Fusion protein Description 190 or 210 kDa (see diagram); BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear; this may have a carcinogenetic role. The hybrid protein has an increased protein kinase activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3 domain, which prevents SH1 activation; with BCR/ABL, the first (N-terminal) exon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot be bound to 3BP1; thereof, SH1 is activated.

Oncogenesis 1-Proliferation is induced: there is activation by BCR/ABL of Ras signal transduction pathway via it's linkage to son-of-sevenless (SOS), a Ras activator; PI3-K (phosphatidyl inositol 3' kinase) pathway is also activated; MYC as well; 2-BCR/ABL inhibits apoptosis; 3-BCR/ABL provokes cell adhesive abnormalities: impaired adherence to bone marrow stroma cells, which allows unregulated proliferation of leukaemic progenitors.

To be noted Blast crisis is sometimes at the first onset of CML, and those cases may be undistinguishable from true ALL with t(9;22) and P210 BCR/ABL hybrid.

References Heisterkamp N, Groffen J. Molecular insights into the Philadelphia translocation. Hematol Pathol 1991; 5(1):1-10. (Review).

Kurzrock R, Talpaz M. The molecular pathology of chronic myelogenous leukemia. Br J Haematol 1991 Oct; 79 Suppl 1:34-7. (Review).

Secker-Walker LM, Craig JM. Prognostic implications of breakpoint and lineage heterogeneity in Philadelphia-positive acute lymphoblastic leukemia: a review. Leukemia 1993 Feb; 7(2):147-51. (Review).

Gotoh A, Broxmeyer HE. The function of BCR/ABL and related proto-oncogenes. Curr Opin Hematol 1997 Jan; 4(1):3-11. (Review).


Huret JL. t(9;22)(q34;q11) in ALL. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):26-28.





t(9;22)(q34;q11) in ANLL Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Anomalies/t0922ANL.html DOI: 10.4267/2042/32036 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Note: Although the same hybrid genes issued from ABL and BCR are the hallmark of the t(9;22) translocation, this translocation may be seen in the following diseases: CML, ANLL, and ALL, and will therefore be described in the 3 different situations: t(9;22)(q34;q11) in CML, t(9;22)(q34;q11) in ALL, t(9;22)(q34;q11) in ANLL. t(9;22)(q34;q11) in ANLL is herein described.

t(9;22)(q34;q11) G-banding (left) - Courtesy Jean-Luc Lai and Alain Vanderhaegen (3 top) and Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, UW Cytogenetic Services (2 bottom); R-banding (right) top: Editor; 2 others Courtesy Jean-Luc Lai and Alain Vanderhaegen); diagram and breakpoints (Editor).

t(9;22)(q34;q11) in ANLL Huret JL


Clinics and pathology Disease ANLL

Phenotype / cell stem origin Mostly M1 or M2 ANLL.

Epidemiology 3% of ANLL; 1% in childhood ANLL.

Prognosis Is very poor.

Cytogenetics Cytogenetics, morphological The chromosomal anomaly disappears during remission, in contrast with BC-CML cases when treated with conventional therapies.

Genes involved and Proteins ABL Location: 9q34

DNA / RNA Alternate splicing (1a and 1b) in 5'.

Protein Giving rise to 2 proteins of 145 kDa; contains SH (SRC homology) domains; N-term SH3 and SH2 - SH1 (tyrosine kinase) - DNA binding motif - actin binding domain C-term; widely expressed; localisation is mainly nuclear; inhibits cell growth.

BCR Location: 22q11

DNA / RNA Various splicings.

Protein Main form: 160 kDa; N-term Serine-Treonine kinase domain, SH2 binding, and C-term domain which functions as a GTPase activating protein for p21rac; widely expressed; cytoplasmic localisation; Protein kinase; probable role in signal transduction.

Results of the chromosomal anomaly Hybrid gene Description The crucial event lies on der(22), id est 5' BCR/3' ABL hybrid gene is pathogenic, while ABL/BCR may or may not be expressed; Breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5' of 1b, or 3' of 1a, but always 5' of exon 2; Breakpoint in BCR is either (as in ALL cases): 1- in the same region as in CML, called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4; transcript is 8.5 kb long; this results in a 210 kDa chimeric protein (P210), with the first 902 or 927 amino acids from BCR; 2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), → 7 kb mRNA, resulting in a 190 kDa protein (P190), with the 427 N-terminal amino acids from BCR.

