vol 4 2 2000 - Revues et Congrèsdocuments.irevues.inist.fr/.../handle/2042/39859/vol_4_2_2000.pdf · OPEN ACCESS JOURNAL AT INIST-CNRS The PDF version of the Atlas of Genetics and

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.



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).


© ATLAS - ISSN 1768-3262

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




Editor

Jean-Loup Huret (Poitiers, France)

Volume 4, Number 2, April - June 2000

Table of contents

Gene Section

AF15q14 (ALL1 fused gene from 15q14) 50 Jean-Loup Huret, Christiane Charrin

Lasp1 (LIM, actin binding and SH3 protein) 51 Marie-Christine Rio

MMP11 (matrix metalloproteinase 11 (stromelysin 3)) 52 Paul Basset, Marie-Christine Rio

STARD3 (START domain containing 3) 54 Marie-Christine Rio

ABI1 (Abl-Interactor 1) 55 Jean-Loup Huret

AF5q31 (ALL1 fused gene from chromosome 5q31) 57 Jean-Loup Huret

ARHGEF12 (Rho guanine nucleotide exchange factor (GEF) 12) 58 Jean-Loup Huret

CDX2 (caudal-related homeobox 2) 60 Nick CP Cross

MSF (MLL septin-like fusion) 62 Jean-Loup Huret

SEPT5 (septin 5) 63 Jean-Loup Huret

HMGIC (High mobility group protein isoform I-C) 64 Florence Pedeutour

MVP (major vault protein) 68 Franck Viguié

Leukaemia Section

t(11;15)(q23;q14) 70 Jean-Loup Huret, Christiane Charrin




t(5;17)(q35;q21) 72 Franck Viguié

ins(5;11)(q31;q13q23) 74 Jean-Loup Huret

t(10;11)(p11.2;q23) 75 Jean-Loup Huret

t(11;17)(q23;q25) 76 Jean-Loup Huret

t(12;13)(p12;q12-14) ETV6/CDX2 78 Nick CP Cross

t(7;12)(q36;p13) 80 Jean-Loup Huret

+12 or trisomy 12 81 Lucienne Michaux

Diffuse large cell lymphoma 83 Antonio Cuneo, Gian Luigi Castoldi

Lymphoplasmacytic lymphoma 85 Antonio Cuneo, Gian Luigi Castoldi

Small lymphocytic lymphoma 86 Antonio Cuneo, Gian Luigi Castoldi

Solid Tumour Section

Soft tissue tumors: Synovial sarcoma 88 Christine Pérot

Cancer Prone Disease Section

Rhabdoid predisposition syndrome 91 Nicolas Sévenet

Multiple endocrine neoplasia type 1 (MEN1) 92 Alain Calender

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




Gene Section Short Communication


50



AF15q14 (ALL1 fused gene from 15q14) Jean-Loup Huret, Christiane Charrin

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH), Service d'Hematologie, Hopital Edouard Herriot, Lyon, France (CC)

Published in Atlas Database: March 2000

Online updated version : http://AtlasGeneticsOncology.org/Genes/AF15q14ID318.html DOI: 10.4267/2042/37605

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 Location : 15q14

DNA/RNA Description Spans more than 35 kb; contains at least 10 exons; from centromere to telomere.

Transcription 5925 bp; open reading frame: 5499 bp.

Protein Description 1833 amino acids; 206 kDa; nuclear localization domain in the c-term.

Expression Ubiquitous in the foetus, nearly restricted to bone marrow, thymus, and testis in the adult.

Homology None so far.

Implicated in t(11;15)(q23;q14)/acute non lymphocytic leukemia (ANLL) --> MLL/AF15q14 Disease Only 1 case with the ascertainment of AF15q14 involvement.

References Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Deleage G, Magaud JP, Rimokh R. AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14). Oncogene. 2000 Sep 7;19(38):4446-50

This article should be referenced as such:

Huret JL, Charrin C. AF15q14 (ALL1 fused gene from 15q14). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):50.



51



Lasp1 (LIM, actin binding and SH3 protein) Marie-Christine Rio

I.G.B.M.C., BP 163, 1 rue Laurent Fries, 67404 Illkirch, France (MCR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/Lasp1ID203.html DOI: 10.4267/2042/37606


Identity Other names: MLN50

HGNC (Hugo): LASP1

Location: 17q12-21

Local order: From centromere to telomere are: TRAF4 (alias MLN62/CART1), Lasp1 (alias MLN50), c-erbB2, and MLN64.

DNA/RNA Transcription cDNA: 4 kb; coding sequence: 783 bp.

Protein Description 261 amino acids; 29 kDa; contains a LIM (Lin-11, Isl-1 and Mec-3) domain at its N-terminal part and a SH3 (Src homology 3) domain at its C-terminal part; it also possesses two tandemly repeated actin binding modules.

Implicated in Breast carcinomas Note 17q11-q21 amplification is found in about 25% of primary breast carcinomas.

Prognosis Poor clinical outcome; increase risk of relapse.

References Tomasetto C, Moog-Lutz C, Régnier CH, Schreiber V, Basset P, Rio MC. Lasp-1 (MLN 50) defines a new LIM protein subfamily characterized by the association of LIM and SH3 domains. FEBS Lett. 1995 Oct 16;373(3):245-9

Tomasetto C, Régnier C, Moog-Lutz C, Mattei MG, Chenard MP, Lidereau R, Basset P, Rio MC. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17. Genomics. 1995 Aug 10;28(3):367-76

Bièche I, Tomasetto C, Régnier CH, Moog-Lutz C, Rio MC, Lidereau R. Two distinct amplified regions at 17q11-q21 involved in human primary breast cancer. Cancer Res. 1996 Sep 1;56(17):3886-90

Schreiber V, Masson R, Linares JL, Mattei MG, Tomasetto C, Rio MC. Chromosomal assignment and expression pattern of the murine Lasp-1 gene. Gene. 1998 Jan 30;207(2):171-5

Schreiber V, Moog-Lutz C, Régnier CH, Chenard MP, Boeuf H, Vonesch JL, Tomasetto C, Rio MC. Lasp-1, a novel type of actin-binding protein accumulating in cell membrane extensions. Mol Med. 1998 Oct;4(10):675-87


Rio MC. Lasp1 (LIM, actin binding and SH3 protein). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):51.

Gene Section Mini Review


52



MMP11 (matrix metalloproteinase 11 (stromelysin 3)) Paul Basset, Marie-Christine Rio

Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM U184/ULP BP 163, Illkirch, CU de Strasbourg, France (PB, MCR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/ST3ID200.html DOI: 10.4267/2042/37608


Identity Other names: ST3 (stromelysin-3); MMP-11 (matrix metalloproteinase 11)

HGNC (Hugo): MMP11

Location: 22q11.2

DNA/RNA Description 8 exons and 7 introns spanning 11.5 kb; cDNA: 2247 bp, coding sequence 1464 bp.

Transcription Expression is induced by retinoic acid and TPA through a DR1-type responsive element and a C/EBP binding site, respectively, expression is induced by epithelial cells in a paracrin manner.

Protein Description 488 amino-acids; 51 kDa; functional domains: signal peptide, targeting the protein to the secretory pathway, prodomain containing a furin-type cleavage site responsible for the intracellular activation, catalytic domain containing a zinc binding site, hemopexin-like domain.

Expression Cells of mesenchymal origin, notably fibroblastic cells, macrophages, osteoclasts.

Function Extracellular zinc-dependent proteinase expressed during tissu remodelling processes (development,

wound healing) and whose specific substrate is unknown.

Homology Member of the matrix metalloproteinases (MMP) subfamily of matrixins.

Implicated in various cancer: Disease Expression of ST3 in 80 to 100% invasive carcinomas of the breast, colon, head and neck, lung, ovary, pancreas, prostate, skin (basal cell carcinoma), uterus (cervix carcinoma and endometrial carcinoma) and in some non-invasive carcinomas that have a high risk of evolving towards invasion; also expression in: fibroblastic stromal cells in the close vicinity of cancerous epithelial cells.

Prognosis Prognostic factor of invasion and aggressiveness of the tumors.

References Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM, Podhajcer OL, Chenard MP, Rio MC, Chambon P. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature. 1990 Dec 20-27;348(6303):699-704

Rouyer N, Wolf C, Chenard MP, Rio MC, Chambon P, Bellocq JP, Basset P. Stromelysin-3 gene expression in human cancer: an overview. Invasion Metastasis. 1994-1995;14(1-6):269-75

Anglard P, Melot T, Guérin E, Thomas G, Basset P. Structure and promoter characterization of the human stromelysin-3 gene. J Biol Chem. 1995 Sep 1;270(35):20337-44

MMP11 (matrix metalloproteinase 11 (stromelysin 3)) Basset P, Rio MC


53

Chenard MP, O'Siorain L, Shering S, Rouyer N, Lutz Y, Wolf C, Basset P, Bellocq JP, Duffy MJ. High levels of stromelysin-3 correlate with poor prognosis in patients with breast carcinoma. Int J Cancer. 1996 Dec 20;69(6):448-51

Ahmad A, Hanby A, Dublin E, Poulsom R, Smith P, Barnes D, Rubens R, Anglard P, Hart I. Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression. Am J Pathol. 1998 Mar;152(3):721-8

Mari BP, Anderson IC, Mari SE, Ning Y, Lutz Y, Kobzik L, Shipp MA. Stromelysin-3 is induced in tumor/stroma cocultures and inactivated via a tumor-specific and basic fibroblast growth factor-dependent mechanism. J Biol Chem. 1998 Jan 2;273(1):618-26

Masson R, Lefebvre O, Noël A, Fahime ME, Chenard MP, Wendling C, Kebers F, LeMeur M, Dierich A, Foidart JM, Basset P, Rio MC. In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy. J Cell Biol. 1998 Mar 23;140(6):1535-41


Basset P, Rio MC. MMP11 (matrix metalloproteinase 11 (stromelysin 3)). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):52-53.



54



STARD3 (START domain containing 3) Marie-Christine Rio

I.G.B.M.C., BP 163, 1 rue Laurent Fries, 67404 Illkirch, France (MCR)


Online updated version : http://AtlasGeneticsOncology.org/Genes/MLN64ID202.html DOI: 10.4267/2042/37607


Identity Other names: MLN64; CAB1

HGNC (Hugo): STARD3

Location: 17q12-21

Local order: From centromere to telomere are: TRAF4 (alias MLN62/CART1), Lasp1 (alias MLN50), c-erbB2, and MLN64.

DNA/RNA Transcription cDNA: 2.1 kb; coding sequence: 1335 bp.

Protein Description 445 amino acids; 50 kDa; contains four putative transmembrane domains at its N-terminal part; posseses a StAR Homology Domain at its C-terminal part.

Homology With StAR (Steroidogenic Acute Regulatory protein).

Implicated in Breast carcinomas Disease 17q11-q21 amplification is found in about 25% of primary breast carcinomas.

Prognosis Poor clinical outcome; increase risk of relapse.

References Tomasetto C, Régnier C, Moog-Lutz C, Mattei MG, Chenard MP, Lidereau R, Basset P, Rio MC. Identification of four novel human genes amplified and overexpressed in breast carcinoma and localized to the q11-q21.3 region of chromosome 17. Genomics. 1995 Aug 10;28(3):367-76

Bièche I, Tomasetto C, Régnier CH, Moog-Lutz C, Rio MC, Lidereau R. Two distinct amplified regions at 17q11-q21 involved in human primary breast cancer. Cancer Res. 1996 Sep 1;56(17):3886-90

Akiyama N, Sasaki H, Ishizuka T, Kishi T, Sakamoto H, Onda M, Hirai H, Yazaki Y, Sugimura T, Terada M. Isolation of a candidate gene, CAB1, for cholesterol transport to mitochondria from the c-ERBB-2 amplicon by a modified cDNA selection method. Cancer Res. 1997 Aug 15;57(16):3548-53

Moog-Lutz C, Tomasetto C, Régnier CH, Wendling C, Lutz Y, Muller D, Chenard MP, Basset P, Rio MC. MLN64 exhibits homology with the steroidogenic acute regulatory protein (STAR) and is over-expressed in human breast carcinomas. Int J Cancer. 1997 Apr 10;71(2):183-91

Watari H, Arakane F, Moog-Lutz C, Kallen CB, Tomasetto C, Gerton GL, Rio MC, Baker ME, Strauss JF 3rd. MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8462-7


Rio MC. STARD3 (START domain containing 3). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):54.



