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Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), 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]

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Database Director of the on-line version Philippe Dessen (Villejuif, France)

Chairman of the on-line version Alain Bernheim (Villejuif, France)

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 4 times a year by ARMGHM, a non profit organisation.

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

Atlas Genet Cytogenet Oncol Haematol. 2006;10(3)



Editor-in-Chief

Jean-Loup Huret (Poitiers, France)

Editorial Board Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukemia Sections Vasantha Brito-Babapulle (London, UK) Leukemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Anne Marie Capodano (Marseille, France) Solid Tumors Section Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections Antonio Cuneo (Ferrara, Italy) Leukemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumors Sections Louis Dallaire (Montreal, Canada) Education Section François Desangles (Paris, France) Leukemia / Solid Tumors Sections Gordon Dewald (Rochester, Minnesota) Leukemia / Deep Insights Sections Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Oskar Haas (Vienna, Austria) Genes / Leukemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumors Section Lisa Lee-Jones (Newcastle, UK) Solid Tumors Section Edmond Ma (Hong Kong, China) Leukemia Section Cristina Mecucci (Perugia, Italy) Genes / Leukemia Sections Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section Fredrik Mertens (Lund, Sweden) Solid Tumors Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukemia Section Florence Pedeutour (Nice, France) Genes / Solid Tumors Sections Susana Raimondi (Memphis, Tennesse) Genes / Leukemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumors Section Franck Viguié (Paris, France) Leukemia Section Thomas Wan (Hong Kong, China) Genes / Leukemia Sections Bernhard Weber (Würzburg, Germany) Education Section




Volume 10, Number 3, July-September 2006

Table of contents

Gene Section HMGA2 (high mobility group AT-hook 2) 142 Karin Broberg

JJAZ1 (joined to JAZF1) 149 Hildegard Kehrer-Sawatzki

MYST3 (MYST histone acetyltransferase (monocytic le ukemia) 3 151 Jean-Loup Huret, Sylvie Senon

PLCB1 (phospholipase C, beta 1 (phosphoinositide-sp ecific)) 154 Matilde Y Follo, Vincenza Rita Lo Vasco, Giovanni Martinelli, Giandomenico Palka, Lucio Cocco

PMS1 (PMS1 postmeiotic segregation increased 1 (S. cerevisiae)) 157 Enric Domingo, Simó Schwartz Jr

PKD1 (protein kinase D1) 159 Cheng Du, Meena Jaggi, Wenguang Zhang, KC Balaji

THBS2 (thrombospondin-2) 161 Elizabeth M Perruccio, David D Roberts

BAALC (brain and acute leukemia, cytoplasmic) 166 Jean-Loup Huret, Sylvie Senon

MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kD a gelatinase, 92kDa type IV collagenase)) 168 Deepak Pralhad Patil, Gopal Chandra Kundu

NF1 (neurofibromin 1) 171 Katharina Wimmer

RCHY1 (ring finger and CHY zinc finger domain conta ining 1) 173 Wenrui Duan, Miguel A Villalona-Calero

Leukaemia Section Follicular lymphoma (FL) 175 Antonio Cuneo, Antonella Russo Rossi, Gianluigi Castoldi

Mucosa-associated lymphoid tissue (MALT) lymphoma 177 Antonio Cuneo, Gianluigi Castoldi

Marginal zone B-cell lymphoma 180 Antonio Cuneo, Gianluigi Castoldi

M3/M3v acute non lymphocytic leukemia (M3-ANLL) 184 M3/M3v acute myeloid leukemia (AML M3/M3v) Acute promyelocytic leukemia (APL) Claudia Schoch

t(10;11)(p11.2;q23) 186 Cristina Morerio, Claudio Panarello




t(5;14)(q33;q32) PDGFRB/KIAA1509 188 Jean-Loup Huret

t(5;15)(q33;q22) 189 Jean-Loup Huret

t(7;8)(q34;p11) 190 Elena Belloni, Francesco Lo Coco, Pier Giuseppe Pelicci

t(1;21)(p36;q22) 194 Marian Stevens-Kroef

t(3;16)(q27;p13) 197 Jean-Loup Huret

t(4;16)(q26;p13) 198 Jean-Loup Huret

t(11;20)(q23;q11) 199 Jen-Fen Fu, Lee-Yung Shih

Solid Tumour Section Liver adenoma 201 Jessica Zucman-Rossi

Cancer Prone Disease Section Birt-Hogg-Dubé Syndrome (BHD) 203 Benedetta Toschi, Maurizio Genuardi

Neurofibromatosis type 1 (NF1) 206 Katharina Wimmer

Familial liver adenomatosis 208 Jessica Zucman-Rossi

Deep Insight Section Ethical issues in cancer genetics 210 Robert Roger Lebel

Gene Section Review

Atlas Genet Cytogenet Oncol Haematol. 2006;10(3) 142



HMGA2 (high mobility group AT-hook 2) Karin Broberg

Department of Occupational and Environmental Medicine, Lund University Hospital, Lund, Sweden

Published in Atlas Database: December 2005

Online updated version: http://AtlasGeneticsOncology.org/Genes/HMGICID82.html DOI: 10.4267/2042/38311

This article is an update of: Pedeutour F. HMGIC (high mobility group protein isoform I-C). Atlas Genet Cytogenet Oncol Haematol.2000;4(2):60-63. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Hugo: HMGA2 Other names: HMGIC (High mobility group protein isoform I-C) Location: 12q15 Local order: telomeric to CDK4, centromeric to MDM2.

Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA Description 5 exons, spans approximately 160 kb; a sixth alternative terminal exon within intron 3 has been described.

Transcription RNA: 4.1 kb. Transcription initiated from two different promoter regions. A polymorphic dinucleotide repeat upstream of the ATG start codon strongly regulates HMGA2 expression. Moreover, HMGA2 is controlled by negatively acting regulatory elements within the 3'UTR.

HMGA2 (high mobility group AT-hook 2) Oberg K


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; expressed in malignant tumours (e.g., in breast tumours, pancreas tumours, lung tumours, nerve system tumours, oral cavity tumours).

Localisation Nuclear.

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; mice with a partial or complete deficiency of HMGA2 resisted diet-induced obesity implicating a role of the gene in fat cell proliferation; truncations of mouse Hmga2 in transgenic mice result in somatic overgrowth and, in particular, increased abundance of fat and lipomas; overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituary adenomas secreting prolactic and growth hormone; HMGA2-null mice had very few spermatids and complete absence of spermatozoa. 8-year-old boy had a de novo pericentric inversion of chromosome 12, with breakpoints at p11.22 and q14.3. The phenotype included extreme somatic overgrowth, advanced endochondral bone and dental ages, a cerebellar tumour, and multiple lipomas. His

chromosomal inversion was found to truncate HMGA2, which maps to the 12q14.3 breakpoint.

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, 2, 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 preferred 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; one lipoma displayed fusion of HMGA2 exon 4 with a sequence from intron 4, indicating abnormal splicing; HMGA2 - CMKOR1 in three cases with aberrations involving 2q35-37 and 12q13-15; HMGA2 - NFIB in one 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 HMGA2-LPP fusion is not established yet, but the transactivation functions of the LPP LIM domains are retained in the fusion protein and the fusion protein can function as a transcription factor; the truncation of HMGA2 by itself 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 two cases (out of 81 primary tumors) exon 7 of RAD51B was fused in frame to either exon 2 or 3 of the HMGA2 gene; 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; three fusion transcripts contained 3' cryptic exonic sequences present in intron 3 of the HMGA2 gene (breakpoints downstream of exons 3 or 4), suggesting that they are due to alternative splicing; one case displayed fusion of the first two exons of HMGA2 to the 3' portion of the CCNB1IP1/C14orf18/HEI10 gene

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.

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 cases with t(3;12)(q27-28;q14-15) (see lipomas), a fusion of HMGA2-LPP was described; only 1/61 cases with normal karyotype displayed HMGA2-LPP fusion; three cases with rearrangements involving 12q14-15 and 13q12-14 lacked rearrangements of HMGA2-LHFP.



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.

Chondrolipoangioma Disease A rare benign type of mesenchyomas composed predominantly of cartilage and adipose tissue with vascular elements and myxoid elements.

Cytogenetics One case demonstrated t(12;15)(q13;q26). FISH analysis revealed rearrangement of chromosomes 2, 12 and 15 and HMGA2.

Chondromas Disease Benign cartilage tumours.

Cytogenetics HMGA2 was expressed in 4/6 soft tissue chondromas (all with 12q-rearrangements cytogenetically), three cases showed truncated (exons 1-3) transcripts, one case displayed a t(3;12)(q27;q15) and RT-PCR demonstrated a HMGA2-LPP fusion transcript composed of HMGA2 exons 1-3 and LPP exons 9-11.

Hyaline vascular Castleman's disease Cytogenetics one case with der(6)t(6;12)(q23;q15)del(12)(q15) is described.

Hybrid/Mutated Gene A combined immunologic-cytogenetic approach demonstrated HMGA2 rearrangement in follicular dendritic cells.

Prolactinoma Disease Prolactin-secreting pituary adenoma, non-metastasizing.

Cytogenetics Trisomy 12 nonrandom finding in pituary adenomas.

Hybrid/Mutated Gene HMGA2 locus amplified in 7/8 prolactinomas.

Aggressive angiomyxoma of the vulva Disease Myxoid mesenchymal neoplasm.

Prognosis Infiltrative neoplasm, locally destructive recurrences, no metastatic potential.

Cytogenetics One case displayed t(8;12)(p12;q15).

Hybrid/Mutated Gene FISH demonstrated a breakpoint 3' of the gene, the tumour expressed HMGA2.

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; rearrangement of HMGA2, in addition to amplification has been described.

Hybrid/Mutated Gene Ectopic sequences from 12q14-15, 1q24, 11q14, and chromosome 2 was shown to be fused to HMGA2 exon 2 or 3.

Uterine leiomyosarcoma Disease Malignant counterpart of uterine leiomyoma.

Prognosis Poor.



Cytogenetics 12q13-15 region is recurrently amplified.

Hybrid/Mutated Gene HMGA2 amplified within this region.

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.

Myelofibrosis with myeloid metaplasia Disease Rare chronic myeloproliferative disorder. Prognosis Variable.

Cytogenetics

One case with t(4;12)(q32;q15) and one case with t(5;12)(p14;q15).

Hybrid/Mutated Gene FISH analysis suggested breakpoint in HMGA2, RT-PCR revealed that HMGA2 is expressed in blood mononuclear cells from patients with this disease.

Acute lymphoblastic leukaemia Disease Heterogenous disease that arises in precursor B or T cells.

Cytogenetics One case with a t(9;12)(p22;q14), frequent deletions at 12q14.3.

Hybrid/Mutated Gene t(9;12): FISH analysis indicated a breakpoint in the 5' region of the gene, RT-PCR showed overexpression of HMGA2 lacking the carboxyterminal tail; deletions covering the 5' end of HMGA2.

Breakpoints

References Ashar HR, Schoenberg Fejzo M, Tkachenko A, Zhou X, Fletcher JA, et al. Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell 1995;82:57-65.

Kazmierczak B, Hennig Y, Wanschura S, Rogalla P, Bartnizke S, Van de Ven WJM, et al. 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;55:6038-6039.

Schoenmakers EFPM, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJM. Recurrent

rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumors. Nature Genet 1995;10:436-444.

Zhou X, Benson KF, Ashar HR, Chada K. Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature 1995;376:771-774.

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;38:223-226.



Kools PF, Van de Ven JM. Amplification of a rearranged form of the high mobility group protein gene HMGIC in OSA-Cl osteosarcoma cells. Cancer Genet Cytogenet 1996;911-917.

Petit MMR, Mols R, Schoenmakers EFPM, Mandahl N, Van de Ven WJM. LPP, the preferred fusion partner gene of HMGI-C in lipomas, is a novel member of the LIM protein gene family. Genomics 1996;36:118-129.

Schoenberg Fejzo M, Ashar HR, Krauter KS Powell WL, Rein MS, Weremowicz S, et al. 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;17:1-6.

Wanschura S, Dal Cin P, Kazmierczak B, Barnitzke S, Van den berghe H, Bullerdiek J. Hidden paracentric inversions of chromosome arm 12 q affecting the HMGIC gene. Genes Chromosomes Cancer 1997;18:322-323.

Hess JL. Chromosomal translocations in benign tumors. The HMGI proteins. Am J Clin Pathol 1998;109:251-261 (Review).

Rogalla P, Kazmierczak B, Meyer-Bolte K, tran KH, Bullerdiek J. The t(3;12)(q27 ;q14-15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype. Genes Chromosomes Cancer 1998;22:100-104.

Gattas GJ, Quade BJ, Nowak RA, Morton CC. HMGIC expression in human adult and fetal tissues and in uterine leiomyomata. Genes Chromosomes Cancer 1999;254:316-322.

Kazmierczak B, Dal Cin P, Sciot R, Van den Berghe H, Bullerdiek J. Inflammatory myofibroblastic tumor with HMGIC rearrangement. Cancer Genet Cytogenet 1999;112:156-160.

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

Anand A, Chada K. In vivo modulation of Hmgic reduces obesity. Nat Genet 2000;24:377-380.

Arlotta P, Tai AK, Manfioletti G. et al. 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;275:14394-1400.

Kurose K, Mine N, Doi D, Ota Y, Yoneyama K, Konoshi H, Araki T, Emi M. Novel gene fusion of COX6C at 8q22-23 to HMGIC at 8q22-23 to HMGIC in a uterine leiomyoma. Genes Chromosomes Cancer 2000;27:303-307.

Borrmann L, Wilkening S, Bullerdiek J. The expression of HMGA genes is regulated by their 3'UTR. Oncogene 2001;20:4537-4541.

Hauke S, Rippe V, Bullerdiek J. Chromosomal rearrangements leading to abnormal splicing within intron 4 of HMGIC?. Genes Chromosomes Cancer 2001;30:302-304.

Kurose K, Mine N, Iida A. et al. Three aberrant splicing variants of the HMGIC gene transcribed in uterine leiomyomas. Genes Chromosomes Cancer 2001;30:212-217.

Meza-Zepeda LA, Berner JM, Henriksen J. Ectopic sequences from truncated HMGIC in liposarcomas are derived from various amplified chromosomal regions. Genes Chromosomes Cancer 2001;31:264-273.

Mine N, Kurose K, Konishi H. et al. Fusion of a sequence from HEI10 (14q11) to the HMGIC gene at 12q15 in a uterine leiomyoma. Jpn J Cancer Res 2001;92:135-139.

Nucci MR,Weremowicz S, Neskey DM. et al. Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. Genes Chromosomes Cancer 2001;32:172-176.

Takahashi T, Nagai N, Oda H. et al. Evidence for RAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma. Genes Chromosomes Cance 2001;30:196-201.

Broberg K, Zhang M, Strömbeck B. et al. Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15. Int J Oncol 2002;21:321-326.

Chieffi P, Battista S, Barchi M. et al. HMGA1 and HMGA2 protein expression in mouse spermatogenesis. Oncogene 2002;21:3644-3650.

Cokelaere K, Debiec-Rychter M, De Wolf-Peeters C. et al. Hyaline vascular Castleman's disease with HMGIC rearrangement in follicular dendritic cells: molecular evidence of mesenchymal tumorigenesis. Am J Surg Pathol 2002;26:662-669.