Transcript 7 or 8.5 kb

t(9;22)(q34;q11) in ANLL Huret JL


Fusion protein Description 190 or 210 kDa (see diagram); BCR/ABL has a cytoplasmic localization, in contrast with ABL, mostly nuclear; this may have a carcinogenetic role. The hybrid protein has an increased protein kinase activity compared to ABL: 3BP1 (binding protein) binds normal ABL on SH3 domain, which prevents SH1 activation; with BCR/ABL, the first (N-terminal) exon of BCR binds to SH2, hidding SH3 which, as a consequence, cannot be bound to 3BP1; thereof, SH1 is activated.

Oncogenesis 1-Proliferation is induced: there is activation by BCR/ABL of Ras signal transduction pathway via it's linkage to son-of-sevenless (SOS), a Ras activator; PI3-K (phosphatidyl inositol 3' kinase) pathway is also activated; MYC as well; 2-BCR/ABL inhibits apoptosis; 3-BCR/ABL provokes cell adhesive abnormalities: impaired adherence to bone marrow stroma cells,

which allows unregulated proliferation of leukaemic progenitors.

To be noted Blast crisis is sometimes at the first onset of CML, and those cases may be undistinguishable from true ANLL with t(9;22) and P210 BCR/ABL hybrid.

References Heisterkamp N, Groffen J. Molecular insights into the Philadelphia translocation. Hematol Pathol 1991; 5(1):1-10. (Review).

Kurzrock R, Talpaz M. The molecular pathology of chronic myelogenous leukemia. Br J Haematol 1991 Oct; 79 Suppl 1:34-7. (Review).

Gotoh A, Broxmeyer HE. The function of BCR/ABL and related proto-oncogenes. Curr Opin Hematol 1997 Jan; 4(1):3-11. (Review).


Huret JL. t(9;22)(q34;q11) in ANLL. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):29-31.

Solid Tumour Section Mini Review




Bladder cancer Jean-Loup Huret, Claude Léonard

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Cytogénétique, Laboratoire d'Anatomo Pathologie, CHU Bicêtre, 78 r Leclerc, F94270 Le Kremlin-Bicêtre, France (CL)


Online version is available at: http://AtlasGeneticsOncology.org/Tumours/blad5001.html DOI: 10.4267/2042/32037 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Classification Existence of different histologic types. Very rare types are: - Squamous cell carcinoma (5%); - Adenocarcinoma (2%); - The most frequent, representing 90-95 % of cases is transitional cell carcinoma of the bladder, herein described.

Clinics and pathology Disease Cancer of the urothelium

Epidemiology Annual incidence: 250/106, 2% of cancers, the fourth cancer in males, the seventh in females, 3M/1F; occurs mainly in the 6th-8th decades of life; risk factors: cigarette smoking and occupational exposure (aniline, benzidine, naphtylamine); 20 to 30 yrs latency after exposure.

Clinics Hematuria, irritation.

Pathology Grading and staging: tumours are:

- graded by the degree of cellular atypia (G0→ G3), and; - staged: pTIS carcinoma in situ (but high grade), and pTa papillary carcinoma, both mucosally confined; pT1 lamina propria invasive; pT2 infiltrates the superficial muscle, and pT3a, the deep muscle; pT3b invasion into perivesical fat; pT4 extends into neighbouring structures and organs.

Treatment Resection (more or less extensive: electrofulguration → cystectomy); chemo and/or radiotherapy, BCG-therapy.

Evolution Recurrence is highly frequent.

Prognosis According to the stage and the grade; pTa is of good prognosis (> 90% are cured); prognosis is uncertain in pT1 and G2 tumours, where cytogenetic findings may be relevant prognostic indicators. 20% survival at 1 yr (stable at 3 yrs) is found in T4 cases; however, identification of individual patient's prognosis is often difficult, although of major concern for treatment decision and for follow up.

Bladder cancer Huret JL, Léonard C


Cytogenetics Cytogenetics, morphological Highly complex and diverse, but non-random. -9: monosomy 9 is frequent (about 50% of cases, and can be the only anomaly; found also in early stages; not associated with tumour progression; loss of heterozygocity (LOH): critical deletion segments are in 9p21 and somewhere in 9q; gensolin could be implicated. -11 or del(11p): are frequent; associated with high stages and tumour progression. del(17p) and LOH at 17p: also frequent; mainly found in pT2 to pT4; also found in a subset of pTIS, which might be a relevant indicator for these tumours with variable but often poor prognostic; the deletion involve P53. del(13q) and Rb loss are corrrelated with the stage. +7: often found, but the same occurs in a number of cancers of various origin; may have no pertinence, inasmuch as +7 has also been found in normal (i.e. non tumoural) cells! Mar, aneuploidy, polyploidy, complex karyotypes: are bad prognostic features. del(3p), del(5q) and i(5p), del(6q), del(8p), del(14q) and del(18q) are also consistantly found; these LOH point to probable tumour suppression genes, which could be implicated in tumour progression.