55



ABI1 (Abl-Interactor 1) Jean-Loup Huret

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

Published in Atlas Database: April 2000

Online updated version : http://AtlasGeneticsOncology.org/Genes/ABI1ID233.html DOI: 10.4267/2042/37609


Identity Other names: E3B1; eps8 SH3 domain binding protein; SSH3BP1

HGNC (Hugo): ABI1

Location: 10p11.2

Local order: Centromeric to the AF10 gene.

ABI1 (10p11) - Courtesy Mariano Rocchi, Resources for

Molecular Cytogenetics.

DNA/RNA Transcription Different splicings (and different names for the gene).

Protein Description 387 (ABI1) to 508 (e3B1) amino acids; 43 to 72 kDa; NH2- an homeodomain homologous region and a SH3 domain -COOH.

Expression Wide, in adults and in the embryo.

Localisation Cytosol.

Function Cell growth inhibitor; interacts with ENL, another fusion partner of MLL, by binding it through its SH3 domain; the mouse Abi-1 protein is an AB-binding protein that suppresses v-ABL transforming activity.

Implicated in t(10;11)(p11.2;q23) acute non lymphoblastic leukemia (ANLL) --> MLL-ABI1 Note Only one case to date.

Disease M4 ANLL in an infant.

Oncogenesis MLL-ABI1 displays a transcriptional transactivator activity similar to MLL-ENL; they may act in a common oncogenic pathway.

References Biesova Z, Piccoli C, Wong WT. Isolation and characterization of e3B1, an eps8 binding protein that regulates cell growth. Oncogene. 1997 Jan 16;14(2):233-41

Taki T, Shibuya N, Taniwaki M, Hanada R, Morishita K, Bessho F, Yanagisawa M, Hayashi Y. ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). Blood. 1998 Aug 15;92(4):1125-30

ABI1 (Abl-Interactor 1) Huret JL


56

Ziemnicka-Kotula D, Xu J, Gu H, Potempska A, Kim KS, Jenkins EC, Trenkner E, Kotula L. Identification of a candidate human spectrin Src homology 3 domain-binding protein suggests a general mechanism of association of tyrosine kinases with the spectrin-based membrane skeleton. J Biol Chem. 1998 May 29;273(22):13681-92

Garcia Cuellar MP, Schreiner S, Birke M, Hamacher M, Slany RK.. ENL, the MLL fusion partner in t(11;19), binds to the c-ABL interactor protein 1 (ABI1) that is fused to MLL in t(10;11). Blood 1999; 94 Suppl 1: Abst 237.


Huret JL. ABI1 (Abl-Interactor 1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):55-56.



57



AF5q31 (ALL1 fused gene from chromosome 5q31) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Genes/AF5q31ID230.html DOI: 10.4267/2042/37610


Identity Location : 5q31

DNA/RNA Description At least 16 exons.

Transcription 4235 bp mRNA; open reading frame: 3491 bp.

Protein Description 1163 amino acids; 127 kDa.

Expression Mostly in fetal tissues (heart, lung, brain, liver); at a low level in adult tissues; therefore, AF5q31 may play a critical role in the fetal development.

Homology With AF4-related proteins: AF4, the gene involved in t(4;11)(q21;q23), LAF4, FMR2.

Implicated in ins(5;11)(q31;q13q23) acute lymphoblastic leukemia (ALL) --> MLL/AF5q31 Note Poorly defined: only 1 case to date, a girl aged 4 months, with CD19+ ALL, and i(17q) as additional anomaly; complete remission, relapse and death at 20 months.

References Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y. AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14535-40


Huret JL. AF5q31 (ALL1 fused gene from chromosome 5q31). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):57.



58



ARHGEF12 (Rho guanine nucleotide exchange factor (GEF) 12) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Genes/LARGID243.html DOI: 10.4267/2042/37613


Identity Other names: LARG (Leukemia Associated Rho Guanine nucleotide exchange factor); KIAA0382

HGNC (Hugo): ARHGEF12

Location: 11q23

Local order: Telomeric to MLL.

DNA/RNA Transcription 9501 bp mRNA; 4634 bp open reading frame.

Protein Description The gene encodes a guanine nucleotide exchange factor; 1544 amino acids; NH2- PDZ domain, Lsc homology (LH) domain, bipartite nuclear localization signal, Dbl homology (DH) domain, and a pleckstrin homology (PH) domain –COOH.

Expression Wide (leukocytes, spleen, prostate, testis, ovary, small intestine, colon, thymus).

Function PDZ domains are involved in protein-protein interactions in transmembrane signaling pathways; LH domains bind G proteins; nuclear localization signals are implicated in translocation of proteins from the cytoplasm to the nucleus; DH domains are responsible

for the nucleotide exchange activity of guanine nucleotide exchange (GEF) toward Rho GTPases, PH domains function in membrane localization; Rho GEF are regulators of GTPases, and have oncogenic properties.

Homology Member of the family of Rho GEF factors, like dbl, vav, tiam, and BCR.

Implicated in Acute non lymphocytic leukemia (ANLL) with apparently normal cromosomes 11 --> MLL-LARG Note Poorly defined: only 1 case to date, a 38 year old male patient with occupational exposure; M4-ANLL; CR; death unrelated to the leukemia.

Cytogenetics The case was 51,XY,+8,+19,+3mar; the interstitial deletion at 11q23 resulting in MLL-LARG fusion cannot be seen at the chromosome level.

Hybrid/Mutated gene 5' MLL fused at exon 6 with the 3' end of almost the entire LARG; LARG is oriented in a 5' to 3'direction, like MLL.

Abnormal protein Excludes the NH2- PDZ domain of LARG, and includes most of LARG, from the Lsc homology (LH) domain to COOH.

ARHGEF12 (Rho guanine nucleotide exchange factor (GEF) 12) Huret JL


59

References Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, Theil KS, Krahe R, Ruutu T, Knuutila S, Bloomfield CD, Caligiuri MA. Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia. Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2145-50


Huret JL. ARHGEF12 (Rho guanine nucleotide exchange factor (GEF) 12). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):58-59.



60



CDX2 (caudal-related homeobox 2) Nick CP Cross

Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK (NCPC)


Online updated version : http://AtlasGeneticsOncology.org/Genes/CDX2ID326.html DOI: 10.4267/2042/37611


Identity Other names: CDX3

HGNC (Hugo): CDX2

Location: 13q12.3

Local order: IPF1-CDX2- FLT3 -FLT1.

CDX2 (13q12) - Courtesy Mariano Rocchi, Resources for

Molecular Cytogenetics.

DNA/RNA Description Three exons transcribed from telomere to centromere.

Protein Description 311 amino acid protein of MW 33kDa. Class I homeobox gene related to Drosophila caudal.

Expression Nuclear protein normally expressed almost exclusively in the intestine, where it plays a role in the proliferation and differentiation of intestinal epithelial cells.

Mutations Somatic Found to be mutated in rare cases of colorectal carcinoma.

Implicated in t(12;13)(p13;q12) acute non lymphocytic leukaemia --> ETV6/CDX2 Abnormal protein Fusion of ETV6 exon 2 to CDX2 exon 2. The predicted protein contains the N-terminal region of ETV6 38 fused to the entire homeobox of CDX2. The single case described that harbours this fusion also expressed normal CDX2, which is not normally expressed in haemopoietic cells.

References Drummond F, Putt W, Fox M, Edwards YH. Cloning and chromosome assignment of the human CDX2 gene. Ann Hum Genet. 1997 Sep;61(Pt 5):393-400

Wicking C, Simms LA, Evans T, Walsh M, Chawengsaksophak K, Beck F, Chenevix-Trench G, Young J, Jass J, Leggett B, Wainwright B. CDX2, a human homologue of Drosophila caudal, is mutated in both alleles in a replication error positive colorectal cancer. Oncogene. 1998 Aug 6;17(5):657-9

Chase A, Reiter A, Burci L, Cazzaniga G, Biondi A, Pickard J, Roberts IA, Goldman JM, Cross NC. Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood. 1999 Feb 1;93(3):1025-31

CDX2 (caudal-related homeobox 2) Cross NCP


61

da Costa LT, He TC, Yu J, Sparks AB, Morin PJ, Polyak K, Laken S, Vogelstein B, Kinzler KW. CDX2 is mutated in a colorectal cancer with normal APC/beta-catenin signaling. Oncogene. 1999 Sep 2;18(35):5010-4


Cross NCP. CDX2 (caudal-related homeobox 2). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):60-61.



62



MSF (MLL septin-like fusion) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Genes/MSFID208.html DOI: 10.4267/2042/37614


Identity Other names: MSF1; AF17q25 (ALL1 fused gene from chromosome 17q25); KIAA0991

HGNC (Hugo): MSF

Location: 17q25

DNA/RNA Transcription Various transcripts: 4.0 kb and 1.7 kb in most tissues, 3.0 kb; cDNA: 2801 bp.

Protein Description Various sized proteins have been described: 422, 568 amino acids (64 kDa), 574, 586, and 594 amino acids.

Expression Wide.

Localisation Cytoplasm.

Homology Septin family: hCDCRel-1 (human), also found involved in fusion protein with MLL in leukemia, H5 and NEDD5 (mouse), CDC10 (yeast), Pnut, Sep 1, and Sep 2 (drosophila).

Implicated in t(11;17)(q23;q25) acute non lymphocytic leukemia (ANLL) --> MLL/MSF Disease De novo and treatment related leukemia.

Prognosis Likely to be poor.

Hybrid/Mutated gene 5' MLL - 3' MSF; fusion at MLL exon 5; the reciprocal MSF-MLL is also transcribed, but out of frame.

Abnormal protein NH2 - AT hook and DNA methyltransferase from MLL fused to most of MSF in COOH.

References Osaka M, Rowley JD, Zeleznik-Le NJ. MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25). Proc Natl Acad Sci U S A. 1999 May 25;96(11):6428-33

Taki T, Ohnishi H, Shinohara K, Sako M, Bessho F, Yanagisawa M, Hayashi Y. AF17q25, a putative septin family gene, fuses the MLL gene in acute myeloid leukemia with t(11;17)(q23;q25). Cancer Res. 1999 Sep 1;59(17):4261-5

Kalikin LM, Sims HL, Petty EM. Genomic and expression analyses of alternatively spliced transcripts of the MLL septin-like fusion gene (MSF) that map to a 17q25 region of loss in breast and ovarian tumors. Genomics. 2000 Jan 15;63(2):165-72


Huret JL. MSF (MLL septin-like fusion). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):62.



63



SEPT5 (septin 5) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Genes/hCDCRel-1ID220.html DOI: 10.4267/2042/37612


Identity Other names: hCDCRel-1 (human cell division cycle regulation 1); PNUTL1 (peanut (drosophila)- like 1); CDCREL; AF22 (ALL1 fused gene from chromosome 22)

HGNC (Hugo): SEPT5

Location: 22q11.2

DNA/RNA Description The gene spans 13 kb; 13 exons; one large intron (3.7kb) between exons 2 and 3.

Transcription Two major splicings in 5' (exons 1 and 2 versus exon 3; 2032 bp mRNA; coding sequence: 1109 bp; the gene is just 5'of GPIb beta (platelet membrane glycoprotein Ib beta precursor), and GPIb beta is co-expressed with hCDCRel-1; this is due to a non-consensus polyadenylation signal in 3' of hCDCRel-1.

Protein Description 369 amino acids; GTPase activity.

Expression High level expression in brain, heart, platelets; low level expression in some other tissues.

Localisation Cytoplasm.

Function See below; may have a role in the synaptic function of neurones in the brain.

Homology Belong to the septin family: filament forming proteins

implicated in the cytoskeleton organization; nucleotide binding proteins; hCDCRel-1 is closely related to AF17q25/MSF, also found involved in fusion protein with MLL in leukemia.