Fedele M, Battista S, Kenyon L. et al. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene 2002;21:3190-3198.

Finelli P, Pierantoni GM, Giardino D. et al. The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas. Cancer Res 2002;62:2398-2405.

Hauke S, Flohr AM, Rogalla P. et al. Sequencing of intron 3 of HMGA2 uncovers the existence of a novel exon. Genes Chromosomes Cancer 2002;34:17-23.

Lemke I, Rogalla P, Grundmann F. et al. Expression of the HMGA2-LPP fusion transcript in only 1 of 61 karyotypically normal pulmonary chondroid hamartomas. Cancer Genet Cytogenet 2002;138:160-164.

Rogalla P, Lemke I, Bullerdiek J. Absence of HMGIC-LHFP fusion in pulmonary chondroid hamartomas with aberrations involving chromosomal regions 12q13 through 15 and 13q12 through q14. Cancer Genet Cytogenet 2002;133:90-93.

Van Dorpe J, Dal Cin P,Weremowicz S. et al. Translocation of the HMGI-C ( HMGA2) gene in a benign mesenchymoma (chondrolipoangioma). Virchows Arch 2002;440:485-490.

Abe N, Watanabe T, Suzuki Y. et al. An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue. Br J Cancer 2003;89:2104-2109.

Borrmann L, Seebeck B, Rogalla P. et al. Human HMGA2 promoter is coregulated by a polymorphic dinucleotide (TC)-repeat. Oncogene 2003;22:56-60.

Dahlen A, Mertens F, Rydholm A. et al. Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol 2003;16:1132-1140.

Pierantoni GM, Santulli B, Caliendo I. et al. HMGA2 locus rearrangement in a case of acute lymphoblastic leukemia. Int J Oncol 2003;23:363-367.

Quade BJ, Weremowicz S, Neskey DM. et al. Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Cancer Res 2003;63:1351-1358.

Akai T, Ueda Y, Sasagawa Y. et al. High mobility group I-C protein in astrocytoma and glioblastoma. Pathol Res Pract 2004;200:619-624.

Andrieux J, Demory JL, Dupriez B. et al. Dysregulation and overexpression of HMGA2 in myelofibrosis with myeloid metaplasia. Genes Chromosomes Cancer 2004;39:82-87.

Cerignoli F, Ambrosi C, Mellone M. HMGA molecules in neuroblastic tumors. Ann N Y Acad Sci 2004;1028:122-132.

Miyazawa J, Mitoro A, Kawashiri S. et al. Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res 2004;64:2024-2029.

Cho YL, Bae S, Koo MS. Et al. Array comparative genomic hybridization analysis of uterine leiomyosarcoma. Gynecol Oncol 2005;99:545-551.

Crombez KR, Vanoirbeek EM, Van de Ven WJ. et al. Transactivation functions of the tumor-specific HMGA2/LPP fusion protein are augmented by wild-type HMGA2. Mol Cancer Res 2005;3:63-70.



Hui P, Li N, Johnson C. et al. HMGA proteins in malignant peripheral nerve sheath tumor and synovial sarcoma: preferential expression of HMGA2 in malignant peripheral nerve sheath tumor. Mod Pathol 2005;18:1519-1526.

Ligon AH, Moore SD, Parisi MA. Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. Am J Hum Genet 2005;76:340-348.

Nilsson M, Panagopoulos I, Mertens F. et al. Fusion of the HMGA2 and NFIB genes in lipoma. Virchows Arch 2005;447:855-858.

Patel HS, Kantarjian HM, Bueso-Ramos CE. Et al. Frequent deletions at 12q14.3 chromosomal locus in adult acute lymphoblastic leukemia. Genes Chromosomes Cancer 2005;42:87-94.

This article should be referenced as such: Broberg K. HMGA2 (high mobility group AT-hook 2). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):142-148.

Gene Section Short Communication




JJAZ1 (joined to JAZF1) Hildegard Kehrer-Sawatzki

Department of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany


Online updated version: http://AtlasGeneticsOncology.org/Genes/JJAZ1ID41039ch17q11.html DOI: 10.4267/2042/38312

This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Hugo: SUZ12 Other names: KIAA0160; CHET9 Location: 17q11.2

DNA/RNA Description 16 exons; spans 64 kb.

Transcription 4,441 kb cDNA.

Pseudogene Yes, also located in 17q11.2, contains exons 1-9.

Protein Description 739 amino acids.

Expression Tissue and stage specifically expressed; expression is noted in embryonic, juvenile and adult tissues. The tissues or organs that express SUZ12 are: bladder, blood, bone, bone marrow, brain, cervix, colon, eye, heart, kidney, liver, lung, lymph node, mammary gland, muscle, ovary, pancreas, peripheral nervous system, placenta, prostate, skin, soft tissue, stomach, tongue, testis, uterus, and the vascular system.

Localisation Nucleus.

Function SUZ12 is a zinc finger protein and member of the polycomb group (PcG) protein family. They act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of

homeotic genes throughout development. PcG proteins are required to maintain the repression during later stages of development. They probably act via the methylation of histones, rendering chromatin heritably changed in its expressibility. SUZ12 is a component of the PRC2 complex, which methylates Lys-9 and Lys-27 residues of histone H3. SUZ12 is induced by E2F1 transcription factor.

Homology Polycomb group of proteins.

Mutations Germinal Deleted in patients with Neurofibromatosis type 1 and large deletions in the NF1 gene region type-1 (spanning 1.4 Mb).

Somatic Disrupted by deletion breakpoints of Neurofibromatosis type 1 patients with deletions that span 1.2 Mb (type-2 deletions). JJAZ1/SUZ12 has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma and the translocation mediated recombination of both leads to a JJAZ1/JAZF1 fusion gene.

Implicated in Endometrial stromal neoplasms with classic histology Cytogenetics Nonrandom t(7;17)(p15;q21) in endometrial stromal neoplasms.

Hybrid/Mutated Gene JJAZ1/JAZF1 fusion gene.

JJAZ1 (joined to JAZF1) hrer-Sawatzki H


Abnormal Protein Unknown.

Oncogenesis Unknown.

References Hrzenjak A, Moinfar F, Tavassoli FA, Strohmeier B, Kremser ML, Zatloukal K, Denk H. JAZF1/JJAZ1 gene fusion in endometrial stromal sarcomas: molecular analysis by reverse transcriptase-polymerase chain reaction optimized for paraffin-embedded tissue. J Mol Diagn 2005;7(3):388-395. (Review).

Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF. High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet 2004;75(3):410-423.

Huang HY, Ladanyi M, Soslow RA. Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology: evidence for genetic heterogeneity. Am J Surg Pathol 2004;28(2):224-232.

Micci F, Walter CU, Teixeira MR, Panagopoulos I, Bjerkehagen B, Saeter G, Heim S. Cytogenetic and molecular genetic analyses of endometrial stromal sarcoma: nonrandom involvement of chromosome arms 6p and 7p and confirmation of JAZF1/JJAZ1 gene fusion in t(7;17). Cancer Genet Cytogenet 2003;144(2):119-124.

Petek E, Jenne DE, Smolle J, Binder B, Lasinger W, Windpassinger C, Wagner K, Kroisel PM, Kehrer-Sawatzki H. Mitotic recombination mediated by the JJAZF1 (KIAA0160) gene causing somatic mosaicism and a new type of constitutional NF1 microdeletion in two children of a mosaic female with only few manifestations. J Med Genet 2003;40(7):520-525.

Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Cin PD, Fletcher JA, Sklar J. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci USA 2001;98(11):6348-6353.

This article should be referenced as such: Kehrer-Sawatzki H. JJAZ1 (joined to JAZF1). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):149-150.

Gene Section Mini Review




MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3 Jean-Loup Huret, Sylvie Senon

Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France


Online updated version: http://AtlasGeneticsOncology.org/Genes/MYST3ID25ch8p11.html DOI: 10.4267/2042/38313


Identity Hugo: MYST3 Other names: MOZ (monocytic leukemia zinc finger); ZNF220; RUNXBP2 Location: 8p11

DNA/RNA Description The gene spans121 kb on minus strand; 17 exons.

Transcription 7.85 kb.

Protein Description 2004 amino acids; 225 kDa; composed from N-term of: a NEMM domain (N-term region of ENOK, MOZ or MORF) including a H15 (linker H1 and H5 like) nuclear localization domain, 2 PHD (plant homeodomain, also known as LAP (leukemia

associated protein)) Zn fingers (C4HC3), a C2HC Zn finger, essential part of the histone acyl transferase domain (HAT MOZ-SAS), an acidic (Glu-Asp) domain, localisation of breakpoints in the inv(8) and in the t(8;22) in 1118, and a Ser-(Pro-Glu)-Met rich domain, localisation of the t(8;16) breakpoint in 1547.

Localisation Nucleus.

Function Lysine acetyltransferase activity (histone acyl transferase); MYST3 (MOZ) and MYST4 (MORF) possess both transcription activation and transcription repression domains; transcriptional regulators; interact with RUNX1 and RUNX2; Moz, the zebrafish ortholog of MYST3, was also found to regulate Hox expression; Moz behaves like a trithorax group factor.

Homology With MYST4 (MORF) (monocytic leukemia zinc finger protein-related factor), a transcription regulator with positive and negative domains and activities.

MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3 Huret JL, Senon S


Implicated in t(2;8)(p23;p11) in therapy related myelodysplastic syndrom → MYST3 / ? Disease Only 1 case to date, a boy aged 6 years.

inv(8)(p11q13) in acute myelomonocytic or monocytic leukaemia (M4 or M5 AML) → MYST3 / NCOA2 Disease Erythrophagocytosis; very rare: less than 10 cases; young age, and female sex.

Prognosis Likely to be poor.

Hybrid/Mutated Gene 5' MYST3 - 3' NCOA2.

Abnormal Protein The fusion product retains the zinc fingers, the the histone acetyl transferase (HAT) domain of MYST3 and the HAT domains and CREBBP interacting domain of NCOA2.

t(8;16)(p11;p13) in acute myelomonocytic or monocytic leukaemia (M4 or M5 AML) and therapy related AML (t-AML) → MYST3 / CREBBP Disease Erythrophagocytosis; rare: less than 1% of AML; found in children and young adults of both sex.

Prognosis Poor.

Hybrid/Mutated Gene 5’ MYST3 - 3’ CREBBP.

Abnormal Protein The fusion product retains the zinc fingers, the HAT domain of MYST3 and most of CREBBP, including the CREBBP interacting domain and the HAT domain; the fusion protein may repress RUNX1-dependant gene expression.

t(8;22)(p11; q13) in acute myelomonocytic or monocytic leukaemia (M4 or M5 AML) → MYST3 / EP300 Disease Erythrophagocytosis; very rare: less than 5 cases.

Prognosis Likely to be poor.

Oncogenesis EP300 is very similar to CRBBP (see above), the breakpoints on these 2 genes are on homologous regions; the breakpoint on MYST3 is more proximal in the t(8;22).

Breakpoints

To be noted Note: MYST3 and MLL share: a common dual transcription activation / repression activity; probable or certain HOX genes expression regulation; 2 common translocation partners: CREBBP and EP300 giving rise to AML and t-AML with poor prognoses.

References Laï JL, Zandecki M, Jouet JP, Savary KB, Lambiliotte A, Bauters F, Cosson A, Deminatti M. Three cases of translocation t(8 ;16)(p11 ;p13) observed in acute myelomonocytic leukaemia : a new specific subgroup?. Cancer Genet Cytogenet 1987;27:101-109.

Brizard A, Guilhot F, Huret JL, Benz-Lemoine E, Tanzer J. The 8p11 anomaly in 'monoblastic' leukaemia. Leuk Res 1988;12:693-697.

Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dubé I, Frischauf AM, Horsman D, Mitelman F, Volinia S, Watmore AE, Housman DE. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 1996;14:33-41.

Aguiar R, Chase A, Coulthard S, Macdonald D, Carapeti M, Reiter A, Sohal J, Lennard A, Goldman J, Cross N. Abnormalities of chromosome band 8p11 in leukemia: two clinical syndromes can be distinguished on the basis of MOZ involvement. Blood 1997;90:3130-3135.

Carapeti M, Aguiar R, Goldman JM, Cross N. A novel fusion between MOZ and the nuclear receptor coactivator TIF-2 in acute myeloid leukemia. Blood 1998;91:3127-313.

Imamura T, Kakazu N, Hibi S, Morimoto A, Fukushima Y, Ijuin I, Hada S, Kitabayashi I, Abe T, Imashuku S. Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11). Genes Chromosomes Cancer 2003;36:413-419.

Miller CT, Maves L, Kimmel CB. moz regulates Hox expression and pharyngeal segmental identity in zebrafish. Development 2004;131:2443-2461.

MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3 Huret JL, Senon S


Yang XJ. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res 2004;32:959-976.

This article should be referenced as such: Huret JL, Senon S. MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3. Atlas Genet Cytogenet Oncol Haematol.2006;10(3):151-153.





PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) Matilde Y Follo, Vincenza Rita Lo Vasco, Giovanni Martinelli, Giandomenico Palka, Lucio Cocco

Cellular Signalling Laboratory, Department of Anatomical Sciences, University of Bologna, Via Irnerio, 48 I-40126 Bologna, Italy


Online updated version: http://AtlasGeneticsOncology.org/Genes/PLCB1ID41742ch20p12.html DOI: 10.4267/2042/38314


Identity Hugo: PLCB1 Other names: PLC-I; PI-PLC; PLC-154 Location: 20p12.3

Local order: between the markers D20S917 and D20S177.

Panel A: structure of PLCB1a and PLCB1b human cDNAs. Upper, PLCB1a; middle, PLCB1b; lower, PLCB1b with different 3'- UTR. Panel B: structure of the splicing variant lacking exons 4-9.

PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) Follo MY et al.


DNA/RNA Description 33 small exons and introns spanning about 250 kbp. Transcription By alternative splicing at the 3-prime end the gene produces 2 variants: PLCB1a (1.216 aminoacids, 6705 bp mRNA) and PLCB1b (1.173 aminoacids, 6823 bp mRNA). An additional exon at the 5-prime end was identified, which gives a smaller isoform, and another PLCB1b isoform, which is produced by using an alternative 3’-UTR.

Pseudogene No known pseudogenes.

Protein

PH = Pleckstrin Homology Domain; EF = EF-Hand Domain; X and Y = Catalytic Domain; C2 = Calcium-binding Domain; NLS = Nuclear Localisation Signal (common to both isoforms); NES = Nuclear Export Signal

Description PLC beta1 contains a PH-domain at the NH2-terminus, which is present in many signalling proteins, that binds to polyphosphoinositides and to inositol phosphates. Two additional modules are also present: an EF-hand domain, located between the PH and X domains, and a C2 domain, which is sometimes represented as part of an extended Y domain.

Expression PLC beta1 is ubiquitous at different levels of expression: higher signal intensities were observed in some CNS areas, such as the amygdala, caudate nucleus, and hippocampus, and PLCB1a appeared to be expressed at slightly higher levels in most tissues. PCR analysis of embryonic and adult rat tissues indicated restricted expression of both isoforms to embryonic and adult brain, with lower levels of expression in lung and testis.