Cytogenetics, molecular Interphase cytogenetics using whole chromosome

paints/comparative genomic hybridization (CGH) should prove useful tools; flow cytometry for DNA index measurement has often been used, but appears to be a ‘blind’ method.

Genes involved and Proteins Note: as the process is multistep, genes involved in transitional cell carcinoma of the bladder should be numerous; most are still unknown; some are quoted above.

References Sandberg AA, Berger CS. Review of chromosome studies in urological tumors. II. Cytogenetics and molecular genetics of bladder cancer. J Urol 1994; 151:545-560.

Sauter G, Moch H, Wagner U, Novotna H, Gasser TC, Mattarelli G, Mihatsch MJ, Waldman FM. Y chromosome loss detected by FISH in bladder cancer. Cancer Genet Cytogenet 1995; 82:163-169.

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

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


Huret JL, Léonard C. Bladder cancer. Atlas Genet Cytogenet Oncol Haematol.1997;1(1):32-33.

Cancer Prone Disease Section Mini Review




Naevoid basal cell carcinoma syndrome (NBCS) Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Kprones/NBC10005.html DOI: 10.4267/2042/32038 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: Gorlin syndrome; Gorlin-Goltz syndrome; Multiple basal cell nevi, odontogenic keratocysts, skeletal anomalies; Fifth phacomatosis; Hydrocephalus, costovertebral dysplasia, sprengel anomaly. Inheritance: autosomal dominant with complete penetrance, but variable expressivity; 40% are de novo mutations; frequency is about 2/105 newborns.

Clinics NBCS is a hamartoneoplastic syndrome; it is also a chromosome instability syndrome; hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia.

Phenotype and clinics Multiple basal cell carcinomas, appearing as early as 15 yrs; Jaw keratocysts; Dyskeratotic palmar/plantar pits; Skeletal malformations (of ribs, spina bifida occulta...); Soft tissue calcifications (falx cerebri, ovarian fibroma, diaphragma sellae...); Facial dysmorphia.

Neoplastic risk Mainly multiple basal cell carcinomas; Other proliferations (see below) in 60% of patients; Other malignancies: medulloblastoma, ovarian fibrosarcoma; Benign proliferations: ovarian fibroma, meningioma, rhabdomyoma, cardiac fibroma.

Treatment Tumour exereses.

Evolution Extensive number of basal cell carcinomas.

Prognosis According to the tumours (basal cell carcinomas are not life threatening, but may be devastating).

Cytogenetics Inborn condition Spontaneous and induced chromosome instability. Delay in the cell cycle. NBCS is therefore a chromosome instability syndrome.

Cancer cytogenetics Poorly documented.

Genes involved and Proteins Complementation groups None so far.

PTCH Location: in 9q22.3 (between FACC and XPAC!!)

Protein Description: glycoprotein with transmembrane domains, extra cellular loops and intracellular domains. Localisation: transmembrane protein. Function: part of a signalling pathway; probable cell to cell adhesion role; may have a repressive activity on cell proliferation; as NBCS syndrome is a chromosome instability syndrome, this protein may have a role in DNA maintenance, repair and/or replication.

Mutations Germinal: most germ-line mutations in NBCS patients lead to protein truncation, which suggests that developmental anomalies seen in NBCS may be due to haplo-insufficiency; no obvious genotype-phenotype correlations.

Naevoid basal cell carcinoma syndrome (NBCS) Huret JL


Somatic: mutation and allele loss events in basal cell carcinoma, in NBCS and in sporadic basal cell carcinoma are, so far, in accordance with the two-hit model for neoplasia, as is found in retinoblastoma.

References Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and neck. Oxford Monogr Med Genet 1990; 19:372-380.

Tabata T, Eaton SE, Kornberg TB. The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Gene Dev 1992; 6:2635-2645.