Implicated in t(11;22)(q23;q11) acute non lymphocytic leukemia (ANLL) --> MLL - hCDCRel-1 Disease M4, M2, and M1 ANLL. Hybrid/Mutated gene 5' MLL - 3' hCDCRel, with fusion of MLL exon 7 to hCDCRel exon 3. Abnormal protein NH2 - AT hook and DNA methyltransferase from MLL fused to hCDCREL-1 - COOH.

References McKie JM, Sutherland HF, Harvey E, Kim UJ, Scambler PJ. A human gene similar to Drosophila melanogaster peanut maps to the DiGeorge syndrome region of 22q11. Hum Genet. 1997 Nov;101(1):6-12

Zieger B, Hashimoto Y, Ware J. Alternative expression of platelet glycoprotein Ib(beta) mRNA from an adjacent 5' gene with an imperfect polyadenylation signal sequence. J Clin Invest. 1997 Feb 1;99(3):520-5

Caltagarone J, Rhodes J, Honer WG, Bowser R. Localization of a novel septin protein, hCDCrel-1, in neurons of human brain. Neuroreport. 1998 Aug 24;9(12):2907-12

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


Huret JL. SEPT5 (septin 5). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):63.



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HMGIC (High mobility group protein isoform I-C) Florence Pedeutour

UF Recherche Clinique 952, Laboratoire de Génétique, Université de Nice-Sophia Antipolis, CHU de Nice, 06202 Nice, France (FP)

Published in Atlas Database: May 2000

Online updated version : http://AtlasGeneticsOncology.org/Genes/HMGICID82.html DOI: 10.4267/2042/37615


Identity HGNC (Hugo): HMGIC

Location: 12q15

Local order: Telomeric to CDK4, centromeric to MDM2.

Probe(s) - Courtesy Mariano Rocchi.

DNA/RNA Description 5 exons, spans approximately 160 kb; the size of intron 3 is 140 kb.

Transcription RNA: 4.1 kb.

Protein Description 109 amino acids; three DNA binding domains (AT hooks) linked to the carboxy-terminal acidic domain that does not activate transcription.

Expression Fetal tissues: expression in various tissues, prominent in kidney, liver and uterus; adult tissues: no expression except in lung and kidney; tumors: expression in benign mesenchymal tumor tissues correlated to 12q15 rearrangements.

Localisation Nuclear.

HMGIC (High mobility group protein isoform I-C) Pedeutour F


65

Function Architectural factor, non histone, preferential binding to AT rich sequences in the minor groove of DNA helix; the precise function remains to be elucidated; probable role in regulation of cell proliferation.

Homology Member of the HMGI protein family.

Mutations Germinal Deletion of HMGIC in mutant mice or transgenic 'knock out' mice for the first two exons of HMGIC have the 'pigmy' phenotype: low birth weight, craniofacial defects, adipocyte hypoplasia adult body weight about 40% of normal.

Implicated in Mesenchymal benign tumors as follows: Lipoma Disease Benign adipocyte tumor.

Prognosis Good.

Cytogenetics Various rearrangements involving 12q15 (translocations, inversions, deletions...); reciprocal translocations involve 12q15 with different partners such as chromosomes 1, 3, 7, 10, 11, 13, 15, 17, 21, X; the most frequent anomaly is t(3;12)(q27-28;q15); cryptic rearrangements, such as paracentric inversions not detectable by conventional cytogenetics but detectable by FISH, have been described.

Hybrid/Mutated gene For t(3;12): HMGIC-LPP (LPP: lipoma prefered partner; 3q27-28); a gene located in 13q, LHFP (lipoma HMGIC fusion partner) was found to be fused with HMGIC in one case of lipoma.

Abnormal protein HMGIC-LPP; the three AT hook domains at the aminoterminal of HMGIC are fused to the LIM domain

of LPP; another fusion protein due to the fusion of HMGIC with a putative gene located at 15q24 predicted to encode a protein with a serine/threonine-rich domain has also been described. Oncogenesis The relevance of the exact role LPP in the HMGIC-LPP fusion is not established yet; the truncation of HMGIC may have a role in the tumorigenesis.

Uterine leiomyoma (uterine fibroids) Disease Benign mesenchymal tumors.

Prognosis Good.

Cytogenetics Approximately 40% of uterine leiomyomas have structural chromosomal rearrangements, about 10% of which involve 12q15 (translocations, inversions, deletions...); the most frequent anomaly is t(12;14)(q15;q23-24).

Hybrid/Mutated gene In a majority of cases, there is no fusion gene: the breakpoint is located 10 kb up to 100 kb 5' to HMGIC; the recombinational repair gene RAD51B is a candidate to be the partner gene of HMGIC in t(12;14); in one case with paracentric inversion, HMGIC exon 3 was fused to ALDH2 exon 13 (12q24.1); in one case (no cytogenetic analysis) HMGIC exon 3 was fused to COX6C 3' UTR (8q22-23); in one case, with apparently normal karyotype, exon 3 of HMGIC was fused to retrotransposon-like sequences RTVLH 3' LTRs.

Abnormal protein HMGIC-ALDH2: ALDH2 contribution was only 10 amino acids.

Oncogenesis HMGIC-ALDH2: it is suggested that the truncation of HMGIC, rather than fusion may be responsible for tumorigenesis; the 3' untranslated region may stabilize the HMGIC messenger RNA.

Pleomorphic adenoma of the salivary gland (or mixed salivary gland tumor) Disease Benign tumors from the major or minor salivary glands.

Prognosis Good.



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Cytogenetics Approximately 12% of pleomorphic adenomas of salivary glands show abnormalities involving HMGIC in 12q15; the most frequent aberration is t(9;12)(p24.1;q15). Hybrid/Mutated gene In t(9;12): HMGIC-NFIB fusion; another type of fusion HMGIC-FHIT (3p14.2) has also been described.

Pulmonary chondroid hamartoma of the lung Disease Benign mesenchymal tumors of the lung.

Prognosis Good.

Cytogenetics Various rearrangements involving 12q15 leading to HMGIC dysregulation; cryptic rearrangements such as paracentric inversions not detectable by conventional cytogenetics but detectable by FISH have been described.

Hybrid/Mutated gene In two cases with apparently normal karyotypes, exon 3 of HMGIC was fused to retrotransposon-like sequences RTVLH 3' LTRs; in five cases with t(3;12)(q27;q15) (see lipomas), a fusion HMGIC-LPP was described.

Endometrial polyps Disease Uterine benign tumors.

Prognosis Good.

Cytogenetics Various rearrangements involving 12q15 leading to HMGIC dysregulation; cryptic rearrangements such as paracentric inversions not detectable by conventional cytogenetics but detectable by FISH have been described; in one case, HMGIC was amplified and overexpressed.

Myofibroblastic inflammatory tumor Disease Benign mesenchymal tumors.

Prognosis Good.

Cytogenetics In one case, a complex rearrangement involving chromosomes 12 (in 12q15), 4 and 21 was described.

Hybrid/Mutated gene

An aberrant transcript was produced by the fusion of HMGIC exon 3 to an ectopic sequence originating from the third intron of HMGIC.

Malignant tumors as follows: Well-differentiated liposarcoma Disease Malignant adipocyte tumor; peripheral or retroperitoneal location.

Prognosis Rather good; borderline malignancy; locally aggressive, rarely metastasizes.

Cytogenetics Supernumerary ring or giant marker chromosomes containing 12q14-15 amplification (surrounding MDM2); HMGIC is frequently amplified together with MDM2; in two cases, a rearrangement of HMGIC, in addition to amplification has been described.

Hybrid/Mutated gene In one case an ectopic sequence from unknown origin was shown to be fused to HMGIC exon 3.

Osteosarcoma Disease Malignant tumor.

Hybrid/Mutated gene In one osteosarcoma cell line (OsA-Cl) the three DNA binding domains of HMGIC fused to the keratan sulfate protein glycan gene LUM (12q22-23); LUM was fused out of frame, and only 3 amino acids were fused to HMGIC; in addition, the rearranged gene was amplified.

References Ashar HR, Fejzo MS, Tkachenko A, Zhou X, Fletcher JA, Weremowicz S, Morton CC, Chada K. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell. 1995 Jul 14;82(1):57-65

Kazmierczak B, Hennig Y, Wanschura S, Rogalla P, Bartnitzke S, Van de Ven W, Bullerdiek J. Description of a novel fusion transcript between HMGI-C, a gene encoding for a member of the high mobility group proteins, and the mitochondrial aldehyde dehydrogenase gene. Cancer Res. 1995 Dec 15;55(24):6038-9

Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJ. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet. 1995 Aug;10(4):436-44

Zhou X, Benson KF, Ashar HR, Chada K. Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature. 1995 Aug 31;376(6543):771-4

Kazmierczak B, Pohnke Y, Bullerdiek J. Fusion transcripts between the HMGIC gene and RTVL-H-related sequences in mesenchymal tumors without cytogenetic aberrations. Genomics. 1996 Dec 1;38(2):223-6



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Kools PF, Van de Ven WJ. Amplification of a rearranged form of the high-mobility group protein gene HMGIC in OsA-CI osteosarcoma cells. Cancer Genet Cytogenet. 1996 Oct 1;91(1):1-7

Petit MM, Mols R, Schoenmakers EF, Mandahl N, Van de Ven WJ. LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family. Genomics. 1996 Aug 15;36(1):118-29

Schoenberg Fejzo M, Ashar HR, Krauter KS, Powell WL, Rein MS, Weremowicz S, Yoon SJ, Kucherlapati RS, Chada K, Morton CC. Translocation breakpoints upstream of the HMGIC gene in uterine leiomyomata suggest dysregulation of this gene by a mechanism different from that in lipomas. Genes Chromosomes Cancer. 1996 Sep;17(1):1-6

Wanschura S, Dal Cin P, Kazmierczak B, Bartnitzke S, Van den Berghe H, Bullerdiek J. Hidden paracentric inversions of chromosome arm 12q affecting the HMGIC gene. Genes Chromosomes Cancer. 1997 Apr;18(4):322-3

Hess JL. Chromosomal translocations in benign tumors: the HMGI proteins. Am J Clin Pathol. 1998 Mar;109(3):251-61

Rogalla P, Kazmierczak B, Meyer-Bolte K, Tran KH, Bullerdiek J. The t(3;12)(q27;q14-q15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype. Genes Chromosomes Cancer. 1998 Jun;22(2):100-4

Gattas GJ, Quade BJ, Nowak RA, Morton CC. HMGIC expression in human adult and fetal tissues and in uterine

leiomyomata. Genes Chromosomes Cancer. 1999 Aug;25(4):316-22

Kazmierczak B, Dal Cin P, Sciot R, Van den Berghe H, Bullerdiek J. Inflammatory myofibroblastic tumor with HMGIC rearrangement. Cancer Genet Cytogenet. 1999 Jul 15;112(2):156-60

Schoenmakers EF, Huysmans C, Van de Ven WJ. Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas. Cancer Res. 1999 Jan 1;59(1):19-23

Anand A, Chada K. In vivo modulation of Hmgic reduces obesity. Nat Genet. 2000 Apr;24(4):377-80

Arlotta P, Tai AK, Manfioletti G, Clifford C, Jay G, Ono SJ. Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas. J Biol Chem. 2000 May 12;275(19):14394-400

Kurose K, Mine N, Doi D, Ota Y, Yoneyama K, Konishi H, Araki T, Emi M. Novel gene fusion of COX6C at 8q22-23 to HMGIC at 12q15 in a uterine leiomyoma. Genes Chromosomes Cancer. 2000 Mar;27(3):303-7


Pedeutour F. HMGIC (High mobility group protein isoform I-C). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):64-67.



68



MVP (major vault protein) Franck Viguié

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


Online updated version : http://AtlasGeneticsOncology.org/Genes/LRPID120.html DOI: 10.4267/2042/37616


Identity Other names: LRP (lung resistance-related protein)

HGNC (Hugo): MVP

Location: 16p11.2

Note: Drug resistance gene, codes for a "lung resistance-related protein" (LRP) originally detected in a lung carcinoma cell line resistant to chemotherapy.

DNA/RNA Transcription Coding sequence, corresponding to full mRNA, is 2840 bp long.

Protein Description 110 kD protein, 896 amino acids; major cytoplasmic vault protein; vaults are nucleoproteic complexes composed of the MVP associated with two high-molecular weight proteins p240 and p193 which surround a small 140 nucleotides RNA species.