Localisation By using confocal immunolocalization of endogenous or transfected epitope-tagged PLC beta1, for subcellular localisation it has been shown that PLCB1a is within the cytoplasm and at the plasma membrane but localises also in the nucleus. PLCB1b is almost completely nuclear.

Function Phospholipase C-beta (PLC beta) catalyzes the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (IP2), a key step in the intracellular transduction of many extracellular signals. PLCB1 is one of several mammalian PLCB isoforms which differ in their function and expression patterns in vivo. PLC beta1 protein is present in the nucleus and is involved in the control of the cell cycle.

Homology 96% with bovine PLC beta1; The amino acid sequences of PLC isozymes are relatively not conserved except for two regions, known as the X and Y domains that form the catalytic core which is 60% homologous among all mammalian isozymes.

Mutations Note: Until now only deletions have been relevated by using FISH analysis.

Implicated in Myelodysplastic Syndrome Note: Transition from Myelodysplastic Syndrome to Acute Myeloid Leukemia.

Disease In patients with normal GTG banding karyotype affected by Myelodysplastic Syndrome (MDS) (9 patients) and with Acute Myeloid Leukemia (AML) (6 patients), a monoallelic loss of the PLCB1 gene was detected. All the MDS patients, even though with normal karyotype, belonged to the high-risk group as scored by IPSS and FAB classifications. Out of 9 MDS patients with normal karyotype 4 had monoallelic deletion of the PLC beta1 gene, and all 4 died within 1 to 6 months after developing AML, compared to survival of over 30 months in the 5 MDS patients without the deletion. Two of 6 AML patients with normal karyotype had a monoallelic deletion of the PLCB1 gene; these 2 patients had a reduced survival (1 to 12 months) compared to the AML patients without the deletion (20 to 29 months). These evidences suggest a possible role for PLC beta1 in the progression of MDS to AML in high-risk patients.

Prognosis Worse in patients having the deletion of the PLC beta1 gene.

Cytogenetics FISH performed using a 115.000 bp probe (PAC clone 881E24) spanning from exon 19 to 32 of the gene. FISH analysis, using KIAA 0581, i.e., part of human PLC beta1 cDNA, of human metaphases showing

PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) Follo MY et al.


signals on both chromosomes 20 at band p12. (a) Q-Like banding; (b) fluorescence signals detected by FISH; (c) a partial karyotype along with a human chromosome 20 ideogram. (d) A schematic representation of the 1.9 cM interval, flanked by microsatellite markers D20S917 and D20S977, to which human PLC beta1 maps.

Oncogenesis PLC beta1 is a key player in the control of cell cycle, namely the physiological progression through the G1 phase, in that the nuclear PLC beta1 evoked signalling targets the cyclin D3/cdk4 complex which phosphorylates retinoblastoma protein (pRb) that in turn activates the transcription factor E2F-1. Possibly alterations of this pathway could be involved in malignancies.

References Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res 1998;5:31-39.

Caricasole A, Sala C, Roncarati R, Formenti E, Terstappen GC. Cloning and characterization of the

human phosphoinositide-specific phospholipase C-beta 1 (PLC-beta 1). Biochim Biophys Acta 2000; 1517:63-72.

Peruzzi D, Calabrese G, Faenza I, Manzoli L, Matteucci A, Gianfrancesco F, Billi AM, Stuppia L, Palka G, Cocco L. Identification and chromosomal localisation by fluorescence in situ hybridisation of human gene of phosphoinositide-specific phospholipase C beta-1. Biochim Biophys Acta 2000;1484:175-182.

Peruzzi D, Aluigi M, Manzoli L, Billi AM, Di Giorgio FP, Morleo M, Martelli AM, Cocco L. Molecular characterization of the human PLC beta-1 gene. Biochim Biophys Acta 2002;1584:46-54.

Lo Vasco VR, Calabrese G, Manzoli L, Palka G, Spadano A, Morizio E, Guanciali-Franchi P, Fantasia D, Cocco L. Inositide-specific phospholipase c beta-1 gene deletion in the progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 2004;18:1122-1126.

This article should be referenced as such: Follo MY, Lo Vasco VR, Martinelli G, Giandomenico Palka G, Cocco L. PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)). Atlas Genet Cytogenet Oncol Haematol.2006; 10(3):154-156.





PMS1 (PMS1 postmeiotic segregation increased 1 (S. cerevisiae)) Enric Domingo, Simó Schwartz Jr

Molecular Oncology and Aging Group, Molecular Biology and Biochemistry Research Center (CIBBIM), Valle Hebron Hospital Research Institute, Barcelona, Spain


Online updated version: http://AtlasGeneticsOncology.org/Genes/PMS1ID345ch2q31.html DOI: 10.4267/2042/38315


Identity Hugo: PMS1 Other names: HNPCC3; PMSL1 Location: 2q31-33

DNA/RNA Description The PMS1 gene is composed of 13 exons spanning in a region of 93056 bp.

Transcription The transcribed mRNA has 3032 bp.

Protein Description Amino acids: 932. Molecular Weight: 105830 Daltons. PMS1 is a protein involved in the mismatch repair process after DNA replication.

Function PMS1 binds to MLH1 to form a heterodimer, although MLH1 can also bind to PMS2 or MLH3. Although MLH1/PMS2 binds to the heteroduplexes MutSa (composed of MSH2 and MSH6) or MutSß (composed of MSH2 and MSH3), which recognize DNA lesions, it remains to be demonstrated the involvement of the

Diagram of the PMS1 gene. Exons are represented by boxes (in scale) transcribed and untranscribed sequences in blue and yellow, with exon numbers on top and number of base pairs at the bottom. Introns are represented by black bars (not in scale) and the number

of base pairs indicated. The arrows show the ATG and the stop codons respectively.

PMS1 (PMS1 postmeiotic segregation increased 1 (S. cerevisiae)) Domingo E, Schwartz S Jr


MLH1/PMS1 heterodimer in the mismatch repair process, despite that the heterodimer MLH1/PMS2 is responsible for the recruitment of the proteins needed for the excision and repair synthesis.

Homology PMS1 is homologue to the bacterial MutL gene and to the Mlh2 gene in yeasts.

Mutations Germinal A truncating germline mutation of PMS1 was found in one HNPCC patient. Nevertheless, a MSH2 mutation was found in this family, which was the only one that co-segregated with colon cancer. In addition, no more HNPCC patients have been found with mutations in this gene, and PMS1-/- mice show no discernible phenotype. So there is no evidence that PMS1 mutations predispose to HNPCC.

References Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Dunlop MG, Hamilton SR, Petersen GM, de la Chapelle A, Vogelstein B, Kinzler KW. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994 Sep 1;371(6492):75-80.

Prolla TA, Baker SM, Harris AC, Tsao JL, Yao X, Bronner CE, Zheng B, Gordon M, Reneker J, Arnheim N, Shibata D, Bradley A, Liskay RM. Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair. Nat Genet 1998;18:276-279.

Yanagisawa Y, Ito E, Iwahashi Y, Akiyama Y, Yuasa Y, Maruyama K. Isolation and characterization of the 5' region of the human mismatch repair gene hPMS1. Biochem Biophys Res Commun 1998;243:738-743.

Raschle M, Marra G, Nystrom-Lahti M, Schar P, Jiricny J. Identification of hMutLbeta, a heterodimer of hMLH1 and hPMS1. J Biol Chem 1999;274:32368-32375.

Kondo E, Horii A, Fukushige S. The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Nucleic Acids Res 2001;29:1695-1702.

Liu T, Yan H, Kuismanen S, Percesepe A, Bisgaard ML, Pedroni M, Benatti P, Kinzler KW, Vogelstein B, Ponz de Leon M, Peltomaki P, Lindblom A. The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. Cancer Res 2001;61:7798-7802.

Jacob S, Praz F. DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie 2002;84:27-47. (Review).

Peltomäki P. Lynch syndrome genes. Fam Cancer 2005;4:227-232.

This article should be referenced as such: Domingo E, Schwartz S Jr. PMS1 (PMS1 postmeiotic segregation increased 1 (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):157-158.





PKD1 (protein kinase D1) Cheng Du, Meena Jaggi, Wenguang Zhang, KC Balaji

Urological Oncology Research, Urological Surgery, 982360, University of Nebraska Medical Center, Omaha, NE 68198-2360, USA

Published in Atlas Database: January 2006

Online updated version: http://AtlasGeneticsOncology.org/Genes/PRKCMID41860ch14q11.html DOI: 10.4267/2042/38316


Identity Hugo: PRKD1 Other names: PKCmu; PRKCM Location: 14q11

DNA/RNA Description The gene spans over 351 kb and the transcript consists of 18 exons.

Transcription About 3.8 kb in length; Expressed in several organs with highest expression in kidney, heart and lungs.

Protein Description 912 amino acids residues, 120 kDa on SDS-PAGE gel; contains an alanine and proline rich (AP), two cysteine-rich domains (CysI and CysII), acidic (AC), pleckstrin

homology (PH) and kinase domain (KD). Several domain specific protein interactions and functions have been described (see figure below).

Localisation In rested cells, the majority of PKD1 are in the cytoplasm. When activated by phorbol ester, PKD1 rapidly moves to plasma membrane and nucleus.

Function Serine/threonine kinase; protein kinase C downstream effector; intracellular trafficking. PKD1 has been shown to play a role in proliferation of keratinocytes in skin, B and T lymphocytes and mast cells signaling, possible role in development of central tolerance in thymus gland, proliferation of pancreatic cancer cells, cardiac myocyte contraction, endothelial cell proliferation, osteoblasts differentiation, and prostate cancer cells adhesion and invasion.

Homology Homologues present in mouse and rat.

PKD1 (protein kinase D1) Du C et al.


Implicated in Advanced prostate cancer Disease PKD1 phosphorylates E-cadherin in prostate cancer cell lines. E-cadherin phosphorylation is associated with altered cellular aggregation and motility in prostate cancer. Inhibition of PKD1 activity by the selective inhibitor Go6976 in LNCaP cells resulted in decreased cellular aggregation and over expression of PKD1 in C4-2 prostate cancer cells increased cellular aggregation and decreased cellular motility.

Cardiac hypertrophy Disease Transcriptional regulation of gene expression is tightly coupled to histone deacetylases (HDAC) and histone acetyltransferase (HAT) that modify the access of transcription factors to DNA binding sites. PKD1 has been shown to participate in nuclear export of HDAC5. HDAC5 is phosphorylated by PKD1 in cardiac myocytes, which results in the binding of 14-3-3 protein to the phosphoserine motif on HDAC5, thus leading to nuclear export through a CRM1-dependent mechanism. This results in increased transcriptional activity of hypertrophy mediating genes in myocytes. Cardiac failure is usually preceded by cardiac hypertrophy that is mediated by altered gene expression involved in myocyte contraction, calcium handling and metabolism. PKD1 specific inhibitors may be of benefit in limiting cardiac hypertrophy.

References Johannes FJ, Prestle J, Eis S, Oberhagemann P, Pfizenmaier K. PKCu is a novel, atypical member of the protein kinase C family. J Biol Chem 1994;269(8):6140-6148.

Valverde AM, Sinnett-Smith J, Van Lint J, Rozengurt E. Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain. Proc Natl Acad Sci USA 1994;91(18):8572-8576.

Van Lint JV, Sinnett-Smith J, Rozengurt E. Expression and characterization of PKD, a phorbol ester and diacylglycerol-stimulated serine protein kinase. J Biol Chem 1995;270(3):1455-1461.

Sidorenko SP, Law CL, Klaus SJ, Chandran KA, Takata M, Kurosaki T, Clark EA. Protein kinase C mu (PKC mu) associates with the B cell antigen receptor complex and regulates lymphocyte signaling. Immunity 1996;5(4):353-363.

Zugaza JL, Sinnett-Smith J, Van Lint J, Rozengurt E. Protein kinase D (PKD) activation in intact cells through a protein

kinase C-dependent signal transduction pathway. EMBO J 1996 Nov 15;15(22):6220-6230.

Bowden ET, Barth M, Thomas D, Glazer RI, Mueller SC. An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation. Oncogene 1999;18(31):4440-4449.

Hausser A, Storz P, Link G, Stoll H, Liu YC, Altman A, Pfizenmaier K, Johannes FJ. Protein kinase C mu is negatively regulated by 14-3-3 signal transduction proteins. J Biol Chem 1999;274(14):9258-9264.

Waldron RT, Iglesias T, Rozengurt E. Phosphorylation-dependent protein kinase D activation. Electrophoresis 1999;20(2):382-390. (Review).

Matthews SA, Rozengurt E, Cantrell D. Protein kinase D. A selective target for antigen receptors and a downstream target for protein kinase C in lymphocytes. J Exp Med 2000;191(12):2075-2082.

Vertommen D, Rider M, Ni Y, Waelkens E, Merlevede W, Vandenheede JR, Van Lint J. Regulation of protein kinase D by multisite phosphorylation. Identification of phosphorylation sites by mass spectrometry and characterization by site-directed mutagenesis. J Biol Chem 2000;275(26):19567-19576.

Rey O, Sinnett-Smith J, Zhukova E, Rozengurt E. Regulated nucleocytoplasmic transport of protein kinase D in response to G protein-coupled receptor activation. J Biol Chem 2001;276(52):49228-49235.

Waldron RT, Rey O, Iglesias T, Tugal T, Cantrell D, Rozengurt E. Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo. J Biol Chem 2001;276(35):32606-32615.

Hausser A, Link G, Bamberg L, Burzlaff A, Lutz S, Pfizenmaier K, Johannes FJ. Structural requirements for localization and activation of protein kinase C mu (PKC mu) at the Golgi compartment. J Cell Biol 2002;156(1):65-74.

Lint JV, Rykx A, Vantus T, Vandenheede JR. Getting to know protein kinase D. Int J Biochem Cell Biol 2002;34(6):577-581. (Review).

Rykx A, De Kimpe L, Mikhalap S, Vantus T, Seufferlein T, Vandenheede JR, Van Lint J. Protein kinase D: a family affair. FEBS Lett 2003;546(1):81-86. (Review).

Waldron RT, Rozengurt E. Protein kinase C phosphorylates protein kinase D activation loop Ser744 and Ser748 and releases autoinhibition by the pleckstrin homology domain. J Biol Chem 2003;278(1):154-163.

Jaggi M, Rao PS, Smith DJ, Wheelock MJ, Johnson KR, Hemstreet GP, Balaji KC. E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer. Cancer Res 2005;65(2):483-492.

Rozengurt E, Rey O, Waldron RT. Protein kinase D signaling. J Biol Chem 2005;280(14):13205-13208. (Review).

This article should be referenced as such: Du C, Jaggi M, Zhang W, Balaji KC. PKD1 (protein kinase D1). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):159-160.

Gene Section Review




THBS2 (thrombospondin-2) Elizabeth M Perruccio, David D Roberts

Laboratory of Pathology and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA


Online updated version: http://AtlasGeneticsOncology.org/Genes/THBS2ID42549ch6q27.html DOI: 10.4267/2042/38317


Identity Hugo: THBS2 Other names: TSP2,; CISP (corticotropin-induced secreted protein) Location: 6q27 Local order: Telomeric to SMOC2 (SPARC related modular calcium binding 2), centromeric to LOC4422783.

DNA/RNA Description The THBS2 gene is 38,261 bases in size and is composed of 23 exons. Exons 3-22 encode the 5,808 base mRNA.