Evans DGR, Ladusans EJ, Rimmer S, Brunell LD, Thakker N, Farndon PA. Complications of the naevoid basal cell carcinoma syndrome : results of a population based study. J Med Genet 1993; 30:460-464.

Basler K, Struhl G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein. Nature 1994; 368:208-214.

Capdevila J, Estrada MP, Sánchez-Herrero E, Guerrero I. The drosophila segment polarity gene patched interacts with decapenta plegic in wing development. EMBO J 1994; 13:71-82.

Gailani MR, Stǻhle-Bäckdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Undén AB, Dean M,Brash DE, Bale AE, Toftgǻrd R. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nature Genetics 1996; 14:78-81.

Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, WainwrightB, Dean M. A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J Biol Chem 1996; 271:12125-12128.

Hahn H, Wicking C, Zaphiropoulos PG, Gailani MA, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffel DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85:841-851.

Johnson R. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996; 272:1668-1671.

Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S, Suthers G, Haites N, Edwards M, Wainwright B, Chenevix-Trench G. Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature tremination of the patched protein, and no genotype-phenotype correlations are evident. Am Hum Genet 1997; 60:21-26.

Shafei-Benaissa E, Savage JRK, Babin P, Larrègue M, Papworth D, Tanzer J, Bonnetblanc JM, Huret JL. The naevoid basal-cell carcinoma syndrome (Gorlin syndrome) is a chromosomal instability syndrome. Mutat Res 1998 Feb 2; 397(2):287-92.


Huret JL. Naevoid basal cell carcinoma syndrome (NBCS). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):34-35.





Neurofibromatosis type 1 (NF1) Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Kprones/NF1ID10006.html DOI: 10.4267/2042/32039 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: Von Recklinghausen neurofibromatosis; Peripheral neurofibromatosis Inheritance: autosomal dominant with almost complete penetrance; frequency is 30/105 newborns (and 1 of 200 mentally handicapped persons): one of the most frequent genetically inheritable disease; neomutation in 50%, mostly from the paternal allele; highly variable expressivity, from very mild to very severe; expressivity is also age-related.

Clinics NF1 is a hamartoneoplastic syndrome; hamartomas are localized tissue proliferations with faulty differentiation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia. The embryonic origin of dysgenetic tissues involved in NF1 is ectoblastic.

Phenotype and clinics Diagnosis is made on the ground of at least 2 of the following: Café-au-lait spots (6 or more, over 0.5 cm of diameter (in pre-puberty)); 2 or more neurofibromas or 1 plexiform neurofibromas (mainly cutaneous); 2 or more Lisch nodules (melanocytic hamartomas of the iris); Freckling in the axillary/inguinal region (Crowe's sign); Glioma of the optic nerve; Distinctive bone anomalies (scoliosis, pseudoarthroses, bony defects (orbital wall)...); Positive family history. Other features: Macrocephaly; Epilepsy;

Mental retardation in 10 %; learning diabilities in half patients; Sexual precocity and other endocrine anomalies; Hypertension (renal artery stenosis).

Neoplastic risk 5% of NF1 patients experience a malignant neoplasm Neurofibromas, especially the plexiform variety; polyclonal (benign) proliferation; may be present at birth or appear later, may be a few or thousands, small or enormous, occur in the skin and in various tissus and organs; neurofibromas localized to the spine are extremely difficult to manage. Neurofibrosarcomatous transformation (malignant) of these in 5-10 %. Schwannomas (optic nerve, see above), meningiomas, astrocytomas, ependymomas. Childhood MDS (myelodysplasia) and ANLL, often with monosomy 7 (monosomy 7 syndrome, 'juvenile myelomonocytic leukaemia'): risk, increased by X 200 to 500, is still low, as childhood MDS is rare; M > F; most often before the age of 5 yrs; no increased risk of leukaemia in the adult. Pheochromocytomas. Various other neoplasias, of which are rhabdomyosarcomas.

Treatment Early diagnosis, lifetime monitoring and surgery are essential.

Cytogenetics Inborn condition No special feature.

Cancer cytogenetics According to the cancer type in most cases. Myelodysplasia and ANLL: monosomy 7.

Neurofibromatosis type 1 (NF1) Huret JL


Genes involved and Proteins NF1 Location: 17q11.2

Protein Description: the protein has been called neurofibromin; GTPase activating protein; tumour suppressor.

Mutations Germinal: nucleotide substitutions, small deletions or insertions on one allele. Somatic: the second allele remains normal in the benign tumours and is often lost in the malignant tumours.