Expression Expressed in a variety of human tumor cell lines, the major part being multidrug resistant; expressed also in primary solid tumors, mainly colon carcinoma or ovarian carcinoma, as well as in hematopoietic cancers (myelodysplastic syndrome, acute myeloid or lymphoid leukemia, multiple myeloma); in normal tissues, LRP expression has a wide distribution, with particularly high levels in epithelial cells of the digestive tract.

Localisation Cytoplasmic, in the cytosol, with a little fraction (approximately 5%) located in the nuclear membrane and nuclear pores.

Function Vault are cytoplasmic organelles which mediate bidirectional nucleocytoplasmic transport of a wide range of substrates, including cytotoxic drugs; vaults would be involved both in vesicule and cytosolic transport of molecules.

Homology 104 kD rat MVP.

Implicated in Implicated in induced multidrug-resistance to anticancer chemotherapy Disease It includes resistance to doxorubicin, vinca alkaloids, mitoxantrone and etoposide; the role of LRP by itself in multidrug-resistance is not completely clear because it is only a part of a nucleo-proteic complex involved in macromolecules transport; the introduction and expression of the LRP gene in cells by transfection does not confer a multidrug-resistance phenotype; overexpression of LRP has been associated with poor response to chemotherapy in various types of leukemia and in ovarian carcinoma, however the role of LRP as pronostic factor remains controversial; in multi-resistant cell lines, LRP amplification within a homogeneous staining region is exceptional.

MVP (major vault protein) Viguié F


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References Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992 Dec 4;258(5088):1650-4

Slovak ML, Ho JP, Cole SP, Deeley RG, Greenberger L, de Vries EG, Broxterman HJ, Scheffer GL, Scheper RJ. The LRP gene encoding a major vault protein associated with drug resistance maps proximal to MRP on chromosome 16: evidence that chromosome breakage plays a key role in MRP or LRP gene amplification. Cancer Res. 1995 Oct 1;55(19):4214-9

Izquierdo MA, Scheffer GL, Flens MJ, Schroeijers AB, van der Valk P, Scheper RJ. Major vault protein LRP-related multidrug resistance. Eur J Cancer. 1996 Jun;32A(6):979-84

Hart SM, Ganeshaguru K, Scheper RJ, Prentice HG, Hoffbrand AV, Mehta AB. Expression of the human major vault protein LRP in acute myeloid leukemia. Exp Hematol. 1997 Nov;25(12):1227-32

Laurençot CM, Scheffer GL, Scheper RJ, Shoemaker RH. Increased LRP mRNA expression is associated with the MDR phenotype in intrinsically resistant human cancer cell lines. Int J Cancer. 1997 Sep 17;72(6):1021-6

Boutonnat J, Bonnefoix T, Mousseau M, Seigneurin D, Ronot X. Coexpression of multidrug resistance involve proteins: a flow cytometric analysis. Anticancer Res. 1998 Jul-Aug;18(4C):2993-9

Damiani D, Michieli M, Ermacora A, Candoni A, Raspadori D, Geromin A, Stocchi R, Grimaz S, Masolini P, Michelutti A, Scheper RJ, Baccarani M. P-glycoprotein (PGP), and not lung resistance-related protein (LRP), is a negative prognostic factor in secondary leukemias. Haematologica. 1998 Apr;83(4):290-7

den Boer ML, Pieters R, Kazemier KM, Rottier MM, Zwaan CM, Kaspers GJ, Janka-Schaub G, Henze G, Creutzig U, Scheper RJ, Veerman AJ. Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. Blood. 1998 Mar 15;91(6):2092-8

Filipits M, Pohl G, Stranzl T, Suchomel RW, Scheper RJ, Jäger U, Geissler K, Lechner K, Pirker R. Expression of the lung resistance protein predicts poor outcome in de novo acute myeloid leukemia. Blood. 1998 Mar 1;91(5):1508-13

Leith C. Multidrug resistance in leukemia. Curr Opin Hematol. 1998 Jul;5(4):287-91

Lepelley P, Poulain S, Grardel N, Preudhomme C, Cosson A, Fenaux P. Expression of lung resistance protein and correlation with other drug resistance proteins and outcome in myelodysplastic syndromes. Leuk Lymphoma. 1998 May;29(5-6):547-51

Raaijmakers HG, Izquierdo MA, Lokhorst HM, de Leeuw C, Belien JA, Bloem AC, Dekker AW, Scheper RJ, Sonneveld P. Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood. 1998 Feb 1;91(3):1029-36

Volm M. Multidrug resistance and its reversal. Anticancer Res. 1998 Jul-Aug;18(4C):2905-17

Filipits M, Drach J, Pohl G, Schuster J, Stranzl T, Ackermann J, Königsberg R, Kaufmann H, Gisslinger H, Huber H, Ludwig H, Pirker R. Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma. Clin Cancer Res. 1999 Sep;5(9):2426-30

Meijer GA, Schroeijers AB, Flens MJ, Meuwissen SG, van der Valk P, Baak JP, Scheper RJ. Increased expression of multidrug resistance related proteins Pgp, MRP1, and LRP/MVP occurs early in colorectal carcinogenesis. J Clin Pathol. 1999 Jun;52(6):450-4

Pohl G, Filipits M, Suchomel RW, Stranzl T, Depisch D, Pirker R. Expression of the lung resistance protein (LRP) in primary breast cancer. Anticancer Res. 1999 Nov-Dec;19(6B):5051-5

Borg AG, Burgess R, Green LM, Scheper RJ, Liu Yin JA. P-glycoprotein and multidrug resistance-associated protein, but not lung resistance protein, lower the intracellular daunorubicin accumulation in acute myeloid leukaemic cells. Br J Haematol. 2000 Jan;108(1):48-54


Viguié F. MVP (major vault protein). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):68-69.

Leukaemia Section Short Communication


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t(11;15)(q23;q14) Jean-Loup Huret, Christiane Charrin

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH), Service d'Hématologie, Hopital Edouard Herriot, Lyon, France (CC)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t1115ID1199.html DOI: 10.4267/2042/37617


Identity

t(11;15)(q23;q14) (R-banding) - Christiane Charrin.

Clinics and pathology Disease Only 1 case with the ascertainment of AF15q14 involvement; a the very few other cases may or may not carry the same rearrangement.

Phenotype/cell stem origin M4 ANLL in the AF15q14 case.

Clinics A 48 year old man with previous history of toxic exposure who died 4 mths after diagnosis.

Cytogenetics Additional anomalies + mar.

Genes involved and proteins

MLL Location 11q23

DNA/RNA 21 exons, spanning over 100 kb; 13-15 kb mRNA.

Protein 3969 amino acids; 431 KDa; contains two DNA binding motifs: a AT hook homologous to high mobility group proteins HMGI-(Y) and HMGI(C) that binds to the minor groove of DNA, and zinc fingers, a DNA methyl transferase motif, a bromodomain, and segments of homology with trithorax, in particular in the C-terminal SET domain.

AF15q14 Location 15q14

DNA/RNA At least 10 exons; spans more than 35 kb.

Protein 1833 amino acids; 206 kDa; nuclear localization domain in the c-term.

References Rubnitz JE, Link MP, Shuster JJ, Carroll AJ, Hakami N, Frankel LS, Pullen DJ, Cleary ML. Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1994 Jul 15;84(2):570-3

t(11;15)(q23;q14) Huret JL, Charrin C


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Hernández JM, Mecucci C, Beverloo HB, Selleri L, Wlodarska I, Stul M, Michaux L, Verhoef G, Van Orshoven A, Cassiman JJ. Translocation (11;15)(q23;q14) in three patients with acute non-lymphoblastic leukemia (ANLL): clinical, cytogenetic and molecular studies. Leukemia. 1995 Jul;9(7):1162-6

Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Deleage G, Magaud JP, Rimokh R. AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid

leukaemia with a t(11;15)(q23;q14). Oncogene. 2000 Sep 7;19(38):4446-50


Huret JL, Charrin C. t(11;15)(q23;q14). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):70-71.



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t(5;17)(q35;q21) Franck Viguié

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




Clinics and pathology Disease Acute non lymphocytic leukemia (ANLL).

Phenotype/cell stem origin Acute promyelocytic leukemia (ANLL-M3 according to the FAB classification).

Etiology Exceptional; only 2 well documented cases.

Clinics Both patients were pediatric cases: F/2.5 years, M/12 years; disseminated intravascular coagulation at diagnosis in one case; remission obtained with chemotherapy and/or ATRA; first relapse at 7 and 5 months respectively.

Cytology Hypergranular and hypogranular bilobed promyelocytes; absence of Auer rods; typical microspeckeled pattern with anti-RARa antibodies; terminal differentiation of blasts and promyelocytes in vitro with ATRA.

Prognosis Probably unfavorable (both patients had a short term first relapse).

Cytogenetics Probes RARa probe commercially available coupled with PML probe in dual color kits; non commercialized probes for NPM, previously used for t(2;5)(p23;q35) of anaplastic large cell lymphoma (same breakpoint into NPM) = cosmid clones 13, 15-2 and 47C12 retained by der(5).

Additional anomalies One of the two cases had complex additional abnormalities.

Variants t(15;17)(q22;q21) t(11;17)(q23;q21) t(11;17)(q13;q21)

Genes involved and proteins NPM1 Location 5q35

Protein Gene for the nucleolar phosphoprotein nucleophosmin; would participate in ribosome assembly.

RARa Location 17 q21

Protein Gene for the retinoic acid receptor alpha; the breakpoint lies within the second intron of the gene, as in t(15;17) and t(11;17) translocations.

Result of the chromosomal anomaly Hybrid gene Description Two reciprocal fusion genes are generated: 5'-NPM + 3'- RARa on der(5) and 5'-RARa + 3'-NPM on der(17); both fusion genes are transcribed, the crucial one is NPM-RARa; two NPM-RARa chimeric cDNAs are generated, one short and one long differing from 129 bp, with corresponding transcripts of 2.3 and 2.4 kb (alternatively spliced transcripts); in one case, only the

t(5;17)(q35;q21) Viguié F


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short NPM-RARa isoform could be detected; the 5' end of NPM-RARa cDNAs contains the first 442 bp of the NPM cDNA; the 3' end contains RARa sequences of exon 3 through the 3' end of RARa; a reciprocal RARa-NPM transcript is detected: RARa exons 1 and 2 are fused to 3' NPM downstream bp 443.

Detection Nested RT-PCR.

Fusion protein Description Two NPM-RARa proteins, of 563 and 520 amino acids, are encoded (MW 62 and 57 kDa); NPM-RARa fusion protein acts as a retinoic acid-responsive transcriptional activator: increase of activity in a concentration dependant manner.

References Corey SJ, Locker J, Oliveri DR, Shekhter-Levin S, Redner RL, Penchansky L, Gollin SM. A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features. Leukemia. 1994 Aug;8(8):1350-3

Brunel V, Lafage-Pochitaloff M, Alcalay M, Pelicci PG, Birg F. Variant and masked translocations in acute promyelocytic leukemia. Leuk Lymphoma. 1996 Jul;22(3-4):221-8

Pandolfi PP. PML, PLZF and NPM genes in the molecular pathogenesis of acute promyelocytic leukemia. Haematologica. 1996 Sep-Oct;81(5):472-82

Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood. 1996 Feb 1;87(3):882-6

Redner RL, Corey SJ, Rush EA. Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia. 1997 Jul;11(7):1014-6

Cheng GX, Zhu XH, Men XQ, Wang L, Huang QH, Jin XL, Xiong SM, Zhu J, Guo WM, Chen JQ, Xu SF, So E, Chan LC, Waxman S, Zelent A, Chen GQ, Dong S, Liu JX, Chen SJ. Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RARalpha and NPM-RARalpha. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6318-23

Grimwade D. The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J Haematol. 1999 Sep;106(3):591-613

Hummel JL, Wells RA, Dubé ID, Licht JD, Kamel-Reid S. Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia. Oncogene. 1999 Jan 21;18(3):633-41


Viguié F. t(5;17)(q35;q21). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):72-73.