Transcription Unlike TSP1, TSP2 is less-to-moderately responsive to serum in mouse NIH3T3 and Swiss 3T3 cells respectively. Transcription of THBS2 in some human cancers is suppressed through hypermethylation. TSP2 mRNA is upregulated by Rac1-induced reactive oxygen species, Hox A5, ACTH, TGFb, cerivastatin and in-vitro, by increasing cell confluency. Downregulation of TSP2 mRNA occurs by inhibiting TGFb-dependent p38 MAPK pathway or perturbing the Smad pathway by dexamethasone, ATF3 overexpression, human papilloma virus positive cells, cytomegalovirus infected cells, tissue factor overexpressing sarcoma cells.

Intron-exon organization of the THBS2 gene.

Domain organization and localization of selected ligand binding sites in TSP2. TSP2 is a homotrimer linked via disulfide bonds. In most cases, sequences recognized by TSP2 receptors are inferred from mutagenesis of the corresponding sequences in TSP1 and supported by peptide inhibitions studies using the TSP2 sequences.

THBS2 (thrombospondin-2) Perruccio EM, Roberts DD


The oncogene c-myb affects TSP 2 expression via a post-transcriptional regulation of its mRNA stability. Potential transcription factor binding sites have been described for: NF-kB, NF-Y, p53, Myc-CF1, Sp1, CF-1, GATA and AP-1.

Pseudogene None described.

Protein Description The TSP2 precursor contains 1172 amino acids; 129,955 Da. The mature secreted protein comprises residues 19-1172 and assembles into a disulfide linked homotrimer. Secreted TSP2 is a glycoprotein with a molecular mass of 150-160 kDa that contains approximately 7 potential Asn-linked oligosaccharide attachment sites and variable numbers of C-mannosylated Trp residues in the type 1 repeats. An X-ray crystal structure for the C-terminal regions of TSP2 revealed that the type 3 repeats when replete with Ca wrap around the globular G domain.

Expression TSP2 is expressed in many tissues during embryonic development, in the healthy adult and in various tumor stromal environments. Predominant expression is found in the connective tissue compartment and based on EST profiling, expression is highest in bone. Mice lacking thrombospondin 2 show an atypical pattern of endocortical and periosteal bone formation in response to mechanical loading. Expression is induced during the later stages of wound repair, during tissue remodeling, in rheumatoid synovium, ovarian follicle development, in wound keratocytes, hypertrophied heart, by ACTH, cAMP analogs and adenylate cyclase activators in bovine adrenocortical cells, in aged mice. Downregulation has been observed in fetal Leydig cells of mice overexpressing human chorionic gonadotropin/ luteinizing hormone, herpes simplex 1 infected cells, and in Cyclosporin A-induced gingival overgrowths. TSP2 expression has been reported in some tumors including invasive breast carcinoma, metastatic malignant melanoma, malignant pleural effusions, cervix of pregnant mice, ischemic brain, aggressive ovarian tumor, gastric cancer, renal cell carcinoma, endometrial cancer, colorectal cancer, chemically-induced skin cancer, osteoclastoma, in ACTH-dependent aldosterone producing adenomas, esophageal cancer. Down regulation of TSP2 was reported in ovarian serous papillary carcinoma, salivary gland carcinoma, invasive cervical cancer, and non-small cell lung cancer.

Localisation TSP2 is secreted but is present only transiently in

extracellular matrix and is rapidly internalized for degradation by fibroblasts after binding to the cell surface. Degradation is similar to TSP1 removal in that it is LRP- and HSPG-dependent and has similar kinetics. Given its pericellular distribution, TSP2, like TSP1, can modulate cell-matrix interactions and cell behavior.

Function TSP2 binds to extracellular matrix ligands including, transforming growth factor-beta-1, histidine rich glycoprotein, TSG6, heparin, matrix metalloproteinase-2, and heparan sulfate proteoglycans. TSP2 binds to cell surface receptors including CD36, CD47, LDL receptor-related protein-1 (via calreticulin) and the integrins alpha-V/beta-3, alpha-4/beta-1, and alpha-6/beta-1. In contrast to TSP1, TSP2 does not activate latent TGF-beta-1 but similarly to TSP1, TSP2 contains EGF-like modules that bind calcium in a cooperative manner. TSP2 in a context-dependent and cell-specific manner stimulates or inhibits cell adhesion, proliferation, motility, and survival. TSP2 is a potent inhibitor of angiogenesis mediated by the TSP2 receptor CD36. However, its N-terminal region exhibits pro-angiogenic activities mediated by beta-1 integrins. By way of alpha-4/beta-1, TSP2, like TSP1, modulates T cell behavior in-vitro. TSP2 stimulates chemotaxis, MMP gene expression, and activation-dependent adhesion of T cells. In a model of rheumatoid synovium, cell-based TSP2 therapy had an anti-inflammatory role in-vivo and depleted the tissue of infiltrating T cells. In the CNS, TSP2 secreted by astrocytes promotes synaptogenesis. TSP2 null mice are viable and fertile but display connective tissue abnormalities associated with a defect in collagen fibrillogenesis that manifests as fragile skin, lax tendons and ligaments. Several defects have been reported in responses of TSP2 null mice to specific stresses. Nulls have an enhanced cutaneous inflammatory response, increased endosteal bone density, increased vascular density in dermis, adipose and thymus, a prolonged bleeding time. Fibroblasts isolated from TSP2 nulls are defective in adhesion. In response-to-injury models, TSP2 null mice have an increased vascularity of wounds with a concomitant increase in activity of MMP2 and MMP9 and demonstrate enhanced wound repair.

Homology TSP2 is a member of the thrombospondin family that also contains thrombospondin-1, thrombospondin-3, thrombospondin-4, and cartilage oligomeric matrix protein (COMP). The central type 1 repeats are also known as thrombospondin-repeats and are shared with the larger thrombospondin/properdin repeat superfamily.



Mutations Germinal t3949g substitution in the 3'-untranslated region is associated with a reduced risk of premature myocardial infarcts.

Somatic LOH in markers proximal to THBS2 were reported in salivary carcinomas, but disruption of the THBS2 gene has not been confirmed to date.

Implicated in Various cancers Disease Loss of TSP2 expression is associated with local invasive behavior, tumor neovascularization, and metastasis.

Prognosis Decreased TSP2 expression has been correlated with malignant progression and angiogenesis in some but not all cancers. In a study of 37 gliomas, a lack of TSP2 expression was significantly associated with higher histological grade (P = 0.0019) and increased vessel counts and density (p < 0.0001). In a study of 61 colon cancers, those expressing TSP2 showed a lower incidence of hepatic metastasis than those not expressing TSP2 (p = 0.02). TSP2 negative/VEGF-189 positive colon cancers showed significantly increased vessel counts and density in the stroma (P < 0.0001). Finally, in a study of 10 normal cervix and 78 invasive cervical cancer samples, TSP2 mRNA expression in normal cervix was significantly higher than that in cervical cancer (p = 0.032). Microvessel counts were marginally increased in the cervical cancer patients lacking TSP2 mRNA expression (p = 0.062). To date, the numbers of specimens examined for each of these cancers are too small to evaluate the independent prognostic value of TSP2 expression. Conversely, TSP2 was strongly expressed in a series of melanoma metastases, but not in primary tumors, and in 55 endometrial cancer specimens TSP2 expression was significantly higher in malignancies exhibiting cervical and lymph-vascular space involvement (p = 0.029 and p = 0.009, respectively).

Oncogenesis Somatic mutation of THBS2 has not been clearly established in human cancers, but loss of TSP2 expression due to hypermethylation of its promoter was reported in a study of endometrial carcinomas. LOH in 6q15-27 between D6S297 and D6S1590 was reported in a study of salivary gland carcinomas and associated in 8 of 9 cases with loss of TSP2 expression. Transgenic mouse models support the tumor suppressor activity of THBS2. Tumor progression of chemically-

induced skin cancer is accelerated in TSP2 null mice, and there is an increased rate of lymph node metastases. The correlated increase in vessel density and size in these nulls also supports a suppressive role for TSP2. Tumor growth and angiogenesis are delayed and decreased when TSP2 is overexpressed in this model. Mouse models have also been used to explore therapeutic use of TSP2 to limit tumor growth and angiogenesis. These utilize a cell-based approach wherein TSP2 cDNA is transfected into a variety of cells including: glioblastoma, fibrosarcoma, squamous cell carcinoma and breast carcinoma cells. In turn, these TSP2 overexpressing cells when injected subcutaneously into immunodeficient mice exhibit decreased tumor growth and angiogenesis.

References Pellerin S, Lafeuillade B, Scherrer N, Gagnon J, Shi DL, Chambaz EM, Feige JJ. Corticotropin-induced secreted protein, an ACTH-induced protein secreted by adrenocortical cells, is structurally related to thrombospondins. J Biol Chem 1993 Feb 25;268(6):4304-4310.

Zhang Y, Deng Y, Luther T, Müller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. J Clin Invest 1994 Sep;94(3):1320-1327.

Adolph KW, Liska DJ, Bornstein P. Analysis of the promoter and transcription start sites of the human thrombospondin 2 gene (THBS2). Gene 1997 Jul 1;193(1):5-11.

Bertin N, Clezardin P, Kubiak R, Frappart L. Thrombospondin-1 and -2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and fibroblastic desmoplasia. Cancer Res 1997 Feb 1;57(3):396-399.

Bein K, Ware JA, Simons M. Myb-dependent regulation of thrombospondin 2 expression. Role of mRNA stability. J Biol Chem 1998 Aug 14;273(33):21423-21429.

Oshika Y, Masuda K, Tokunaga T, Hatanaka H, Kamiya T, Abe Y, Ozeki Y, Kijima H, Yamazaki H, Tamaoki N, Ueyama Y, Nakamura M. Thrombospondin 2 gene expression is correlated with decreased vascularity in non-small cell lung cancer. Clin Cancer Res 1998 Jul;4(7):1785-1788.

Zhu H, Cong JP, Mamtora G, Gingeras T, Shenk T. Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays. Proc Natl Acad Sci USA 1998 Nov 24;95(24):14470-14475.

Carron JA, Bowler WB, Wagstaff SC, Gallagher JA. Expression of members of the thrombospondin family by human skeletal tissues and cultured cells. Biochem Biophys Res Commun 1999 Sep 24;263(2):389-391.

Kazuno M, Tokunaga T, Oshika Y, Tanaka Y, Tsugane R, Kijima H, Yamazaki H, Ueyama Y, Nakamura M. Thrombospondin-2 (TSP2) expression is inversely correlated with vascularity in glioma. Eur J Cancer 1999 Mar;35(3):502-506.

Streit M, Riccardi L, Velasco P, Brown LF, Hawighorst T, Bornstein P, Detmar M. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci USA 1999 Dec 21;96(26):14888-14893.

Yoshida Y, Oshika Y, Fukushima Y, Tokunaga T, Hatanaka H, Kijima H, Yamazaki H, Ueyama Y, Tamaoki N, Miura S, Nakamura M. Expression of angiostatic factors in colorectal cancer. Int J Oncol 1999 Dec;15(6):1221-1225.



Bequet-Romero M, López-Ocejo O. Angiogenesis modulators expression in culture cell lines positives for HPV-16 oncoproteins. Biochem Biophys Res Commun 2000 Oct 14;277(1):55-61.

Adams JC. Thrombospondins: multifunctional regulators of cell interactions. Annu Rev Cell Dev Biol 2001;17:25-51. (Review).

de Fraipont F, Nicholson AC, Feige JJ, Van Meir EG. Thrombospondins and tumor angiogenesis. Trends Mol Med 2001 Sep;7(9):401-407. (Review).

Hawighorst T, Velasco P, Streit M, Hong YK, Kyriakides TR, Brown LF, Bornstein P, Detmar M. Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. EMBO J 2001 Jun 1;20(11):2631-2640.

Kan T, Shimada Y, Sato F, Maeda M, Kawabe A, Kaganoi J, Itami A, Yamasaki S, Imamura M. Gene expression profiling in human esophageal cancers using cDNA microarray. Biochem Biophys Res Commun 2001 Aug 31;286(4):792-801.

Kodama J, Hashimoto I, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T. Thrombospondin-1 and -2 messenger RNA expression in epithelial ovarian tumor. Anticancer Res 2001 Jul-Aug;21(4B):2983-2987.

Kodama J, Hashimoto I, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T. Thrombospondin-1 and -2 messenger RNA expression in invasive cervical cancer: correlation with angiogenesis and prognosis. Clin Cancer Res 2001 Sep;7(9):2826-2831.

Lee JH, Koh JT, Shin BA, Ahn KY, Roh JH, Kim YJ, Kim KK. Comparative study of angiostatic and anti-invasive gene expressions as prognostic factors in gastric cancer. Int J Oncol 2001 Feb;18(2):355-361.

Perez S, Vial E, van Dam H, Castellazzi M. Transcription factor ATF3 partially transforms chick embryo fibroblasts by promoting growth factor-independent proliferation. Oncogene 2001 Mar 1;20(9):1135-1141.

Seki N, Kodama J, Hashimoto I, Hongo A, Yoshinouchi M, Kudo T. Thrombospondin-1 and -2 messenger RNA expression in normal and neoplastic endometrial tissues: correlation with angiogenesis and prognosis. Int J Oncol 2001 Aug;19(2):305-10.

Agah A, Kyriakides TR, Lawler J, Bornstein P. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Am J Pathol 2002 Sep;161(3):831-839.

Armstrong DJ, Hiscott P, Batterbury M, Kaye S. Corneal stromal cells (keratocytes) express thrombospondins 2 and 3 in wound repair phenotype. Int J Biochem Cell Biol 2002 Jun;34(6):588-593.

Gerritsen ME, Peale FV Jr, Wu T. Gene expression profiling in silico: relative expression of candidate angiogenesis associated genes in renal cell carcinomas. Exp Nephrol 2002;10(2):114-119. (Review).

Hatakeyama H, Nishizawa M, Nakagawa A, Nakano S, Kigoshi T, Miyamori I, Uchida K. Thrombospondin expression in aldosterone-producing adenomas. Hypertens Res 2002 Jul;25(4):523-527.

Kunz M, Koczan D, Ibrahim SM, Gillitzer R, Gross G, Thiesen HJ. Differential expression of thrombospondin 2 in primary and metastatic malignant melanoma. Acta Derm Venereol 2002;82(3):163-169.

Lange-Asschenfeldt B, Weninger W, Velasco P, Kyriakides TR, von Andrian UH, Bornstein P, Detmar M. Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2--deficient mice. Blood 2002 Jan 15;99(2):538-545.

Petrik JJ, Gentry PA, Feige JJ, LaMarre J. Expression and localization of thrombospondin-1 and -2 and their cell-surface receptor, CD36, during rat follicular development and formation of the corpus luteum. Biol Reprod 2002 Nov;67(5):1522-1531.

Streit M, Stephen AE, Hawighorst T, Matsuda K, Lange-Asschenfeldt B, Brown LF, Vacanti JP, Detmar M. Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy. Cancer Res 2002 Apr 1;62(7):2004-2012.

Armstrong LC, Bornstein P. Thrombospondins 1 and 2 function as inhibitors of angiogenesis. Matrix Biol 2003 Mar;22(1):63-71. (Review).