To be noted Beside neurofibromatoses 1 and 2 (NF2), other types of neurofibromatoses are numbered and named 3 to 9, some of them being known to involve other loci.

References NIH Consensus Development Conference. Arch Neurol 1988; 45: 575.

Huson SM, Compston DA, Clark P, Harper PS. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet 1989 Nov;26(11):704-711.

Kaneko Y, Maseki N, Sakurai M, Shibuya A, Shinohara T, Fujimoto T, Kanno H, Nishikawa A. Chromosome pattern in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis. Leukemia 1989 Jan; 3(1):36-41.

Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and neck. Oxford Monogr Med Genet 1990;19:392-399.

Henry I. médecine/sciences 1995; 11: 93.

Metheny LJ, Cappione AJ, Skuse GR. Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I. J Neuropathol Exp Neurol 1995 Nov;54(6):753-760.

Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997 Jul 2; 278(1):51-57.


Huret JL. Neurofibromatosis type 1 (NF1). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):36-37.





Neurofibromatosis type 2 (NF2) Jean-Loup Huret



Online version is available at: http://AtlasGeneticsOncology.org/Kprones/NF2Kpr10007.html DOI: 10.4267/2042/32040 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 1997 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: Central neurofibromatosis; Bilateral acoustic neurofibromatosis; Bilateral acoustic neurinoma; Bilateral acoustic schwannomas Inheritance: autosomal dominant with almost complete penetrance; frequency is 3/105 newborns; neomutation represent 50% of cases; variable expressivity from mild disease through life (Gardner type) to severe condition at young age (Wishart type: with more than 3 tumours).

Clinics NF2 is an hamartoneoplastic syndrome; hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia.

Phenotype and clinics Bilateral vestibular (8th cranial pair) schwannomas; other central or peripheral nerve schwannomas; meningiomas; ependymomas. Hearing loss (average age 20 yrs), tinnitus, imbalance, headache, cataract in 50%, facial paralysis. Café-au-lait spots and cutaneous and peripheral neurofibromas may be present, but far less extensively than in neurofibromatosis type 1.

Neoplastic risk NF2 cases represent about 5 % of schwannomas and meningiomas (i.e. risk increased by 2000), appearing at the age of 20, while they are found in the general population at the age of 50 and over.

Prognosis These tumours are usually benign, but their location within the central nervous system gives them a grave prognosis; patients with the Wishart severe form usually do not survive past 50 yrs.

Cytogenetics Inborn condition Normal.

Cancer cytogenetics Chromosome 22 loss is very frequent both in sporadic and in NF2 schwannomas and meningiomas.

Genes involved and Proteins SCH Location: 22q12.1-12.2 junction, (incidentally not far from EWS (Ewing tumour))

DNA/RNA Description: 16 exons; 120 kb. Transcription: alternate splicing after exon 15.

Protein Protein has been called schwannomin or SCH. Description: 590 or 595 amino acids; 66 kDa; domains: NH2 -- membrane binding -- a helix binding to actin of the cytoskeleton -- COOH. Expression: in lung, kidney, ovary, breast, placenta, neuroblasts. Function: membrane-cytoskeleton anchor (as APC also appears to be); has characteristics of a tumour suppressor, as has been found in sporadic as well as NF2 induced schwannomas and meningiomas (accordingly to the Rb model). Homology ezrin, radixin, moesin, members of the erythrocytes band 4.1 family, especially so in the N-term.

Mutations Germinal: (inborn condition of NF2 patients): protein truncations due to various frameshift deletions or insertions or nonsense mutations; splice-site or missense mutations are also found; phenotype-genotype correlations are observed (i.e. that severe

Neurofibromatosis type 2 (NF2) Huret JL


phenotypes are found in cases with protein truncations rather than those with amino acid substitution).

Somatic: tumourigenesis in NF2 patients.

References Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988 May; 45(5):575-8.

Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and neck. Oxford Monogr Med Genet 1990;19:392-399.

Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 1993 Jun 10; 363(6429):515-21.

Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet 1994 Oct 1; 52(4):450-61.

Marineau C, Mérel P, Rouleau GA, Thomas G. Le gène de la neurofibromatose de type 2. Médecine/sciences 1995; 11:35-42. (Review). French.

Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF. Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet 1996 Sep; 59(3):529-39.

Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn JM, Hall BD, Propping P, Rouleau GA. Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Am J Hum Genet 1996 Aug; 59(2):331-42.


Huret JL. Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):38-39.



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