74



ins(5;11)(q31;q13q23) Jean-Loup Huret



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/ins511ID1167.html DOI: 10.4267/2042/37619


Clinics and pathology Disease Acute lymphoblastic leukemia (ALL).

Phenotype/cell stem origin CD19+

Epidemiology Poorly defined: only 1 case to date.

Clinics A girl aged 4 months, who entered complete remission, relapsed and died 20 months after diagnosis.

Prognosis Yet unknown, likely to be poor.

Cytogenetics Additional anomalies i(17q)

Variants A few cases of t(5;11)(q31;q23) have been described, but it is unknown if they involve the same genes.

Genes involved and proteins AF5q31 Location 5q31.1

Protein Present homologies with AF4.

MLL Location 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.

Result of the chromosomal anomaly Hybrid gene Description 5' MLL - 3' AF5q31; fusion at MLL exon 10.

References Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y. AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23). Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14535-40


Huret JL. ins(5;11)(q31;q13q23). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):74.



75



t(10;11)(p11.2;q23) Jean-Loup Huret





Identity Note: Must not be confused with the t(10;11)(p12;q23) involving AF10 in 10p12 and MLL, or the t(10;11)(p13;q14-21), also involving AF10, but with CALM on chromosome 11.

Clinics and pathology Disease Acute non lymphoblastic leukemia (ANLL).

Phenotype/cell stem origin M4

Epidemiology Poorly known: only 1 case.

Clinics A boy aged 8 months; achieved complete remission, had bone marrow transplantation; alive 5 years+.

Genes involved and proteins ABI-1 Location 10p11.2

DNA/RNA Different splicings.

Protein Possesses a SH3 domain; cell growth inhibitor.

MLL Location 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.

Result of the chromosomal anomaly Hybrid gene Description 5' MLL - 3' ABI1; fusion at MLL exon 7.

Fusion protein Description 1727 amino acids (1406 from MLL and 321 from ABI-1); NH2- AT-hook, DNA methyltransferase, and transcriptional repression domain of MLL, fused to the homeodomain homologous region and the SH3 domain of ABI-1 in COOH.

References Taki T, Shibuya N, Taniwaki M, Hanada R, Morishita K, Bessho F, Yanagisawa M, Hayashi Y. ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23). Blood. 1998 Aug 15;92(4):1125-30


Huret JL. t(10;11)(p11.2;q23). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):75.



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t(11;17)(q23;q25) Jean-Loup Huret





Identity

t(11;17)(q23;q25) G-banding - Courtesy Jean Luc Lai.

Clinics and pathology Disease De novo and treatment related acute non lymphocytic leukemia (ANLL), myelodysplastic syndromes (MDS); acute lymphoblastic leukemia (ALL) at times.

Phenotype/cell stem origin Various subtypes of ANLL may be found, M4 in particular, but also M1, M2, M5.

Epidemiology At least 24 cases described; often found in children and young adults.

Prognosis Poor.

Genes involved and proteins MLL

Location 11q23

Protein Contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation.

MSF Location 17q25

Protein Protein which belongs to the septin family.

Result of the chromosomal anomaly Hybrid gene Description 5' MLL - 3' MSF; fusion at MLL exon 5; the reciprocal MSF-MLL is also transcribed, but out of frame.

Fusion protein Description NH2 - AT hook and DNA methyltransferase from MLL fused to most of MSF in COOH.

References Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage-Pochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM. Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants. Leukemia. 1998 May;12(5):811-22

Osaka M, Rowley JD, Zeleznik-Le NJ. MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25). Proc Natl Acad Sci U S A. 1999 May 25;96(11):6428-33

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Taki T, Ohnishi H, Shinohara K, Sako M, Bessho F, Yanagisawa M, Hayashi Y. AF17q25, a putative septin family gene, fuses the MLL gene in acute myeloid leukemia with t(11;17)(q23;q25). Cancer Res. 1999 Sep 1;59(17):4261-5


Huret JL. t(11;17)(q23;q25). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):76-77.



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t(12;13)(p12;q12-14) ETV6/CDX2 Nick CP Cross

Wessex Regional Genetics Laboratory Salisbury District Hospital Salisbury, SP2 8BJ, UK (NCPC)




Clinics and pathology Disease Chronic myelogenous leukemia (CML) in transformation, myelodysplastic syndrome (MDS), acute non lymphocytic leukemia (ANLL), B and T- acute lymphocytic leukemias (ALL).

Cytogenetics Probes The chromosome 13 breakpoint in most myeloid cases falls within YAC 875a8. Other cases are further proximal and may involve CDX2, contained in BAC RP11-328P22. In most lymphoid cases the chromosome 13 breakpoint falls within YAC 879f5.

Additional anomalies No consistent additional abnormalities.

Genes involved and proteins ETV6 Location 12p13

CDX2 Location 13q12.3

To be noted Note The t(12;13) is heterogeneous at the molecular level. A single case of ANLL has been reported with an ETV6-CDX2 fusion and ectopic expression of normal CDX2 but in the same study two other t(12;13) positive ANLL

patients did not have CDX2 involvement. FISH analysis has suggested that the chromosome 13 breakpoints are different in myeloid and lymphoid disease. ETV6 seems to be involved in some cases but not others.

References Raimondi SC, Privitera E, Williams DL, Look AT, Behm F, Rivera GK, Crist WM, Pui CH. New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Blood. 1991 May 1;77(9):2016-22

Tosi S, Stilgenbauer S, Giudici G, Capalbo S, Specchia G, Liso V, Castagna S, Lanzi E, Lichter P, Biondi A. Reciprocal translocation t(12;13)(p13;q14) in acute nonlymphoblastic leukemia: report and cytogenetic analysis of two cases. Cancer Genet Cytogenet. 1994 Oct 15;77(2):106-10

Fugazza G, Cerri R, Bruzzone R, Patrone F, Sessarego M. Duplication of the der(13)t(12;13)(p13;q14) in chronic myelomonocytic leukemia. Haematologica. 1997 May-Jun;82(3):336-7

La Starza R, Wlodarska I, Aventin A, Falzetti D, Crescenzi B, Martelli MF, Van den Berghe H, Mecucci C. Molecular delineation of 13q deletion boundaries in 20 patients with myeloid malignancies. Blood. 1998 Jan 1;91(1):231-7

Streubel B, Sauerland C, Heil G, Freund M, Bartels H, Lengfelder E, Wandt H, Ludwig WD, Nowotny H, Baldus M, Grothaus-Pinke B, Büchner T, Fonatsch C. Correlation of cytogenetic, molecular cytogenetic, and clinical findings in 59 patients with ANLL or MDS and abnormalities of the short arm of chromosome 12. Br J Haematol. 1998 Mar;100(3):521-33

Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den Berghe H, Marynen P. Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. Blood. 1998 Feb 15;91(4):1399-406

Chase A, Reiter A, Burci L, Cazzaniga G, Biondi A, Pickard J, Roberts IA, Goldman JM, Cross NC. Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). Blood. 1999 Feb 1;93(3):1025-31

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Coignet LJ, Lima CS, Min T, Streubel B, Swansbury J, Telford N, Swanton S, Bowen A, Nagai M, Catovsky D, Fonatsch C, Dyer MJ. Myeloid- and lymphoid-specific breakpoint cluster regions in chromosome band 13q14 in acute leukemia. Genes Chromosomes Cancer. 1999 Jul;25(3):222-9


Cross NCP. t(12;13)(p12;q12-14) ETV6/CDX2. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):78-79.



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t(7;12)(q36;p13) Jean-Loup Huret





Clinics and pathology Phenotype/cell stem origin ANLL of various subtypes: M1, M3V (with t(15;17) FISH negative), M4, M5, M7, and RAEB-t.

Epidemiology At least 9 cases known; may be overlooked, and therefore underestimated; was found in 3% of children cases of ANLL, that was also 15% of infant cases of ANLL under 18 months; sex ratio 3M/3F, age : 0-20 months (n= 9), median 8 months (n=6).

Clinics WBC range 8-230 x 109/L, median 12 x 109/L; organomegaly, central nervous system involvement in 3 of 6 cases.

Prognosis Poor prognosis: of 6 cases, one case had no remission and died at 7 months; 4 case had relapse (duration first remission 1-20 months), 2 cases are still alive (16 months + and 33 months +).

Cytogenetics Cytogenetics morphological May be misdiagnosed as del(12)(p13).

Cytogenetics molecular Therefore, molecular cytogenetics is recommended.

Additional anomalies +19 in 4 of 6 cases.

Genes involved and proteins Note: The gene in 7q36 is still unknown.

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 Tosi S, Giudici G, Mosna G, Harbott J, Specchia G, Grosveld G, Privitera E, Kearney L, Biondi A, Cazzaniga G. Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies. Genes Chromosomes Cancer. 1998 Mar;21(3):223-9

Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den Berghe H, Marynen P. Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. Blood. 1998 Feb 15;91(4):1399-406

Satake N, Maseki N, Nishiyama M, Kobayashi H, Sakurai M, Inaba H, Katano N, Horikoshi Y, Eguchi H, Miyake M, Seto M, Kaneko Y. Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants. Leukemia. 1999 Jul;13(7):1013-7


Huret JL. t(7;12)(q36;p13). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):80.

Leukaemia Section Mini Review


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+12 or trisomy 12 Lucienne Michaux

Department of Hematology and Center for Human Genetics, Cliniques Universitaires Saint Luc Avenue Hippocrate 10 1200 Brussels, Belgium (LM)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/tri12ID2024.html DOI: 10.4267/2042/37627


Identity Note: Trisomy 12 is the most common cytogenetic change in chronic lymphocytic leukemia (CLL); however, it has also been observed in other subtypes of B-cell lymphoproliferative disorders, where it is not seldomly a secondary change.

Clinics and pathology Disease B-cell chronic lymphocytic leukemia (B-CLL).

Phenotype/cell stem origin virgin CD5+ recirculating B-cell; the classical CLL phenotype is CD5+, CD23+, CD22-, CD79a-, FMC7-, sIg weak; trisomy 12 is more often observed in CLL with morphologically and immunologically atypical cells, displaying CD5 negativity or FMC7 positivity and strong surface immunoglobulin staining; trisomy 12 is present in proliferating cells and seems to be associated with the absence of mutation of the Ig variable region genes.

Epidemiology Trisomy 12 is found in one third of cytogenetically abnormal CLLs by conventional karyotype, and in about 12-54% of cases when interphase FISH is used.

Prognosis A significant difference comparing the therapy-free interval of patients with +12 and patients with other anomalies was found; this observation was repeatedly confirmed; however an adverse impact of +12 on survival could not be demonstrated until the IWCLL compiled karyotype and survival data from more than 400 patients and showed a median survival of 5.4 years versus 8.6 years versus 14 years in patients with +12 versus another single abnormality versus a normal

karyotype, respectively; the preliminary results on a large series of patients analyzed by interphase FISH showed that +12 and 14q+ changes are associated with shorter survival times, compared to patients with 13q abnormalities and normal karyotypes; however prospective data are needed to further assess the prognostic value of this cytogenetic change.

Disease B-cell non Hogkin's lymphomas, distinct from CLL, i.e. prolymphocytic leukemia, hairy cell leukemia, splenic lymphoma with villous lymphocytes (SLVL), Waldenström's disease, follicular lymphoma, mantle cell lymphoma, and diffuse large cell lymphoma.

Phenotype/cell stem origin Lack of specificity for a particular immunophenotype.

Prognosis No data are available concerning the prognostic significance of +12, except in one series of mantle cell lymphomas in which it was the only single cytogenetic parameter associated with poor prognosis.

Cytogenetics Cytogenetics morphological Using restriction fragment length polymorphism analysis, the extra chromosome 12 has been shown to derive from duplication of one chromosome 12, with retention of the other homolog rather than from triplication of one homolog; trisomy 12 is thought to be a secondary change since combined immunological and cytogenetic studies showed that it is present in only a part of the neoplastic B-cells; cases with partial duplication 12q were analyzed by FISH, and a "minimal duplicated region" could be defined in segment 12q13-12q15.