Denoyelle C, Albanese P, Uzan G, Hong L, Vannier JP, Soria J, Soria C. Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells. Cell Signal 2003 Mar;15(3):327-338.

Kishi M, Nakamura M, Nishimine M, Ishida E, Shimada K, Kirita T, Konishi N. Loss of heterozygosity on chromosome 6q correlates with decreased thrombospondin-2 expression in human salivary gland carcinomas. Cancer Sci 2003 Jun;94(6):530-535.

Lin TN, Kim GM, Chen JJ, Cheung WM, He YY, Hsu CY. Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion. Stroke 2003 Jan;34(1):177-186.

Lopes N, Gregg D, Vasudevan S, Hassanain H, Goldschmidt-Clermont P, Kovacic H. Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling. Mol Cell Biol 2003 Aug;23(15):5401-5408.

Sadoun E, Reed MJ. Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. J Histochem Cytochem 2003 Sep;51(9):1119-1130.

Whitcomb BP, Mutch DG, Herzog TJ, Rader JS, Gibb RK, Goodfellow PJ. Frequent HOXA11 and THBS2 promoter methylation, and a methylator phenotype in endometrial adenocarcinoma. Clin Cancer Res 2003 Jun;9(6):2277-2287.

Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol 2004 Jun;36(6):961-968. (Review).

Agah A, Kyriakides TR, Letrondo N, Björkblom B, Bornstein P. Thrombospondin 2 levels are increased in aged mice: consequences for cutaneous wound healing and angiogenesis. Matrix Biol 2004 Jan;22(7):539-547.

Bard MP, Hegmans JP, Hemmes A, Luider TM, Willemsen R, Severijnen LA, van Meerbeeck JP, Burgers SA, Hoogsteden HC, Lambrecht BN. Proteomic analysis of exosomes isolated from human malignant pleural effusions. Am J Respir Cell Mol Biol 2004 Jul;31(1):114-121.

Bornstein P, Agah A, Kyriakides TR. The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol 2004 Jun;36(6):1115-1125. (Review). Erratum in Int J Biochem Cell Biol 2005 Jan;37(1): 239-240.

Horiguchi H, Jin L, Ruebel KH, Scheithauer BW, Lloyd RV. Regulation of VEGF-A, VEGFR-I, thrombospondin-1, -2, and -3 expression in a human pituitary cell line (HP75) by TGFbeta1, bFGF, and EGF. Endocrine 2004 Jul;24(2):141-146.

Koh JT, Kim OJ, Park YS, Kim SH, Kim WJ, Chung HJ, Lee SE, Jeong BC, Jung JY, Kim KK. Decreased expressions of thrombospondin 2 in cyclosporin A-induced gingival overgrowth. J Periodontal Res 2004 Apr;39(2):93-100.

Kokenyesi R, Armstrong LC, Agah A, Artal R, Bornstein P. Thrombospondin 2 deficiency in pregnant mice results in



premature softening of the uterine cervix. Biol Reprod 2004 Feb;70(2):385-390.

Lawler J, Detmar M. Tumor progression: the effects of thrombospondin-1 and -2. Int J Biochem Cell Biol 2004 Jun;36(6):1038-1045. (Review).

Park YW, Kang YM, Butterfield J, Detmar M, Goronzy JJ, Weyand CM. Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis. Am J Pathol 2004 Dec;165(6):2087-2098.

Santin AD, Zhan F, Bellone S, Palmieri M, Cane S, Bignotti E, Anfossi S, Gokden M, Dunn D, Roman JJ, O'Brien TJ, Tian E, Cannon MJ, Shaughnessy J Jr, Pecorelli S. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. Int J Cancer 2004 Oct 20;112(1):14-25.

Schroen B, Heymans S, Sharma U, Blankesteijn WM, Pokharel S, Cleutjens JP, Porter JG, Evelo CT, Duisters R, van Leeuwen RE, Janssen BJ, Debets JJ, Smits JF, Daemen MJ, Crijns HJ, Bornstein P, Pinto YM. Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy. Circ Res 2004 Sep 3;95(5):515-522.

Stenina OI, Byzova TV, Adams JC, McCarthy JJ, Topol EJ, Plow EF. Coronary artery disease and the thrombospondin single nucleotide polymorphisms. Int J Biochem Cell Biol 2004 Jun;36(6):1013-1030. (Review).

Ahtiainen P, Rulli SB, Shariatmadari R, Pelliniemi LJ, Toppari J, Poutanen M, Huhtaniemi IT. Fetal but not adult Leydig cells are susceptible to adenoma formation in response to persistently high hCG level: a study on hCG overexpressing transgenic mice. Oncogene 2005 Nov 10;24(49):7301-7309.

Calzada MJ, Roberts DD. Novel integrin antagonists derived from thrombospondins. Curr Pharm Des 2005;11(7):849-866. (Review).

Carlson CB, Bernstein DA, Annis DS, Misenheimer TM, Hannah BL, Mosher DF, Keck JL. Structure of the calcium-rich signature domain of human thrombospondin-2. Nat Struct Mol Biol 2005 Oct;12(10):910-914.

Choudhary A, Hiscott P, Hart CA, Kaye SB, Batterbury M, Grierson I. Suppression of thrombospondin 1 and 2 production by herpes simplex virus 1 infection in cultured keratocytes. Mol Vis 2005 Mar 2;11:163-168.

Greenaway J, Gentry PA, Feige JJ, LaMarre J, Petrik JJ. Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development. Biol Reprod 2005 May;72(5):1071-1078.

Hankenson KD, Ausk BJ, Bain SD, Bornstein P, Gross TS, Srinivasan S. Mice lacking thrombospondin 2 show an atypical pattern of endocortical and periosteal bone formation in response to mechanical loading. Bone 2005 Nov 11.

Lindert S, Wickert L, Sawitza I, Wiercinska E, Gressner AM, Dooley S, Breitkopf K. Transdifferentiation-dependent expression of alpha-SMA in hepatic stellate cells does not involve TGF-beta pathways leading to coinduction of collagen type I and thrombospondin-2. Matrix Biol 2005 May;24(3):198-207.

Rhoads K, Arderiu G, Charboneau A, Hansen SL, Hoffman W, Boudreau N. A role for Hox A5 in regulating angiogenesis and vascular patterning. Lymphat Res Biol 2005;3(4):240-252.

Simantov R, Febbraio M, Silverstein RL. The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Matrix Biol 2005 Feb;24(1):27-34.

This article should be referenced as such: Perruccio EM, Roberts DD. THBS2 (thrombospondin-2). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):161-165.





BAALC (brain and acute leukemia, cytoplasmic) Jean-Loup Huret, Sylvie Senon

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

Published in Atlas Database: February 2006

Online updated version: http://AtlasGeneticsOncology.org/Genes/BAALCID739ch8q22.html DOI: 10.4267/2042/38318


Identity Hugo: BAALC Other names: FLJ12015; LOC79870 Location: 8q22.3

DNA/RNA Description The gene spans over 90kb on plus strand; 8 exons; 3 polyadenylation signals in the 3' untranslated region of exon 8.

Protein Description Various transcripts: involving exons 1, 6, and 8 (145 amino acids) or 1, and 8 (54 amino acids) in the neurectoderm; transcripts involving exons 1,5,6,8 or 1,4,5,6,8, or 1,5,6,7,8, or 1,2,6,8, or 1,2,5,6,8 or 1,2,3,6,8 in leukemic cells; altogether, 8 different transcripts of BAALC, giving rise to 5 different proteins

Expression Transcripts involving exons 1, 6, and 8, or 1, and 8 are found in neurectoderm tissues; BAALC is also expressed in normal early progenitor cells (CD34+) of the hematopoietic tissues: both uncommitted and lineage-committed progenitor cells (lymphoid T- and B-cell progenitors, myeloid and erytroid progenitors); down regulation occurs with cell differentiation; various transcripts are found in leukemic blasts (see above and below); also found expressed in the mesoderm and the muscle in the Mouse.

Localisation Cytoplasmic; found adjacent to the cell membrane in the mouse; may be localized to lipid rafts and may play a synaptic role in the rat brain.

Homology No homology with other proteins; the ortholog lacks in lower vertebrates.

Mutations Somatic Overexpressed in a subset of acute leucemias.

Implicated in 1/4 of acute non lymphocytic leukemia (ANLL) cases and 2/3 of acute lymphocytic leukemia (ALL) case have been found to exhibit high BAALC expression; no expression in chronic leukemias (e.g. chronic myeloid leukemia (CML)); expression in blast crisis of CML Disease ANLL cases: M0 ANLL, M1, M2 and M4eo cases, rarely M4 or M5 cases; no M3 case so far; association with the more immature blasts; no correlation with age, sex, haemoglobin level or platelets count, or FLT3 phenotype; BAALC expression is associated with a higher WBC count.

Prognosis Poor prognosis is associated with BAALC

BAALC (brain and acute leukemia, cytoplasmic) Huret JL, Senon S


overexpression in ANLL cases: at 3 years, only 35-40% of patients with high BAALC expression were alive; independant risk factor; in particular, BAALC overexpression remains a poor prognostic factor in the absence of FLT3 internal tandem duplication.

Cytogenetics Patients present with normal karyotypes, with +8, or with various anomalies.

Glioblastoma Note: BAALC in also upregulated in normal astrocytes.

References Tanner SM, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K, Mrózek K, Sill H, Knuutila S, Kolitz JE, Archer KJ, Caligiuri MA, Bloomfield CD, de La Chapelle A. BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci USA 2001;98:13901-1396.

Baldus CD, Tanner SM, Kusewitt DF, Liyanarachchi S, Choi C, Caligiuri MA, Bloomfield CD, de la Chapelle A. BAALC, a novel marker of human hematopoietic progenitor cells. Exp Hematol 2003;31:1051-1056.

Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G, Caligiuri MA, Carroll AJ, Vardiman JW, Powell BL, Allen SL, Moore JO, Larson RA, Kolitz JE, de la Chapelle A, Bloomfield CD. BAALC expression predicts clinical outcome of

de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 2003;102:1613-1618.

Marcucci G, Mrózek K, Bloomfield CD. Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. Curr Opin Hematol 2005; 12:68-75.

Satoskar AA, Tanner SM, Weinstein M, Qualman SJ, de la Chapelle A. Baalc, a marker of mesoderm and muscle. Gene Expr Patterns 2005;5:463-473.

Wang X, Tian QB, Okano A, Sakagami H, Moon IS, Kondo H, Endo S, Suzuki T. BAALC 1-6-8 protein is targeted to postsynaptic lipid rafts by its N-terminal myristoylation and palmitoylation, and interacts with alpha, but not beta, subunit of Ca/calmodulin-dependent protein kinase II. J Neurochem 2005;92:647-659.

Moodbidri MS, Shirsat NV. Induction of BAALC and down regulation of RAMP3 in astrocytes treated with differentiation inducers. Cell Biol Int 2005 Dec 21. in press.

Baldus CD, Thiede C, Soucek S, Bloomfield CD, Thiel E, Ehninger G. BAALC Expression and FLT3 Internal Tandem Duplication Mutations in Acute Myeloid Leukemia Patients With Normal Cytogenetics: Prognostic Implications. J Clin Oncol 2006 Jan 17. in press.

This article should be referenced as such: Huret JL, Senon S. BAALC (brain and acute leukemia, cytoplasmic). Atlas Genet Cytogenet Oncol Haematol.2006; 10(3):166-167.





MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)) Deepak Pralhad Patil, Gopal Chandra Kundu

National Center for Cell Science, NCCS Complex, Ganeshkhind, Pune 411007, India


Online updated version: http://AtlasGeneticsOncology.org/Genes/MMP9ID41408ch20q11.html DOI: 10.4267/2042/38319


Identity Hugo: MMP9 Other names: CLG4 (Collagenase Type IV); CLG4B (Collagenase Type IV-B); GELB (Gelatinase B) Location: 20q11.2-q13.1

DNA/RNA Description This gene can be found on Chromosome 26 at location: 44,070,954 - 44,078,606.

Transcription The DNA sequence contains 13 exons and the transcript length: 2,335 bps translated to a 707 residues protein.

Protein Description MMP-9 is a Zn+2 dependent endopeptidase,

synthesized and secreted in monomeric form as zymogen. The structure is almost similar to MMP2, another member of matrixmetalloproteinase family. The nascent form of the protein shows an N-terminal signal sequence ('pre' domain) that directs the protein to the endoplasmic reticulum. The pre domain is followed by a propeptide-'pro' domain that maintains enzyme-latency until cleaved or disrupted, and a catalytic domain that contains the conserved zinc-binding region. A hemopexin/vitronectin-like domain is also seen, that is connected to the catalytic domain by a hinge or linker region. The hemopexin domain is involved in TIMP (Tissue Inhibitors of Metallo-Proteinases) binding e.g. TIMP-1 & TIMP-3, the binding of certain substrates, membrane activation, and some proteolytic activities. It also shows a series of three head-to-tail cysteine-rich repeats within its catalytic domain. These inserts resemble the collagen- binding type II repeats of fibronectin and are required to bind and cleave collagen and elastin. Like other proteolytic enzymes, MMP-9 is first synthesized as inactive proenzyme or zymogens.

Domain structure of the MMP9. Pre: signal sequence; Pro: propeptide with a free zinc-ligating thiol (SH) group; Zn: zinc-binding site; II: collagen-binding fibronectin type II inserts; H: hinge region; The hemopexin/vitronectin-like domain contains four repeats with the first and last linked by a disulfide bond.

MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)) Patil DP, Kundu GC


Activation of proMMP-9 is mediated by plasminogen activator/plasmin (PA/plasmin) system. The regulation of MMP-9 activity is also controlled through TIMP-3.

Expression MMP-9 expression is regulated by several cytokines and growth factors, including interleukins, interferons, EGF (Epidermal growth factor), NGF (Nerve growth factor), basic FGF (Fibroblast growth factor), VEGF (Vascular endothelial growth factor), PDGF (Platelet derived growth), TNF-a (Tumor necrosis factor), TGF-b (Tranforming growth factor), the extracellular matrix metalloproteinase inducer EMMPRIN and also osteopontin. Many of these stimuli induce the expression and/or activation of c-fos and c-jun proto-oncogene products, which heterodimerize and bind activator protein-1 (AP-1) sites within of MMP9 gene promoters.

Localisation Peri/extracellular.

Function Primary function is degradation of proteins in the extracellular matrix. It proteolytically digests decorin, elastin, fibrillin, laminin, gelatin (denatured collagen), and types IV, V, XI and XVI collagen and also activates growth factors like proTGFb and proTNFa. Physiologically, MMP-9 in coordination with other MMPs, play a role in normal tissue remodeling events such as neurite gowth, embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. MMP-9 with other MMPs is also involved in osteoblastic bone formation and/or inhibits osteoclastic bone resorption.

Homology Homology in amino acid sequence is seen with the other members of Metalloproteinase family especially with MMP-2.

Mutations Germinal Not yet reported.

Implicated in Invasive and highly tumorigenic cancers Disease Elevated expression of MMP-9, along with MMP-2 is usually seen in invasive and highly tumorigenic cancers such as colorectal tumors, gastric carcinoma, pancreatic carcinoma, breast cancer, oral cancer, melanoma, malignant gliomas, chondrosarcoma, gastrointestinal adenocarcinoma. Levels are also increased in malignant

astrocytomas, carcinomatous meningitis, and brain metastases.

Oncogenesis MMPs promote tumor progression and metastasis in invasive cancers by degradation of the ECM (ExtraCellular Matrix), which consists of two main components: basement membranes and interstitial connective tissue. Though ECM comprises of many proteins (laminin-5, proteoglycans, entactin, osteonectin) collagen IV is the major element. MMP-2 & MMP-9 efficiently degrade collagen IV and laminin-5 thereby, assisting the metastatic cancerous cells to pass through the basement membrane. The degradation of ECM not only assists migration of metastatic cancerous cells, but also allows enhanced tumor growth by providing necessary space. Further, it is noteworthy that the ratio of active to latent form of MMP-9 increased with tumor progression in invasive cancers. MMP-9, with its family members also promotes angiogenesis (a critical process required for tumor cell survival) by degrading the vascular basement membrane interstitium and also by releasing sequestered VEGF, which is a well know angiogenic molecule. Localization of MMP9 to the cell surface is required to promote tumor invasion and angiogenesis.

Arthritis, autosomal recessive osteolysis disorder, coronary artery disease, pulmonary-emphysema and diabetic retinopathy

References Hangauer D G, Monzingo AF and Matthews BW. An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides. Biochemistry 1984;23:5730-5741.

Davies B, Miles DW, Happerfield MLC et al. Activity of type IV collagenase in benign and malignant breast tissue. Br J Cancer 1993;67:1126-1131.

Stetler-Stevenenson W. Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 1999;103:1237-1241. (Review).

Zeng ZS, Cohen AM and Guillem JG. Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. Carcinogenesis 1999;20(5):749-755.

Woessner JF, Nagase H. Matrix Metalloproteinases and TIMPs. New York:Oxford Univ. Press 2000.

Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000;14:163-176.

John A and Tuszynski G. The Role of Matrix Metalloproteinases in Tumor Angiogenesis and Tumor Metastasis. Path. Onco. Research 2001;7(1):14-23. (Review).

Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463-516. (Review).

MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)) Patil DP, Kundu GC


Bloomston M, Zervos EE and Rosemurgy AS. Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials. Annals of Surgical Oncology 2002, 9(7):668-674. (Review).

Matsuyama A, Sakai N, Ishigami M, Hiraoka H, Kashine S, Hirata A, Nakamura T, Yamashita S and Matsuzawa Y. Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Circulation 2003, 108:1469-1473.

Rangaswami H, Bulbule A and Kundu GC. Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkBa kinase-dependent nuclear factor kB-mediated promatrix metalloproteinase-9 activation. J Biol Chem 2004;279(37):38921-38935.

Rangaswami H, Bulbule A and Kundu GC. JNK1 differentially regulates osteopontin-induced NIK/MEKK1-dependent AP1-mediated promatrix metalloproteinase-9 activation. J Biol Chem 2005;280(19):19381-19392.

This article should be referenced as such: Patil DP, Kundu GC. MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):168-170.





NF1 (neurofibromin 1) Katharina Wimmer

Abteilung Humangenetik des Klinischen Instituts für Medizinische und Chemische Labordiagnostik (KIMCL), Medizinische Universität Wien, Wien, Austria


Online updated version: http://AtlasGeneticsOncology.org/Genes/NF1ID134.html DOI: 10.4267/2042/38320

This article is an update of: Huret JL. NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):5-6 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Hugo: NF1 Location: 17q11.2

DNA/RNA Description 60 exons (57 constitutive, 3 alternative); spans 280 kb; presence of 3 cryptic genes: OMGP, EVI2A, and EVI2B ('overlapping genes'), hidden (!) within NF1 intron 27b with an opposite transcription direction.

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

Protein Description The protein has been called neurofibromin; 2818 and 2839 amino acids (type-1 and type-2 isoform).

Expression Is tissue and development stage specific.

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

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

Mutations Germinal Large submicroscopic deletions in 5-10% of cases, translocations rare and point mutations in app. 85-90% of cases; widely dispersed, with no clustering, unusual splicing mutations yield difficulties in molecular genetic testing, truncating effect in large majority of cases.

Somatic Second inactivating mutation occurs in the Schwann cell of benign neurofibromas; additional genetic alterations in this cell lead to malignant transformation; the spectrum of inactivating somatic mutation not fully elucidated, LOH owing to copy number loss and mitotic recombination, point mutations; another inactivating process may involve RNA editing (for the second allele), which gives rise to a truncated neurofibromin having lost it's GAP activity.

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

NF1 (neurofibromin 1) Wimmer K


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

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

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

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

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

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

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

Legius E, Marchuk DA, Collins FS, Glover TW. Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet 1993 Feb;3(2):122-126.

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

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

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

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

Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat 2000;15(6):541-555.

Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner VF. Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat 2004 Feb;23(2):111-116.

Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglbock H, Maertens O, Messiaen L. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer 2006 Mar;45(3):265-276.

Serra E, Rosenbaum T, Winner U, Aledo R, Ars E, Estivill X, Lenard HG, Lazaro C. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Hum Mol Genet 2000 Dec 12;9(20):3055-3064.

Serra E, Rosenbaum T, Nadal M, Winner U, Ars E, Estivill X, Lazaro C. Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas. Nat Genet 2001 Jul;28(3):294-296.

Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF. High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Am J Hum Genet 2004 Sep;75(3):410-423.

De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet 2005 Dec;77(6):1092-1101.

This article should be referenced as such: Wimmer K. NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol Haematol.2006; 10(3):171-172.





RCHY1 (ring finger and CHY zinc finger domain containing 1) Wenrui Duan, Miguel A Villalona-Calero

Comprehensive Cancer Center, 1230 JCHRI, 300 West 10th Ave, Columbus, Ohio 43210, USA

Published in Atlas Database: March 2006

Online updated version: http://AtlasGeneticsOncology.org/Genes/RCHY1ID43012ch04q21.html DOI: 10.4267/2042/38321


Identity Hugo: RCHY1 Other names: PIRH2; ARNIP; CHIMP; RNF199; ZNF363; PRO1996; DKFZp586C1620 Location: 4q21.1

DNA/RNA Description The gene encompasses 32 kb of DNA; 9 exons.

Transcription 4.3 kb nucleotides mRNA. 783 bp open reading frame.

Protein Description 261 amino acids; 32 kDa protein.

Expression RCHY1 expresses at higher level in liver, testis and heart. Lower expression is detected in lung, brain, muscle and spleen. RCHY1 is overexpressed in non-small cell lung cancers.

Localisation The localization of RCHY1 protein in human lung tumors was evaluated immunohistochemically. RCHY1 protein was found primarily in the cytoplasm and membrane and a small portion in the nucleus of malignant cells.

Function RCHY1 is an ubiquitin-protein E3 ligase that promotes p53 degradation. The RCHY1 gene encodes a RING-H2 domain-containing protein with intrinsic ubiquitin-protein ligase activity. It has been reported that

RCHY1(Pirh2) physically interacts with p53 and promotes ubiquitination of p53 independently of Mdm2. RCHY1 was also reported to be transactivated by the p53 product in MEFs, murine proB cell BaF3 and human BJT fibroblasts cells. Therefore, like MDM2, RCHY1 participates in an autoregulatory feedback loop that controls p53 function. Expression of RCHY1 decreased the level of p53 protein, while abrogation of endogenous RCHY1 expression increased the level of p53. Furthermore, RCHY1 represses p53 functions, including p53-dependent transactivation and growth inhibition. RCHY1 is overexpressed in both human and murine lung cancers by comparing Pirh2 mRNA and protein level between lung neoplastic tissues and uninvolved adjacent lung tissue. The increased RCHY1 protein could cause degradation of wild type p53 and reduce the tumor suppression function in tumor cells. It has been reported that coexpression of RCHY1(ARNIP) and androgen receptor (AR) in COS-1 cells reduces the interaction between AR N- and C-terminus. The RING-H2 domain of the RCHY1 functions as an ubiquitin-protein ligase in vitro in the presence of a specific ubiquitin-conjugating enzyme, Ubc4-1. Mutation of a single cysteine residue in the RCHY RING-H2 domain (Cys145Ala) abolished this E3 ubiquitin ligase activity. Fluorescent protein tagging studies revealed that AR-RCHY1 interaction was hormone-independent in COS-1 cells, and suggest that co-localization of both AR and RCHY1 to the nucleus upon androgen addition may allow RCHY1 to play a role in nuclear processes. It has been reported that wild-type RCHY1is an unstable protein with a short half-life and coexpression of TIP60 enhances RCHY1 protein stability and alters RCHY1 subcellular localization. In addition, MVP (measles virus phosphoprotein ) is able to specifically

RCHY1 (ring finger and CHY zinc finger domain containing 1) Duan W, Villalona-Calero MA


Immunohistochemical detection of human RCHY1 protein in non-small cell lung cancers. (A) squamous cell carcinoma, and (B) large cell carcinoma.

interact with and stabilize the RCHY1 by preventing its ubiquitination. It has been reported that the RCHY1 also interacts with NTKL-BP1 (N-terminal kinase-like protein-binding protein 1) proteína.

Homology It belongs to the ring finger ubiquitin protein E3 ligase family. Containing Conserved RING-finger Domain (residues 145-186) and CHY zinc finger (residues 20-94).

Mutations Note: Unknown.

Implicated in Non-Small Cell Lung Cancer Disease Lung cancers are pathologically classified as small cell lung cancer and non-small cell lung cancer (non-small cell lung cancer includes large cell carcinomas, squamous cell carcinomas and adenocarcinomas).

Oncogenesis RCHY1 protein is overexpressed in about 84% human lung cancers compared to uninvolved lung tissue. The RCHY1 protein was also elevated in about 93% of murine lung tumors. Because RCHY1 is an ubiquitin-protein ligase that promotes p53 protein degradation,

the increased RCHY1 expression could play an important role in lung tumorigenesis.

References Beitel LK, Elhaji YA, Lumbroso R, Wing SS, Panet-Raymond V, Gottlieb B, Pinsky L, Trifiro MA. Cloning and characterization of an androgen receptor N-terminal-interacting protein with ubiquitin-protein ligase activity. J Mol Endocrinol 2002;29:41-60.

Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 2003;112:779-791.

Duan W, Gao L, Druhan LJ, Zhu WG, Morrison C, Otterson GA, Villalona-Calero MA. Expression of Pirh2, a newly identified ubiquitin protein ligase, in lung cancer. J Natl Cancer Inst 2004;96:1718-1721.

Logan IR, Sapountzi V, Gaughan L, Neal DE, Robson CN. Control of human PIRH2 protein stability: involvement of TIP60 and the proteosome. J Biol Chem 2004;279:11696-11704.

Zhang L, Li J, Wang C, Ma Y, Huo K. A new human gene hNTKL-BP1 interacts with hPirh2. Biochem Biophys Res Commun 2005;330:293-297.

Chen M, Cortay JC, Logan IR, Sapountzi V, Robson CN, Gerlier D. Inhibition of ubiquitination and stabilization of human ubiquitin E3 ligase PIRH2 by measles virus phosphoprotein. J Virol 2005;79:11824-11836.

This article should be referenced as such: Duan W, Villalona-Calero MA. RCHY1 (ring finger and CHY zinc finger domain containing 1). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):173-174.

Leukaemia Section Mini Review




Follicular lymphoma (FL) Antonio Cuneo, Antonella Russo Rossi, Gianluigi Castoldi

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


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/FollLymphomID2075.html DOI: 10.4267/2042/38322

This article is an update of: Cuneo A, Castoldi GL. Follicular lymphoma (FL). Atlas Genet Cytogenet Oncol Haematol.2001;5(2):123-124. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Phenotype / cell stem origin Pan-B antigens test positive. The immunophenotypic profile is CD10+, CD5-, sIg+ and the cell of origin is a germinal centre B-cell that has encountered the antigen.

Epidemiology This lymphoma accounts for 30-40% of all lymphomas occurring in the adult population in western countries. Its peak incidence is in the fifth and sixth decade.

Clinics The patients most often present widespead disease at diagnosis, with nodal and extranodal (bone marrow) involvement. Peripheral blood involvement is detectable by light microscopy in approximately 10% of the cases, but the majority of cases can be shown to have circulating malignant cells by sensitive molecular genetic methods. The disease usually runs an indolent course. Grade 3 FL may be characterized by earlier relapse, especially if treated with regimens not including an anthracycline drug.

Pathology The lymphoma is composed of a mixture of centrocytes and centroblasts with a follicular and diffuse pattern. Lymphoma grading by the number of large cells/centroblasts is recommended: three grades are recognized with incresing number of centroblasts.

Treatment Depending on age and stage at presentation it may vary from a 'watch and wait' policy in initial stages to multiagent chemotherapy in advanced stages. Immunotherapy using chimeric anti-CD20 monoclonal

antibody has an important role in combination with chemotherapy. Radioimmunotherapy has an important role in relapsed or refractory patients.

Evolution The majority of patients cannot be cured by chemotherapy and eventually relapse. Histologic switch into high grade lymphoma may occur. A positive impact on long term disease free survival and overall survival is likely to derive from the introduction of monoclonal antibodies in association with multiagent chemotherapy.

Prognosis Approximately 60% of the patients presenting with limited disease are alive at 10 years. Patients in stages III and IV were reported to have a median survival in the 8-12 years range.

Cytogenetics Cytogenetics morphological Seventy-80% of the cases carry the t(14;18)(q32;q21) as the primary chromosome anomaly. Rare variant translocation t(2;18)(p11;q21) and t(18;22)(q21;q11) were described. Approximately 15% of the cases show a 3q27 break, half of which include the t(3;14)(q27;q32) and the variant translocations t(3;22)(q27;q11) and t(2;3)(p11;q27).

Cytogenetics molecular The incidence of 6q21 deletion and 17p13/p53 deletion (see below) by interphase FISH analysis may be around 60% and 20%, respectively.

Additional anomalies Secondary chromosome changes are both numerical and structural. Trisomy 7, +8, +12, +3, +18, +X each

Follicular lymphoma (FL) Cuneo A et al.


occur in 10-20% of the cases. There is an association between +7 and the presence of a large cell component, but no numerical anomaly has an independent impact on prognosis. Deletions of 6q23-26 occur at a 25-30% incidence; 17p anomalies are present in approximately 10% of the cases. The presence of these anomalies may have a correlation with disease transfornation and it was associated with an inferior prognosis. Rarely, histologic switch into a high grade lymphoma may be associated with the development of an additional t(8;14)(q24;q32). The clinical course in these cases is aggressive. The incidence of 6q21 deletion and 17p13/p53 deletion by interphase FISH analysis may be around 60% and 20%, respectively. Other anomalies include 1p36 deletion in 10-12% of the cases, probably centered around the p73 gene; 10q22-24 deletions in 10-13% of the cases and 9p21 deletions/p16 deletions, associated with histologic transformation.

Results of the chromosomal anomaly Fusion protein Description No fusion protein. The t(14;18) brings about the juxtaposition of BCL-2 with the Ig heavy chain joining segment, with consequent marked overexpression of the BCL2 protein product. The majority of breakpoints on 18q22 fall into two regions: the major breakpoint region (60-70% of the cases) and the minor cluster region (20-25% of the cases). In those cases with 3q27/BCL6 involvement the breakpoints on 3q27 are usually located in a different region with respect to high grade diffuse large cell lymphoma. This region is located 245 and 285 kb 5’ of BCL6 (alternative breakpoint cluster region).