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References Mitelman F, Johansson B, Mertens F. Catalogue of chromosome aberrations in cancer. http://cgap.nci.nih.gov/Chromosomes/Mitelman

Sadamori N, Han T, Minowada J, Sandberg AA. Clinical significance of cytogenetic findings in untreated patients with B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet. 1984 Jan;11(1):45-51

Crossen PE, Horn HL. Origin of trisomy 12 in B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet. 1987 Sep;28(1):185-6

Juliusson G, Friberg K, Gahrton G. Consistency of chromosomal aberrations in chronic B-lymphocytic leukemia. A longitudinal cytogenetic study of 41 patients. Cancer. 1988 Aug 1;62(3):500-6

Einhorn S, Burvall K, Juliusson G, Gahrton G, Meeker T. Molecular analyses of chromosome 12 in chronic lymphocytic leukemia. Leukemia. 1989 Dec;3(12):871-4

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

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 Jul 15;82(2):571-5

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 leukaemias. Br J Haematol. 1994 Jul;87(3):523-8

Garcìa-Marco J, Matutes E, Morilla R, Ellis J, Oscier D, Fantes J, Catovsky D, Price CM. Trisomy 12 in B-cell chronic lymphocytic leukaemia: assessment of lineage restriction by simultaneous analysis of immunophenotype and genotype in interphase cells by fluorescence in situ hybridization. Br J Haematol. 1994 May;87(1):44-50

GarciaMarco J, Matutues E, Price CM, Ellis J, Que TH, Lens D, Catovsky D. Correlation of trisomy 12 with expression of the

proliferating nuclear antigen K-67 in chronic lymphocytic leukemia. Br J Haematol. 1994;86(Suppl 1):p24.

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

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):382-8

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

Dierlamm J, Wlodarska I, Michaux L, Vermeesch JR, Meeus P, Stul M, Criel A, Verhoef G, Thomas J, Delannoy A, Louwagie A, Cassiman JJ, Mecucci C, Hagemeijer A, Van den Berghe H. FISH identifies different types of duplications with 12q13-15 as the commonly involved segment in B-cell lymphoproliferative malignancies characterized by partial trisomy 12. Genes Chromosomes Cancer. 1997 Oct;20(2):155-66

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

Döhner H, Stilgenbauer S, Döhner K, Bentz M, Lichter P. Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis. J Mol Med. 1999 Feb;77(2):266-81

Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1848-54


Michaux L. +12 or trisomy 12. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):81-82.



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Diffuse large cell lymphoma Antonio Cuneo, Gian Luigi Castoldi

Hematology Section, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca 203, Ferrara, Italy (AC)


Online updated version : http://AtlasGeneticsOncology.org/Anomalies/DLCLID2076.html DOI: 10.4267/2042/37624


Clinics and pathology Disease Diffuse large cell lymphoma (DLCL) includes centroblastic lymphoma, B-cell immunoblastic lymphoma and B-cell large cell anaplastic lymphoma in the Kiel classification; this neoplasia may present as a de novo condition or it may derive from the transformation of follicle centre cell lymphoma or, less frequently, of marginal zone lymphoma.

Phenotype/cell stem origin The tumor cells are pan-B+ and CD45+; CD5 and CD10 are positive in a minority of cases; positivity for surface Ig is found in the majority of cases, a minority of which also show intracytoplasmic Ig; some cases of the anaplastic subtype may be CD30+; usually, BCL6 is positive in cases with predominant centroblastic morphology, whereas syndecan-1 (CD138) tests positive in the immunoblastic variant; the putative normal cellular counterparts are cells of follicle / post follicle centre origin that have encountered the antigen and harbour somatic hypermutations of the Ig-gene variable region.

Pathology The cells are large, with vesicular nuclei at least twice the size of the nucleus of a small lymphocyte; there is a mixture of cells resembling centroblasts and immunoblasts; in rarer cases the cells are morphologically indistinguishable from those seen in anaplastic lymphoma of T- or null cell type.

Genetics Note The large majority of cases show clonal cytogenetic lesions; some of these changes are associated with a

known primary genetic defect responsible for lymphomagenesis, whereas a plethora of additional changes may be involved in tumor progression. Most studies failed to establish the prognostic predictivity for any primary chromosome defect, whereas there is evidence that several secondary aberrations may affect prognosis.

Cytogenetics Cytogenetics morphological Primary changes: t(14;18)(q32;q21) / BCL2-rearrangement: this molecular cytogenetic defect is found in approximately 15-25% of the cases, many of which are thought to derive from the transformation of an antecedent follicle centre cell lymphoma; in virtually all cases additional cytogenetic defects are present, including 17p13/p53 lesions; this balanced translocation can be demonstrated by conventional cytogenetics, by FISH and by molecular genetic methods, including southern blotting and PCR; the latter method is useful for the monitoring of minimal residual disease. t(3;V)(q27;V) / BCL6-rearrangement: chromosome translocations involving the 3q27 band with a number of partner chromosomes (14q32, 2p11, 22q11, 4p11, 6p21, 11q23 ) are found in 5-10% of the cases by cytogenetic analysis, but the incidence of BCL6 rearrangement may reach 20-30% of the cases when investigated by southern blotting; there is not an absolute correlation between rearrangement of the 3q27 band and BCL6 involovement; cryptic BCL6 rearrangements were demonstrated by FISH, consisting of an insertion of IgH sequences within the regulatory portion of the BCL6 gene. t(8;14)(q24;q32) / MYC rearrangements: this aberration is found by cytogenetic or molecular genetic methods in 7-10% of the cases; probes for FISH

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detection of myc rearrangements were also tested succesfully; an association with the centroblastic variant of DLCL was proposed.

Additional anomalies Secondary anomalies: Trisomies of chromosomes 3, 5, 7, 11, 12, 18 and X are usually encoutered in >10% of the cases. The most frequent monosomies include -13, -14, -15. Gains of 1q and 6p were reported in more than 10% of the cases. Frequently occurring deletions involve 1p, 6q, 7q32-ter, 8p, 9p, 11q, 17p. The most frequent breakpoints are clustered in the following regions: 1cen-p13; 1p34-36; 3q21-22; 3q27-29; 6q12-16; 6q21-25; 7q32, 9cen-p21; 17cen-p12. There are reports suggesting that an inferior prognosis may be associated with 1q21-23 breaks, with 1q23-32 duplications, with 6q21-25 breaks and with 11q22-23 deletion; complex karyotype may have an adverse impact on prognosis.

References Offit K, Wong G, Filippa DA, Tao Y, Chaganti RS. Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: clinical correlations. Blood. 1991 Apr 1;77(7):1508-15

Offit K, Lo Coco F, Louie DC, Parsa NZ, Leung D, Portlock C, Ye BH, Lista F, Filippa DA, Rosenbaum A. Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med. 1994 Jul 14;331(2):74-80

Tse KF, Morrow JK, Hughes NK, Gallicchio VS. Stromal cell lines derived from LP-BM5 murine leukemia virus-infected long-term bone marrow cultures impair hematopoiesis in vitro. Blood. 1994 Sep 1;84(5):1508-18

Chaganti SR, Chen W, Parsa N, Offit K, Louie DC, Dalla-Favera R, Chaganti RS. Involvement of BCL6 in chromosomal aberrations affecting band 3q27 in B-cell non-Hodgkin

lymphoma. Genes Chromosomes Cancer. 1998 Dec;23(4):323-7

Chaganti SR, Rao PH, Chen W, Dyomin V, Jhanwar SC, Parsa NZ, Dalla-Favera R, Chaganti RS. Deregulation of BCL6 in non-Hodgkin lymphoma by insertion of IGH sequences in complex translocations involving band 3q27. Genes Chromosomes Cancer. 1998 Dec;23(4):328-36

Siebert R, Matthiesen P, Harder S, Zhang Y, Borowski A, Zühlke-Jenisch R, Metzke S, Joos S, Weber-Matthiesen K, Grote W, Schlegelberger B. Application of interphase fluorescence in situ Hybridization for the detection of the Burkitt translocation t(8;14)(q24;q32) in B-cell lymphomas. Blood. 1998 Feb 1;91(3):984-90

Bentz M, Stilgenbauer S, Lichter P, Döhner H. Interphase FISH in chronic lymphoproliferative disorders and comparative genomic hybridisation in the study of lymphomas. Haematologica. 1999 Jun;84 Suppl EHA-4:102-6

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999 Dec;17(12):3835-49

Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Müller-Hermelink K, Feller A, Heinz R. Clinicopathogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-Lymphoma Study Group. Blood. 1999 Nov 1;94(9):3114-20

Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Milani R, Bardi A, Minotto C, Agostini P, De Angeli C, Narducci MG, Sabbioni S, Russo G, Negrini M, Castoldi G. Acquired chromosome 11q deletion involving the ataxia teleangiectasia locus in B-cell non-Hodgkin's lymphoma: correlation with clinicobiologic features. J Clin Oncol. 2000 Jul;18(13):2607-14


Cuneo A, Castoldi GL. Diffuse large cell lymphoma. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):83-84.



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Lymphoplasmacytic lymphoma Antonio Cuneo, Gian Luigi Castoldi



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/LPLID2074.html DOI: 10.4267/2042/37625


Clinics and pathology Disease Lymphoplasmacytic lymphoma (LPL) includes most cases of Waldenstrom's macroglobulinemia and consists of a diffuse proliferation of small lymphocytes, plasmacytoid lymphocytes and plasma cells; the typical histologic features of small lymphocytic lymphoma, mantle cell lymphoma and marginal zone lymphoma must be absent.

Phenotype/cell stem origin B-cell antigens are positive; whereas CD5 and, usually, CD23 test negative; the cells express surface and cytoplasmic IgM and are IgD-. CD10 is negative, whereas a proportion of cases have faint CD25 and CD11c expression; the postulated normal counterpart is a B-lymphocyte differentiating into an IgM-secreting plasma cell.

Cytogenetics Note The number of cases studied is small and the interpretation of data must take into account possible variability of histologic classification.

Cytogenetics morphological The t(9;14)(p13;q32), fusing the IgH gene with the BSAP (B-cell specific activator protein), also called PAX5, was found in 50% of the cases in a study; this balanced translocation cannot be viewed as specific for this lymphoma, having been reported in rare marginal zone lymphomas and large cell lymphomas. Other recurrent anomalies include 14q32 translocations with 8q24 (t(8;14)(q24;q32)), 18q21 (t(14;18)(q32;q21)), trisomies of chromosomes 3 (+3) and 12 (+12) and an isochromosome 6p (i(6p))

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

Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994 Sep 1;84(5):1361-92

Panayiotidis P, Kotsi P. Genetics of small lymphocyte disorders. Semin Hematol. 1999 Apr;36(2):171-7


Cuneo A, Castoldi GL. Lymphoplasmacytic lymphoma. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):85.



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Small lymphocytic lymphoma Antonio Cuneo, Gian Luigi Castoldi



Online updated version : http://AtlasGeneticsOncology.org/Anomalies/SLLID2073.html DOI: 10.4267/2042/37626


Clinics and pathology Disease Small lymphocytic lymphoma (SLL) represents the lymphomatous counterpart of B-cell chronic lymphocytic leukemia.

Phenotype/cell stem origin The typical cases have faint surface IgM/IgD expression with k/l light chain restriction; pan-B antigens are positive, but CD22 expression is weak. CD5 and CD23 test positive, whereas CD10 and FMC7 are negative; the expression of CD11c and CD25 is variable; the postulated normal counterpart is a peripheral CD5+/CD23+ B cell; based on the presence/absence of the CD38 antigen, a distinction was suggested for CLL, that may potentially apply also to SLL, between virgin B-cells that have not encoutered the antigen and cells harbouring somatic hypermutation of the Ig-gene variable region, corresponding to post-germinal memory-B cells.

Epidemiology Accounts for 5-10% of NHL.

Clinics The disease usually presents with bone marrow and peripheral blood (PB) involvement and typically runs an indolent course; transformation into diffuse large cell lymphoma (Richter's syndrome) may occur.

Pathology Enlarged lymph nodes show an infiltrate consisting of a majority of small lymphocytes with clumped chromatin and inconspicuous nucleolus; larger cells (prolymphocytes and paraimmunoblasts) are also present, usually clustered in pseudo-follicles, referred to as "proliferation centres"; in some cases having the

histologic features of SLL, the cells may have plasmacytoid differentiation with cytoplasmic Ig and a paraprotein (monoclonal component) may be found in the serum; plasmacytoid differentiation, corresponding to many cases included in the category "immunocytoma, lymphoplasmacytoid type" in the Kiel classsification does not constitute at the present time an indication of a different disease and should not be confused with the "lymphoplasmacytoid lymphoma", corresponding to most cases of Waldenstrom's macroglobulinemia, the prognostic impact of plasmacytic differentiation in SLL remains a subject for research.