Oncogenesis BCL-2 overexpression prevents cell to die by apoptosis. BCL-2 forms heterodimers with BAX and the relative proportion of BCL-2 to BAX determines the functional activity of BCL-2. In vitro, BCL-2 constitutive expression has a definite role in sustaining cell growth, whereas in vivo, BCL-2 transgenes induce a pattern of polyclonal proliferation of mature B-cells.

References Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F, Fruchart C, Duval C, Monconduit M, Tilly H. LAZ3 rearrangements in Non-Hodgkin's lymphoma: correlation with histoogy, immunophenotype, karyotype and clinical outcome in 217 patients. Blood 1994;83:2423-2427.

Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink HK, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA. A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Blood 1994;84:1361.

Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, Monconduit M, Bastard C. Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood 1994;84:1043-1049.

Gaidano G. Molecular genetics of malignant lymphoma. In:Foö R (ed): Reviews in clinical and experimental hematology. Forum Service Editore, Genova and Martin Dunitz, London, 1997.

Rohatiner A, Lister TA. Follicular lymphoma. In:Magrath I (ed): The non Hodgkin's lymphomas. Pp 867-895. Arnold, London 1997.

Zhang Y, Weber-Matthiesen K, Siebert R, Matthiesen P, Schlegelberger B. Frequent deletions of 6q23-24 in B-cell non-Hodgkin's lymphomas detected by fluorescence in situ hybridization. Genes Chromosomes Cancer 1997;18:310-313.

Bernell P, Jacobsson B, Liliemark J, Hjalmar V, Arvidsson I, Hast R. Gain of chromosome 7 marks the progression from indolent to aggressive follicle centre lymphoma and is a common finding in patients with diffuse large B-cell lymphoma: a study by FISH. Br J Haematol 1998;101:487-491.

Elenitoba-Johnson KS, Gascoyne RD, Lim MS, Chhanabai M, Jaffe ES, Raffeld M. Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma. Blood 1998;91:4677-4685.

Butler MP, Wang SI, Chaganti RS, Parsons R, Dalla-Favera R. Analysis of PTEN mutations and deletions in B-cell non-Hodgkin's lymphomas. Genes Chromosomes Cancer 1999;24:322-327.

Dave BJ, Hess MM, Pickering DL, Zaleski DH, Pfeifer AL, Weisenburger DD, Armitage JO, Sanger WG. Rearrangements of chromosome band 1p36 in non-Hodgkin's lymphoma. Clin Cancer Res 1999;5:1401-1409.

Harris NNL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of hematopoietic and lymphoid tissues: Report of the clinical advisory committee - Airlie House, Virginia, Novembre 1997. J Clin Oncol 1999;17:3835-3849.

Bosga-Bouwer AG, Haralambieva E, Booman M, Boonstra R, van den Berg A, Schuuring E, van den Berg E, Kluin P, Poppema S. BCL6 alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B. Genes Chromosomes Cancer 2005;44:301-304.

Voorhees PM, Carder KA, Smith SV, Ayscue LH, Rao KW, Dunphy CH. Follicular lymphoma with a burkitt translocation--predictor of an aggressive clinical course: a case report and review of the literature. Arch Pathol Lab Med 2004;128:210-213.

This article should be referenced as such: Cuneo A, Russo Rossi A, Castoldi GL. Follicular lymphoma (FL). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):175-176.





Mucosa-associated lymphoid tissue (MALT) lymphoma Antonio Cuneo, Gianluigi Castoldi



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/MALTlymphID2095.html DOI: 10.4267/2042/38323


Identity

t(11;18)(q21;q21) FISH - Courtesy Charles Bangs, Ilana Galperin.

Mucosa-associated lymphoid tissue (MALT) lymphoma Cuneo A, Castoldi GL


Clinics and pathology Disease MALT lymphoma is the extra-nodal presentation of marginal zone B-cell lymphomas (MZBCL).

Phenotype / cell stem origin The morphologic and phenotypic characteristics of malignant cells correspond to those of lymphocytes belonging to the marginal zone, harbouring hypermutated IgV genes with the following immunophenotype: pan-B+; CD5-/+; CD10-; CD23-; CD11c+/-; cyIg+ (40% of the cells); sIgM+ bright; sIgD-.

Epidemiology The incidence of extra-nodal MZBCL of MALT type in western countries is approximately 7% of all NHL diagnosed by histologic examination.

Clinics Extra-nodal MZBCL of MALT type is an indolent disease involving most often the stomach, where it usually follows chronic gastritis due to Helicobacter pylori (HP) infection. The disease may also localize in the lung, the thyroid the salivary gland and in the orbit, where an association was documented with Chlamydia Psittaci infection. AS with other clinicopathological forms of MZBCL (i.e. splenic MZBCL and nodal MZBCL) transformation into high grade lymphoma may occur.

Pathology The tumour consists of a cytologically heterogeneous infiltrate including centrocyte-like cells, monocytoid B-cells small lymphocytes and plasma cells. Large cells and/or blast-like cells may be present. Typically, lymphoepithelial lesions are seen in the stomach.

Treatment Low grade MALT with limited disease involving the stomach is usually HP+ and respond to eradication of the HP infection. Cases presenting at a more advanced stage or with transformation into high grade lymphoma require single-agent or multi-agent chemotherapy. Rituximab (anti-CD20 monoclonal antibody) is an effective treatment. Gastrectomy is indicated in non-responding patients.

Prognosis The patients usually have prolonged survival, as in other indolent lymphomas, but some cases may feature an aggressive disease.

Cytogenetics Cytogenetics molecular The most common anomalies in extra-nodal MZBCL of MALT type include:

The t(11;18)(q21;q21)/API2 -MLT fusion, having a 20-50% incidence. The translocation is associated with low-grade MALT lymphoma of the stomach, and of the lung. Importantly, this translocation was associated with increased rates of persistent disease or recurrence after HP eradication therapy. The translocation t(14;18)(q32;q21)/IgH -MLT1 fusion, leading to enhanced MLT1 expression may occur in 10-20% of all MALT lymphomas. It is associated with MALT lymphoma of the liver, skin, ocular adnexa, lung and salivary gland. It was not found in MALT lymphomas of the stomach, intestine, thyroid, or breast. The translocation t(1;14)(p22;q32) and/or the corresponding deregulation or rearrangement of BCL10 at 1p22 is another recurrent chromosome aberration in a minority of cases (6% by molecular genetics, including cases with BCL10 mutations and small deletions not detectable by cytogenetics) and it appears to be more frequent in high grade-MALT than in low grade MALT lymphoma. The t(3;14)/IgH- FOXP1 fusion may occur in 10% of all MALT lymphomas. It is associated with MALT lymphoma of the orbit, of the thyroid and skin, whereas it was not found in MALT lymphoma of the stomach, of the salivary gland and in other forms of MZBCL. Trisomy 3 and trisomy 18 were reported in low-grade as well as high-grade MALT lymphoma. FISH studies found a 20-60% incidence for +3, the difference being possibly accounted for by the variable sensitivity of methods adopted in different studies and by heterogeneity of patient populations. At the present time, there is no evidence that +3 plays an important role in disease progression. Trisomy 18 was observed more frequently in high grade MALT than in low grade MALT lymphomas. BCL6 rearrangements were documented to occur in a minority of cases, especially in the presence of a high-grade component.

Probes BCL6 rearrangements and the API2-MLT fusion, encoded on the derivative chromosome 11 resulting form the t(11;18)(q21;q21), can be studied by FISH as well as by molecular genetic methods. IgH-FOXP1 and IgH-MLT1 fusions can be studied by FISH. BCL10 rearrangements associated with the t(1;14) can be detected by Southern blotting, whereas mutations or small deletion not associated with the t(1;14) can be studied by PCR-SSCP analysis and gene sequencing.

Results of the chromosomal anomaly Fusion protein Oncogenesis

Mucosa-associated lymphoid tissue (MALT) lymphoma Cuneo A, Castoldi GL


MALT1 overexpression and API2-MALT fusion confer constitutional NFkB activity. This, in turn, leads to enhanced proliferation and resistance to apoptosis by B lymphocytes. BCL10 functions in conjunction with intracellular proteins (Carma1 and MALT1), producing the ubiquitination of NFkB inhibitor, leading to NFkB activation. These findings, along with the documented role of BCL10 in promoting survival of antigen-stimulated lymphocytes, suggest the IgH/BCL10 translocation may contribute to lymphomagenesis by enhancing BCL10 function.

References 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;84:1361-1392.

Dierlamm J, Pittaluga S, Stul M, Wlodarska I, Michaux L, Thomas J, Verhoef G, Verhest A, Depardieu C, Cassiman JJ, Hagemeijer A, De Wolf-Peeters C, Van den Berghe H. BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma. Br J Haematol 1997;98:719-725.

Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, Ott MM, Müller-Hermelink HK. The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT-) type. Cancer Res 1997;57:3944-3948.

The Non Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997;89:3909-3918.

Zucca E, Roggero E, Pileri S. B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours. Br J Haematol 1998;100:3-14.

Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 1999;93:3601-3609.

Gaidano G, Capello D, Gloghini A, Fassone L, Vivenza D, Ariatti C, Migliazza A, Saglio G, Carbone A. Frequent mutation of bcl-6 proto-oncogene in high grade, but not low grade, MALT lymphomas of the gastrointestinal tract. Haematologica 1999;84:582-588.

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;17:3835-3849.

Hoeve MA, Gisbertz IA, Schouten HC, Schuuring E, Bot FJ, Hermans J, Hopman A, Kluin PM, Arends JW, van Krieken JH. Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy. Leukemia 1999;13:799-807.

Alpen B, Neubauer A, Dierlamm J, Marynen P, Thiede C, Bayerdörfer E, Stolte M. Translocation t(11;18) absent in early gastric marginal zone B-cell lymphoma of MALT type

responding to eradication of Helicobacter pylori infection. Blood 2000;95:4014-4015.

Dierlamm J, Baens M, Stefanova-Ouzounova M, Hinz K, Wlodarska I, Maes B, Steyls A, Driessen A, Verhoef G, Gaulard P, Hagemeijer A, Hossfeld DK, De Wolf-Peeters C, Marynen P. Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes. Blood 2000;96:2215-2218.

Du MQ, Peng H, Liu H, Hamoudi RA, Diss TC, Willis TG, Ye H, Dogan A, Wotherspoon AC, Dyer MJ, Isaacson PG. BCL10 gene mutation in lymphoma. Blood 2000;95:3885-3890.

Maes B, Baens M, Marynen P, De Wolf-Peeters C. The product of the t(11;18), an API2-MLT fusion, is an almost exclusive finding in marginal zone cell lymphoma of extranodal MALT-type. Ann Oncol 2000;11:521-526.

Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P, Cavazzini F, Minotto C, De Angeli C, Bardi A, Tammiso E, Negrini M, Cavazzini P, Castoldi G. Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases. Haematologica 2001;86:64-70.

Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, Ye H, Molina T, Bouhnik Y, Hamoudi RA, Diss TC, Dogan A, Megraud F, Rambaud JC, Du MQ, Isaacson PG. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 2001;357:39-40.

Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood 2003;101:2335-2339.

Remstein ED, Kurtin PJ, Einerson RR, Paternoster SF, Dewald GW. Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1. Leukemia 2004;18:156-160.

Ho L, Davis RE, Conne B, Chappuis R, Berczy M, Mhawech P, Staudt LM, Schwaller J. MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. Blood 2005;105:2891-2899.

Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 2005;23:1979-1983.

Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 2005;19:652-658.

Tian MT, Gonzalez G, Scheer B, DeFranco AL. Bcl10 can promote survival of antigen-stimulated B lymphocytes. Blood 2005;106:2105-2112.

Wündisch T, Thiede C, Morgner A, Dempfle A, Günther A, Liu H, Ye H, Du MQ, Kim TD, Bayerdörffer E, Stolte M, Neubauer A. Long-Term Follow-Up of Gastric MALT Lymphoma After Helicobacter Pylori Eradication. J Clin Oncol 2005;23(31):8018-8024.

This article should be referenced as such: Cuneo A, Castoldi GL. Mucosa-associated lymphoid tissue (MALT) lymphoma. Atlas Genet Cytogenet Oncol Haematol.2006;10(3):177-179.





Marginal zone B-cell lymphoma Antonio Cuneo, Gianluigi Castoldi



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/MarginalZoneBID2078.html DOI: 10.4267/2042/38324

This article is an update of: Cuneo A, Castoldi GL. Marginal zone B-cell lymphoma. Atlas Genet Cytogenet Oncol Haematol.2001;5(3).204-206 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease Marginal zone B-cell lymphoma (MZBCL), including three distinct clinicopathological forms (Harris et al., 1999), namely: 1- extra-nodal MZBCL of mucosa-associated lymphoid tissue ( MALT ) type; 2- splenic MZBCL, corresponding to splenic lymphoma with villous lymphocytes (SLVL); 3- nodal MZBCL

Phenotype / Stem. cell origin The morphologic and phenotypic characteristics of malignant cells correspond to those of lymphocytes belonging to the marginal zone, harbouring hypermutated IgV genes with the following immunophenotype: pan-B+; CD5-/+; CD10-; CD23-; CD11c+/-; cyIg+ (40% of the cells), sIgM+ bright; sIgD-.

Epidemiology The global incidence of MZBCL in western countries is approximately 10% of all non Hodgkin lymphomas (NHL) diagnosed by histologic examination.

Clinics Extra-nodal MZBCL of MALT type (7% of all NHL) is an indolent disease involving most often the stomach, where it usually follows chronic gastritis due to Helicobacter pylori (HP) infection. The disease may also localize in the lung, the thyroid the salivary gland and in the orbit, where an association was documented with Chlamydia Psittaci infection. Splenic MZBCL (1% of all NHL on histologic

samples) usually, though not invariably, presents. Splenomegaly associated circulating villous lymphocytes and BM involvement. It runs an indolent course. Nodal MZBCL (2% of al NHL) is a low-grade lymphoma, frequently presenting with advanced-stage disease, but not with large masses. Early relapse after chemotherapy may be observed in some patients and survival is shorter that in MZBCL of MALT type. All subsets may transform into a high grade lymphoma.

Pathology The tumour consists of a cytologically heterogeneous infiltrate including centrocyte-like cells, monocytoid B-cells small lymphocytes and plasma cells. Large cells and/or blast-like cells may be present. In epithelial tissues (i.e. stomach) typical lymphoepithelial lesions are characteristically seen. In the spleen, involvement of the mantle zone and marginal zone of the white pulp occur, usually centered around a residual germinal centre. The red pulp is usually involved.

Treatment Low grade MALT with limited disease involving the stomach is usually HP+ and respond to eradication of the HP infection. Cases presenting at a more advanced stage or with transformation into high grade lymphoma require single-agent or multi-agent chemotherapy. Rituximab (anti-CD20 monoclonal antibody) is an effective treatment. Gastrectomy is indicated in non-responding patients. Splenic MZBCL and nodal MZBCL are treated using various forms of chemotherapy depending on the disease stage and patient's conditions. Splenectomy is an option for splenic MZBCL.

Marginal zone B-cell lymphoma Cuneo A, Castoldi GL


Prognosis The patients usually have prolonged survival, as in other indolent lymphomas, but some cases may feature an aggressive disease.