Cytogenetics Note - Relatively few studies were performed on lymph node material; though it is reasonable to assume that a similar profile of molecular cytogenetic lesions may characterize SLL and CLL no formal proof that this is really the case was provided; data here summarized refer to those cases diagnosed as SLL and do not take into account the data described in CLL. - A chromosome anomaly was detected by cytogenetics in 60-90% of the cases.

Cytogenetics morphological Trisomy 12 was seen in 10-30% of the cases and other trisomies, involving chromosomes 3 (+3) and 18 (+18) in approximately 10% of the cases; Deletions/translocations 6q21-23 were detected in 15-25% of the cases and they showed a correlation with leukemic involvement by large prolymphocytoid cells; Structural changes of 11q, mostly deletions involving the q22-23 segment (del(11q)) were detected in 10-20% of the cases and structural anomalies of 12p13 in 10% of the cases in one study;

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The t(14;19)(q32;q13.3), deletions/translocations 14q22 and the t(11,14)(q13;q32) were reported in several cases; other chromosome 14q32 translocations with 1p32 and other unknown partners may be found in SLL; in general, those cases with a 14q anomaly require a precise histologic characterization because their distinction from mantle cell lymphomas and marginal zone B-cell lymphomas may pose difficult diagnostic problems; FISH studies found an approximate 50% incidence for cryptic 13q14 deletions and a 5-10% incidence for 17p13 deletions (advanced disease).

Cytogenetics molecular Molecular cytogenetic lesions and methods for detection: the following associations were proposed: 6q21-q23: loss of a putative oncosuppressor gene; detection by FISH with 6q21 probe, CGH and LOH studies; 11q deletions: no study was specifically devoted to SLL; in CLL, ATM gene deletion with postulated loss of function in some cases; the most sensitive mean for detection is FISH with ATM-probes; SSCP and sequencing of exons with altered motility can be used for the demonstration of lesions of the remaining ATM allele; 13q14 deletions: putative oncosuppressor gene. FISH with probes mapping between the Rb and the D13S25 marker are ideal for the detection of small deletions. CGH is less sensitive; 17p13 deletions: loss of p53 function; detection is usually achieved by FISH with a p53 probe and SSCP and sequencing of exons with altered motility for the demonstration of lesions of the remaining allele; t(14;19): fusion of IgH and BCL3 (transcription factor); the translocation exchanges chromosome bands similar in size and banding pattern; FISH with chromosome painting is useful; southern blotting detects most BCL3 rearrangements; t(11;14)(q13;q32): fusion of IgH and BCL1/CCND1 (cyclin); dual-color FISH with BCL1 and IgH probes or

with probes proximal and distal to the BCL1 locus. PCR and southern blotting have limited application due to variability of the breakpoint location.

References Offit K, Parsa NZ, Gaidano G, Filippa DA, Louie D, Pan D, Jhanwar SC, Dalla-Favera R, Chaganti RS. 6q deletions define distinct clinico-pathologic subsets of non-Hodgkin's lymphoma. Blood. 1993 Oct 1;82(7):2157-62

Richardson C, Ward M, Podda S, Bank A. Mouse fetal liver cells lack functional amphotropic retroviral receptors. Blood. 1994 Jul 15;84(2):433-9

Whang Peng J, Knutsen T. Cytogenetics of non-Hodgkin's lymphomas. Magrath I (ed). The non-Hodgkin’s lymphomas, pp. 277-303; Arnold, London 1997.

Ong ST, Le Beau MM. Chromosomal abnormalities and molecular genetics of non-Hodgkin's lymphoma. Semin Oncol. 1998 Aug;25(4):447-60

Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Campioni D, Minotto C, Agostini P, Milani R, Bullrich F, Negrini M, Croce C, Castoldi G. 13q14 deletion in non-Hodgkin's lymphoma: correlation with clinicopathologic features. Haematologica. 1999 Jul;84(7):589-93

Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999 Dec;17(12):3835-49

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

Zhang Y, Matthiesen P, Harder S, Siebert R, Castoldi G, Calasanz MJ, Wong KF, Rosenwald A, Ott G, Atkin NB, Schlegelberger B. A 3-cM commonly deleted region in 6q21 in leukemias and lymphomas delineated by fluorescence in situ hybridization. Genes Chromosomes Cancer. 2000 Jan;27(1):52-8


Cuneo A, Castoldi GL. Small lymphocytic lymphoma. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):86-87.

Solid Tumour Section Mini Review


88



Soft tissue tumors: Synovial sarcoma Christine Pérot

Laboratoire de Cytogenetique, Hopital Saint-Antoine, Paris, France (CP)

Published in Atlas Database: February 2000

Online updated version : http://AtlasGeneticsOncology.org/Tumors/SynovSarcID5044.html DOI: 10.4267/2042/37628


Identity Phylum: Soft Tissue Tumors: Uncertain differentiation: Synovial sarcoma.

Alias : t(X;18)(p11.2;q11.2) in synovial sarcoma

t(X;18)(p11.2;q11.2) in synovial sarcoma G-banding - Courtesy Charles Bangs.

Clinics and pathology Epidemiology Rare soft tissue tumor, it accounts for up to 5 to 8% of soft tissue sarcomas, the fourth most common type of sarcoma after malignant fibrous histyocytoma, liposarcoma and rhabdomyosarcoma; the most common pediatric non rhabdomyosarcomatous soft tissue cancer; average incidence: 2,75 per 100000 population based on a canandian study.

Clinics Most prevalent in adolescents and young adults, it occurs primarily in the para-articular regions of the extremities, especially the lower ones; rarely, it is

encountered in various areas such as parapharyngeal region, abdominal wall, lung or cardiac tissue, ….

Pathology Well-defined, apparently unrelated to synovium (cf various rare localisations), it displays characteristics of concurrent epithelial and spindle cell proliferation; several types are recognized: two major ones: Biphasic, with epithelial and spindle cell components in various proportions and Monophasic fibrous type; Monophasic epithelial type is much less common; May also present as a poorly differentiated small cell neoplasm; diagnosis may be difficult especially for the two later.

Soft tissue tumors: Synovial sarcoma Pérot C


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In general, very few problems in diagnosis in the biphasic type, may be not ascertained in some instances even after immunohistochemical examination.

Treatment Complete surgical excision of the primary tumor is actually the basis of the treatment; the optimal treatment approach is to be determined as post operative radiotherapy and adjuvant chemotherapy may permit limb preserving surgery and limit local recurrence and (micro) metastasis disease (lung+++).

Prognosis Traditionnally has had a bad prognosis what either the biphasic or monophasic type, poorer in the poorly differentiated small cell neoplasm. EFS at 5 years: 45-60%; improved in a recent german study to 74% for children and adolescents; improvements in adults too. Recents prognostic studies to identify risk groups and adequate treatment strategies indicate that synovialosarcomas might not be uniformely high grade tumors.

Cytogenetics Cytogenetics Morphological A t(X;18)(p11.2;q11.2) is found in almost all synovial sarcomas (80%) whatsoever the histologic type may be; t(X;18)(p11.2;q11.2) seems to be specific: it is not found in other spindle cell sarcomas, and very rarely detected in other tumors as malignant fibrous histyocytoma or fibrosarcomas.

Cytogenetics Molecular Detectable by metaphasic and/or interphasic dual colour fluorescent in situ cytogenetics; hybridization combining centomere X or 18 probes with respectively 18 or X whole chromosome painting or YAC probes.

Additional anomalies Both numerical and structural anomalies are found in 50% of cases, numerical anomalies only in 20% (+7,+8,+12,+21,-3, -11, -14, -22) and structural.anomalies only in 20% (involving chromosomes 1, 3, 11, 12, 15, 17 and 21: tumors may be hypodiploid, pseudodiploid, hyperdiploid or near tetraploid without a common pattern; DNA flow cytometry study revealed poorer prognosis for aneuploid tumors.

Variants A few variants have been described, involving chromosomes 1, 3, 15 or 21,...; masked translocations were identified as t(5 ;18), t(X ;7) without chromosome X or 18 apparent involvement respectively.

Genes involved and proteins SYT (Synovial tumor) Location 18q11.2

DNA / RNA 3,7 kb mRNA.

Protein 387 amino acids; glutamin, prolin and glycin rich; three potential SH2 binding domains and one SH3; widely expressed, limited to cartlagenous and nervous tissues in early embryonal development; biological properties still unknown.

SSX1, SSX2, SSX4 (one case) (Synovial Sarcoma X) Location Xp11.2

DNA / RNA 1,6 kb mRNA.

Protein 188 amino acids; 81% homologie for SSX1 and SSX2; Kruppel associated box (KRAB) homology; restricted expression to testis and thyroid; biological properties still unknown.

Result of the chromosomal anomaly Hybrid Gene Description 5 prime SYT- 3 prime SSX1/2.

Fusion Protein Description Substitution of the 8 last amino acids of SYT by 78 amino acids of SSX, with exclusion of KRAB and one SH2 domain.

Oncogenesis The important role is that of the transcript situated on the der(X). RT-PCR diagnosis: there is a correlation between biphasic type and SYT/SSX1 variant (where SSX2 involvement is never detected), SYT/SSX2 is more common than SYT/SSX1 in monophasic one. SYT/SSX1 variant might be less favorable, associated with higher tumor proliferating rate and reduced overall survival (metastasis free survival 42% vs 80%).

References Limon J, Dal Cin P, Sandberg AA. Translocations involving the X chromosome in solid tumors: presentation of two sarcomas with t(X;18)(q13;p11). Cancer Genet Cytogenet. 1986 Sep;23(1):87-91

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Turc-Carel C, Dal Cin P, Limon J, Li F, Sandberg AA. Translocation X;18 in synovial sarcoma. Cancer Genet Cytogenet. 1986 Sep;23(1):93

Griffin CA, Emanuel BS. Translocation (X;18) in a synovial sarcoma. Cancer Genet Cytogenet. 1987 May;26(1):181-3

Smith S, Reeves BR, Wong L, Fisher C. A consistent chromosome translocation in synovial sarcoma. Cancer Genet Cytogenet. 1987 May;26(1):179-80

Turc-Carel C, Dal Cin P, Limon J, Rao U, Li FP, Corson JM, Zimmerman R, Parry DM, Cowan JM, Sandberg AA. Involvement of chromosome X in primary cytogenetic change in human neoplasia: nonrandom translocation in synovial sarcoma. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1981-5

Le Marc'hadour F, Pasquier B, Leroux D, Jacrot M. Mediastinal synovial sarcoma with t(X;18) Cancer Genet Cytogenet. 1991 Sep;55(2):265-7

Limon J, Mrozek K, Mandahl N, Nedoszytko B, Verhest A, Rys J, Niezabitowski A, Babinska M, Nosek H, Ochalek T. Cytogenetics of synovial sarcoma: presentation of ten new cases and review of the literature. Genes Chromosomes Cancer. 1991 Sep;3(5):338-45

Dal Cin P, Rao U, Jani-Sait S, Karakousis C, Sandberg AA. Chromosomes in the diagnosis of soft tissue tumors. I. Synovial sarcoma. Mod Pathol. 1992 Jul;5(4):357-62

Knight JC, Reeves BR, Kearney L, Monaco AP, Lehrach H, Cooper CS. Localization of the synovial sarcoma t(X;18)(p11.2;q11.2) breakpoint by fluorescence in situ hybridization. Hum Mol Genet. 1992 Nov;1(8):633-7

de Leeuw B, Berger W, Sinke RJ, Suijkerbuijk RF, Gilgenkrantz S, Geraghty MT, Valle D, Monaco AP, Lehrach H, Ropers HH. Identification of a yeast artificial chromosome (YAC) spanning the synovial sarcoma-specific t(X;18)(p11.2;q11.2) breakpoint. Genes Chromosomes Cancer. 1993 Mar;6(3):182-9

de Leeuw B, Suijkerbuijk RF, Balemans M, Sinke RJ, de Jong B, Molenaar WM, Meloni AM, Sandberg AA, Geraghty M, Hofker M. Sublocalization of the synovial sarcoma-associated t(X;18) chromosomal breakpoint in Xp11.2 using cosmid cloning and fluorescence in situ hybridization. Oncogene. 1993 Jun;8(6):1457-63

Clark J, Rocques PJ, Crew AJ, Gill S, Shipley J, Chan AM, Gusterson BA, Cooper CS. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat Genet. 1994 Aug;7(4):502-8

de Leeuw B, Suijkerbuijk RF, Olde Weghuis D, Meloni AM, Stenman G, Kindblom LG, Balemans M, van den Berg E, Molenaar WM, Sandberg AA. Distinct Xp11.2 breakpoint regions in synovial sarcoma revealed by metaphase and

interphase FISH: relationship to histologic subtypes. Cancer Genet Cytogenet. 1994 Apr;73(2):89-94

Shipley JM, Clark J, Crew AJ, Birdsall S, Rocques PJ, Gill S, Chelly J, Monaco AP, Abe S, Gusterson BA. The t(X;18)(p11.2;q11.2) translocation found in human synovial sarcomas involves two distinct loci on the X chromosome. Oncogene. 1994 May;9(5):1447-53

Shipley J, Crew J, Birdsall S, Gill S, Clark J, Fisher C, Kelsey A, Nojima T, Sonobe H, Cooper C, Gusterson B. Interphase fluorescence in situ hybridization and reverse transcription polymerase chain reaction as a diagnostic aid for synovial sarcoma. Am J Pathol. 1996 Feb;148(2):559-67

Fisher C. Synovial sarcoma. Ann Diagn Pathol. 1998 Dec;2(6):401-21

Geurts van Kessel A, de Bruijn D, Hermsen L, Janssen I, dos Santos NR, Willems R, Makkus L, Schreuder H, Veth R. Masked t(X;18)(p11;q11) in a biphasic synovial sarcoma revealed by FISH and RT-PCR. Genes Chromosomes Cancer. 1998 Oct;23(2):198-201

Kawai A, Woodruff J, Healey JH, Brennan MF, Antonescu CR, Ladanyi M. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med. 1998 Jan 15;338(3):153-60

Bergh P, Meis-Kindblom JM, Gherlinzoni F, Berlin O, Bacchini P, Bertoni F, Gunterberg B, Kindblom LG. Synovial sarcoma: identification of low and high risk groups. Cancer. 1999 Jun 15;85(12):2596-607

Ferrari A, Casanova M, Massimino M, Luksch R, Cefalo G, Lombardi F, Galimberti S, Riganti G, Fossati-Bellani F. Synovial sarcoma: report of a series of 25 consecutive children from a single institution. Med Pediatr Oncol. 1999 Jan;32(1):32-7

Nilsson G, Skytting B, Xie Y, Brodin B, Perfekt R, Mandahl N, Lundeberg J, Uhlén M, Larsson O. The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome. Cancer Res. 1999 Jul 1;59(13):3180-4

Skytting B, Nilsson G, Brodin B, Xie Y, Lundeberg J, Uhlén M, Larsson O. A novel fusion gene, SYT-SSX4, in synovial sarcoma. J Natl Cancer Inst. 1999 Jun 2;91(11):974-5

van de Rijn M, Barr FG, Collins MH, Xiong QB, Fisher C. Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma. Am J Clin Pathol. 1999 Jul;112(1):43-9


Pérot C. Soft tissue tumors: Synovial sarcoma. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):88-90.

Cancer Prone Disease Section Mini Review


91



Rhabdoid predisposition syndrome Nicolas Sévenet

Laboratoire de Pathologie Moleculaire des Cancers, INSERM U 509, Institut Curie, Paris, France (NS)

Published in Atlas Database: February 2000

Online updated version : http://AtlasGeneticsOncology.org/Kprones/rhabdKpronID10051.html DOI: 10.4267/2042/37629

This article is an update of : Huret JL. Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol.2000;4(1):49. 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 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.

Phenotype and clinics No apparent stigmata.

Neoplastic risk 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.

Genes involved and proteins hSNF5/INI1 Location

22q11.2

Mutations Germinal Found in this syndrome.

Somatic Mutation and allele loss events in sporadic rhabdoid tumors, primitive neurectodermal tumors, medulloblastoma, or choroid plexus carcinoma 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

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

Sévenet N, Lellouch-Tubiana A, Schofield D, Hoang-Xuan K, Gessler M, Birnbaum D, Jeanpierre C, Jouvet A, Delattre O. Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. Hum Mol Genet. 1999 Dec;8(13):2359-68

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


Sévenet N. Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):91.

Cancer Prone Disease Section Mini Review


92



Multiple endocrine neoplasia type 1 (MEN1) Alain Calender

Service de génétique moléculaire et médicale, hôpital Edouard-Herriot, bâtiment B7, 5, place d'Arsonval, 69437 Lyon 03, France (AC)


Online updated version : http://AtlasGeneticsOncology.org/Kprones/MEN1KproneID10008.html DOI: 10.4267/2042/37630


Identity Alias: Wermer's syndrome

Note: Multiple Endocrine Neoplasia type 1 or Wermer's syndrome (MEN1) is a complex disease predisposing to a variety of endocrine tumors multifocal and/or bilateral localization and uncommonly to non-endocrine tumors mainly of the skin and central nervous system.

Inheritance: An autosomal dominant disorder with high penetrance (increasing with age: 90% by age 50 years) but variable expressivity (with phenotype/genotype correlations); frequency is unkown but estimated between 1/50000 and 1/30000.

Clinics Phenotype and clinics Onset of the disease occurs commonly between 15 and 40 years and most patients (90-100%) present primary hyperparathyroidism related to multiglandular hyperplasia and/or adenomas; other endocrine lesions and relative percentages are neuroendocrine tumors of the pancreas (either functionnal such as gastrinomas, insulinoma, and more rarely glucagonoma, VIPoma or non functionnal) (50-70%), pituitary adenoma (20-40%), adrenocortical hyperplasia, adenomas or cancers (20-70%) and thymic/bronchial neuroendocrine tumors (5-10%); cutaneous lesions, such as angiofibromas, collagenomas, lentiginosis, melanocytic lesions and lipoma might occur in 5-10% of MEN1 patients; less common lesions are infratentorial papillary ependymoma, rhabdomyosarcoma and leiomyosarcoma, and renal and thyroid cancers.

Neoplastic risk Pancreatic neuroendocrine tumors such as gastrinoma have malignant evolution in 30 to 50% of the cases. Insulinoma might be frequently benign. Most agressive tumors are glucagonoma and VIPoma (VIP: vasoactive intestinal peptide) in pancreas and some tumors occuring in the adrenal cortex. Pituitary adenomas in MEN1 are classical benign lesions but complications might be related to local nervous compression by the tumor. Parathyroid adenomas in MEN1 remain benign lesions. Cutaneous and CNS (Central Nervous System) lesions in MEN1 might be malignant in a few cases. Strikingly, melanomas, ependymomas and rare astrocytomas observed in the MEN1 context have better prognosis than the same lesions occuring sporadically.

Treatment Parathyroids: the recommended procedure is 3 and half parathyroidectomy and cautious exploration of the thymic tissues in which ectopic adenomas and/or carcinoids (neuroendocrine tumors) have been described. Pancreas: in most cases (insulinoma, glucagonomas, > 2cm non functionnal tumors, surgery is a best procedure and might be duodenopancreactomy in the heavy cases; nevertheless, in gastrinomas and non functionnal small tumors identified by US endoscopy, the best procedure is the medical (antiacid) treatment and a careful follow-up of patients. Pituitary adenomas: the treatment is the same than for sporadic lesions. Adrenal glands tumors: surgery is the best recommended procedure when lesions are clearly identified by imagery.

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Thymic/bronchial carcinoids: they must be cured by surgery because they are malignant and alter prognosis in MEN1 patients.

Prognosis according to the severity of the disease in a given patient, and to the quality of a regular follow up; mean age at death is relatively similar to that of the general population; nevertheless, death may occur early in life (10 to 50 year) due to the complications of hormonal secretions by tumors (hemorrhagic ulcers, malignant hypercalcaemia, carcinoid syndromes) or evolution of the maligant process (pancreatic neuroendocrine tumors and thoracic carcinoids): 50 years; a presymptomatic diagnosis improves survival data and might prevent earlier the main causes of death in this disease.

Genes involved and proteins MEN1 Location 11q13

DNA/RNA Description: 10 exons. Transcription: Different splicing.

Protein Description: 610 amino-acids, 67 Kda; contains two nuclear localization signals. Expression: Wide. Function: Growth-suppressor gene.

Mutations Germinal: Causes multiple endocrine neoplasia type 1.

References WERMER P. ENDOCRINE ADENOMATOSIS AND PEPTIC ULCER IN A LARGE KINDRED. INHERITED MULTIPLE TUMORS AND MOSAIC PLEIOTROPISM IN MAN. Am J Med. 1963 Aug;35:205-12

Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature. 1988 Mar 3;332(6159):85-7

Shepherd JJ. The natural history of multiple endocrine neoplasia type 1. Highly uncommon or highly unrecognized? Arch Surg. 1991 Aug;126(8):935-52

Skogseid B, Rastad J, Gobl A, Larsson C, Backlin K, Juhlin C, Akerström G, Oberg K. Adrenal lesion in multiple endocrine neoplasia type 1. Surgery. 1995 Dec;118(6):1077-82

Kato H, Uchimura I, Morohoshi M, Fujisawa K, Kobayashi Y, Numano F, Goseki N, Endo M, Tamura A, Nagashima C. Multiple endocrine neoplasia type 1 associated with spinal ependymoma. Intern Med. 1996 Apr;35(4):285-9

Trump D, Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, Edwards CR, Heath DA, Jackson CE, Jansen S, Lips K, Monson JP, O'Halloran D, Sampson J, Shalet SM, Wheeler MH, Zink A, Thakker RV. Clinical studies of multiple

endocrine neoplasia type 1 (MEN1) QJM. 1996 Sep;89(9):653-69

Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC, Doppman JL, Kim YS, Lubensky IA, Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi SE, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet. 1997 Jul;6(7):1169-75

Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404-7

Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol. 1997 Jul;133(7):853-7

Giraud S, Choplin H, Teh BT, Lespinasse J, Jouvet A, Labat-Moleur F, Lenoir G, Hamon B, Hamon P, Calender A. A large multiple endocrine neoplasia type 1 family with clinical expression suggestive of anticipation. J Clin Endocrinol Metab. 1997 Oct;82(10):3487-92

Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol. 1997 Apr;9(2):240-6

Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Pugeat M, Calender A, Parente F, Quincey D, Gaudray P, De Wit MJ, Lips CJ, Höppener JW, Khodaei S, Grant AL, Weber G, Kytölä S, Teh BT, Farnebo F, Thakker RV. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet. 1997 Jul;6(7):1177-83

Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH, Thakker RV. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet. 1998 Feb;62(2):232-44

Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, Mignon M. [Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Study Group of Multiple Endocrine Neoplasia (GENEM)]. Ann Endocrinol (Paris). 1998;59(6):444-51

Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem MC, Assayag M, Peix JL, Pugeat M, Rohmer V, Vallotton M, Lenoir G, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A, Calender A. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet. 1998 Aug;63(2):455-67

Proye C, Carnaille B, Quievreux JL, Combemale F, Oudar C, Lecomte-Houcke M. Late outcome of 304 consecutive patients with multiple gland enlargement in primary hyperparathyroidism treated by conservative surgery. World J Surg. 1998 Jun;22(6):526-9; discussion 529-30

Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins



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G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Salmela P. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab. 1998 Aug;83(8):2621-6

Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 1999 Jan 8;96(1):143-52

Huang SC, Zhuang Z, Weil RJ, Pack S, Wang C, Krutzsch HC, Pham TA, Lubensky IA. Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin. Lab Invest. 1999 Mar;79(3):301-10


Calender A. Multiple endocrine neoplasia type 1 (MEN1). Atlas Genet Cytogenet Oncol Haematol. 2000; 4(2):92-94.



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