Cytogenetics Cytogenetics morphological The most common anomalies in extra-nodal MZBCL of MALT type include: The t(11;18)(q21;q21) / API2 - MLT fusion, having a 20-50% incidence. The translocation is associated with low-grade MALT lymphoma of the stomach and of the lung. Importantly, this translocation was associated with resistance to HP eradication therapy. The translocation t(14;18)(q32;q21) / IgH - MLT1 fusion, leading to enhanced MLT1 expression may occur in 10-20% of all MALT lymphomas. It is associated with MALT lymphoma of the liver, skin, ocular adnexa, lung and salivary gland. It was not found in MALT lymphomas of the stomach, intestine, thyroid, or breast. The translocation t(1;14)(p22;q32) and/or the corresponding deregulation or rearrangement of BCL10 at 1p22 is another recurrent chromosome aberration in a minority of cases (6% by molecular genetics, including cases with BCL10 mutations and small deletions not detectable by cytogenetics) and it appears to be more frequent in high grade-MALT than in low grade MALT lymphoma. The t(3;14) / IgH - FOXP1 fusion may occur in 10% of all MALT lymphomas. It is associated with MALT lymphoma of the orbit, of the thyroid and skin, whereas it was not found in MALT lymphoma of the stomach, of the salivary gland and in other forms of MZBCL. Trisomy 3 and trisomy 18 were reported in low-grade as well as high-grade MALT lymphoma. FISH studies found a 20-60% incidence for +3, the difference being possibly accounted for by the variable sensitivity of methods adopted in different studies and by heterogeneity of patient populations. At the present time, there is no evidence that +3 plays an important role in disease progression. Trisomy 18 was observed more frequently in high grade MALT than in low grade MALT lymphomas. The most common anomalies in splenic MZBCL include: 7q deletions or unbalanced 7q translocations, usually involving a relatively large segment, centred around the 7q22-q32 region. The incidence is 10-30%, but as many as 40% of the cases may harbour a sub-microscopic deletion of this region. The commonly deleted segment spans a region between 7q32.1 to 7q32-3. Total or partial trisomy 3, involving the 3q21-23 and 3q25-29 chromosome regions. The incidence of +3q falls in the 30-50% range.

Total or partial trisomy 12, found in 20-30% of the cases. 17p- involving the p53 gene, found in 10-30% of the cases. This aberration is associated with a more aggressive clinical course. A recurrent translocation t(11;14)(p11;q32) was found in a minority of cases featuring a relatively aggressive disease with PB involvement by a blast-like cell component. The classical t(11;14)(q13;q32) was found in some cases of splenic lymphoma with villous lymphocytes (Oscier et al, 1993), but more recent studies did not detect this translocation in histologically documented splenic MZBCL. Nodal MZBCL: At the present time there is insufficient data to establish whether nodal MZBCL has a distinct cytogenetic profile. Trisomy 12 may be more frequent in nodal MZBCL, but there is evidence that this disease subset may share clinicopathologic and cytogenetic features with other forms of MZBCL. In the 3 principal clinicopathological subsets of MZBCL, BCL6 rearrangements were documented to occur in a minority of cases, especially in the presence of a high-grade component.

Probes The most frequently occurring DNA gains or losses which can be studied by interphase/metaphase fluorescence in situ hybridisation (FISH) are the following: Deletions: a 5cM segment at 7q31, defined by the D7S685 and D7S514 markers; 17p/p53. Total/partial trisomies: 3q21-23; 3q25-29; 5q13-15; 12q15-21. BCL6 rearrangements and the API2-MLT fusion, encoded on the derivative chromosome 11 resulting form the t(11;18)(q21;q21), can be studied by FISH as well as by molecular genetic methods. IgH-FOXP1 and IgH-MLT1 fusions can be studied by FISH. BCL10 rearrangements associated with the t(1;14) can be detected by Southern blotting, whereas mutations or small deletion not associated with the t(1;14) can be studied by PCR-SSCP analysis and gene sequencing.

Genes involved and Proteins Oncogenesis MALT1 overexpression and API2-MALT fusion confer constitutional NFkB activity. This, in turn, leads to enhanced proliferation and resistance to apoptosis by B lymphocytes. BCL10 has a pro-apoptotic action on cell lines. However, it functions in conjunction with intracellular proteins (Carma1 and MALT1), producing the ubiquitination of NFkB inhibitor, leading to NFkB activation. These findings, along with the documented



role of BCL10 in promoting survival of antigen-stimulated lymphocytes, suggest that IgH/BCL10 translocation may contribute to lymphomagenesis by enhancing BCL10 function. P53 is a key tumour suppressor gene having an established role in disease progression in a number of hematologic and extra-hematologic neoplasias, including MZBCL.

References Oscier DG, Matutes E, Gardiner A, Glide S, Mould S, Brito-Babapulle V, Ellis J, Catovsky D. Cytogenetic studies in splenic lymphoma with villous lymphocytes. Br J Haematol 1993;85:487-491.

Imamura J, Miyoshi I, Koeffler HP. p53 in hematologic malignancies. Blood 1994;84:2412-2421.

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;84:1361-1392.

Dierlamm J, Rosenberg C, Stul M, Pittaluga S, Wlodarska I, Michaux L, Dehaen M, Verhoef G, Thomas J, de Kelver W, Bakker-Schut T, Cassiman JJ, Raap AK, De Wolf-Peeters C, Van den Berghe H, Hagemeijer A. Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. Leukemia 1997;11:747-758.

Dierlamm J, Pittaluga S, Stul M, Wlodarska I, Michaux L, Thomas J, Verhoef G, Verhest A, Depardieu C, Cassiman JJ, Hagemeijer A, De Wolf-Peeters C, Van den Berghe H. BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma. Br J Haematol 1997;98:719-725.

Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, Ott MM, Müller-Hermelink HK. The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT-) type. Cancer Res 1997;57:3944-3948.

The Non Hodgkin's Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 1997;89:3909-3918.

Zucca E, Roggero E, Pileri S. B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours. Br J Haematol 1998;100:3-14.

Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer A, Van den Berghe H, Marynen P. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21)p6ssociated with mucosa-associated lymphoid tissue lymphomas. Blood 1999;93:3601-3609.

Gaidano G, Capello D, Gloghini A, Fassone L, Vivenza D, Ariatti C, Migliazza A, Saglio G, Carbone A. Frequent mutation of bcl-6 proto-oncogene in high grade, but not low grade, MALT lymphomas of the gastrointestinal tract. Haematologica 1999;84:582-588.

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;17:3835-3849.

Hoeve MA, Gisbertz IA, Schouten HC, Schuuring E, Bot FJ, Hermans J, Hopman A, Kluin PM, Arends JW, van Krieken JH. Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy. Leukemia 1999;13:799-807.

Mateo M, Mollejo M, Villuendas R, Algara P, Sanchez-Beato M, Martínez P, Piris MA. 7q31-32 allelic loss is a frequent finding in splenic marginal zone lymphoma. Am J Pathol 1999;154:1583-1589.

Nathwani BN, Anderson JR, Armitage JO, Cavalli F, Diebold J, Drachenberg MR, Harris NL, MacLennan KA, Müller-Hermelink HK, Ullrich FA, Weisenburger DD. Marginal zone B-cell lymphoma: A clinical comparison of nodal and mucosa-associated lymphoid tissue types. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1999;17:2486-2492.

Alpen B, Neubauer A, Dierlamm J, Marynen P, Thiede C, Bayerdörfer E, Stolte M. Translocation t(11;18) absent in early gastric marginal zone B-cell lymphoma of MALT type responding to eradication of Helicobacter pylori infection. Blood 2000;95:4014-4015.

Dierlamm J, Baens M, Stefanova-Ouzounova M, Hinz K, Wlodarska I, Maes B, Steyls A, Driessen A, Verhoef G, Gaulard P, Hagemeijer A, Hossfeld DK, De Wolf-Peeters C, Marynen P. Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes. Blood 2000;96:2215-2218.

Du MQ, Peng H, Liu H, Hamoudi RA, Diss TC, Willis TG, Ye H, Dogan A, Wotherspoon AC, Dyer MJ, Isaacson PG. BCL10 gene mutation in lymphoma. Blood 2000;95:3885-3890.

Maes B, Baens M, Marynen P, De Wolf-Peeters C. The product of the t(11;18), an API2-MLT fusion, is an almost exclusive finding in marginal zone cell lymphoma of extranodal MALT-type. Ann Oncol 2000;11:521-526.

Macintyre E, Willerford D, Morris AW. Non Hodgkin's lymphoma: Molecular features of non Hodgkin's lymphoma. Congress of the American Society of Hematology. Educational book 2000:pp. 180-204.

Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P, Cavazzini F, Minotto C, De Angeli C, Bardi A, Tammiso E, Negrini M, Cavazzini P, Castoldi GL. Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases. Haematologica 2001;86:64-70.

Cuneo A, Bardi A, Wlodarska I, Selleslag D. Roberti MG, Bigoni R, Cavazzini F, De Angeli C, Senno L, Cavazzini P, Hagemeijer A, Castoldi GL. A novel recurrent translocation t(11;14)(p11;q32) in splenic marginal zone B-cell lymphoma. Leukemia in press, 2001.

Gruszka-Westwood AM, Hamoudi RA, Matutes E, Tuset E, Catovsky D. p53 abnormalities in splenic lymphoma with villous lymphocytes. Blood 2001;97:3552-3558.

Hernández JM, García JL, Gutiérrez NC, Mollejo M, Martínez-Climent JA, Flores T, González MB, Piris MA, San Miguel JF. Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics. Am J Pathol 2001;158:1843-1850.

Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, Ye H, Molina T, Bouhnik Y, Hamoudi RA, Diss TC, Dogan A, Megraud F, Rambaud JC, Du MQ, Isaacson PG. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 2001;357:39-40.

Solé F, Salido M, Espinet B, García JL, Martínez Climent JA, Granada I, Hernández JM, Benet I, Piris MA, Mollejo M, Martinez P, Vallespi T, Domingo A, Serrano S, Woessner S, Florensa L. Splenic marginal zone B-cell lymphomas: two cytogenetic subtypes, one with gain of 3q and the other with loss of 7q. Haematologica 2001;86:71-77.



Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A. T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Blood 2003;101:2335-2339.

Remstein ED, Kurtin PJ, Einerson RR, Paternoster SF, Dewald GW. Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1. Leukemia 2004;18:156-160.

Ho L, Davis RE, Conne B, Chappuis R, Berczy M, Mhawech P, Staudt LM, Schwaller J. MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. Blood 2005;105:2891-2899.

Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L,

Zucca E. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 2005;23:1979-1983.

Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 2005;19:652-658.

Tian MT, Gonzalez G, Scheer B, DeFranco AL. Bcl10 can promote survival of antigen-stimulated B lymphocytes. Blood 2005;106:2105-2112.

This article should be referenced as such: Cuneo A, Castoldi GL. Marginal zone B-cell lymphoma. Atlas Genet Cytogenet Oncol Haematol.2006;10(3):180-183.





M3/M3v acute non lymphocytic leukemia (M3-ANLL) M3/M3v acute myeloid leukemia (AML M3/M3v) Acute promyelocytic leukemia (APL) Claudia Schoch

MLL Münchner Leukämielabor GmbH, Max-Lebsche-Platz 31, 81377 München, Germany


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/M3ANLLID1240.html DOI: 10.4267/2042/38325


Identity FAB criteria AML M3: Great majority of cells are abnormal promyelocytes, with a characteristic pattern of heavy granulation. Characteristic cells contain bundles of Auer rods ('faggots'). FAB criteria AML M3v: Minimal granulation, relative scarcity of cells with heavy granulation and cells containing multiple Auer rods. The nucleus of every cell in the peripheral blood is bilobed, multilobed or reniform, but the majority of cells are either devoid of granules or contain only a few fine azurophil granules. However, at least a few cells with all the cytoplasmic features of typical AML M3 are present. If these are overlooked, the cases are likely misdiagnosed as atypical monocytic leukemia. The atypical morphology is mainly a feature of the peripheral blood cells - bone marrow morphology is closer to that of typical AML M3. Both subtypes show a very strong myeloperoxidase reaction and a negative reaction for non-specific esterase. Immunophenotype: Characteristic but not diagnostic myeloid phenotype. CD33 positive, HLA-DR is generally absent. In M3 but not M3v: characteristic light scatter pattern, strong unspecific fluorescence signal. WHO classification: Distinct entity in category AML with recurrent genetic abnormalities: Acute promyelocytic leukemia (AML with t(15;17)(q22;q12) (PML / RARA) and variants).

Clinics and pathology Epidemiology Rare: 5-8 % of ANLL, incidence higher in Spain, Italy and Latinos; occurs at any age, predominantly adults in mid-life accounting for aprox. 5% of treatment related leukemias (t-AML).

Clinics Low WBC in AML M3, high WBC in AML M3v; frequently associated with disseminated intravascular coagulation (DIC) and hyperfibrinolysis.

Cytology The cytomorphology of APL blasts is obviously different in the two subtypes: in AML M3, the abnormal promyelocytes show a heavy granulation and bundles of Auer rods; in AML M3v blasts have a non- or hypogranular cytoplasm or contain fine dustlike cytoplasmic granules that may not be apparent by light microscopy. Furthermore, M3v blasts show a typical bilobed nuclear configuration. This latter morphologic phenotype, together with missing granulation, often resulted in the misleading diagnosis of acute monocytic or myelo-monocytic leukemia before the cytogenetic correlation of both AML M3 and M3v with t(15;17)(q22;q12) was observed. AML M3v accounts for approximately 1/3 of APL cases.

Prognosis Favourable if treated with an ATRA (all trans-retinoic acid) and anthracycline containing regimen: CR in >80% of cases, med survival: in most studies with

M3/M3v acute non lymphocytic leukemia (M3-ANLL); M3/M3v acute myeloid leukemia (AML M3/M3v); Schoch C Acute promyelocytic leukemia (APL)


ATRA treatment not reached yet, adverse prognosis factors: high WBC, FLT3 - internal tandem duplication (ITD), bleeding episodes.

Cytogenetics Cytogenetics morphological t(15;17)(q22;q12) leading to a PML-RARA-rearrangement on the molecular level. Variant translocations involving one ore more chromosomes in addition to 15 and 17 are found in 2-5% of cases with PML-RARA-rearrangement. Cytogenetically cryptic PML-RARA-rearrangements are observed in 2-3% of APL cases.

Additional anomalies Are observed in 35-45% of cases, most frequent: +8, del(9q), ider(17)(q10)t(15;17).

Variants 3 variant translocations involving RARA: t(11;17)(q23;q12) leading to a fusion of RARA and PLZF; t(5;17)(q23;q12) leading to a fusion of RARA and NPM; t(11;17)(q13;q12) leading to a fusion of RARA and NuMA. The cases with variant translocation have initially been reported as having APL morphology. However, morphological differences exist. Clinically important is that APL variant with t(5;17)(q12;q12) seems to respond to ATRA, while APL variant with t(11;17)(q23;q12) does not.

References Bennett JM, Catovsky D, Daniel M-T, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Proposals for the Classification of the acute leukemias. Br J Haematol 1976;33:451-458.

Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1977;1:549-550.

Bennett JM, Catovsky D, Daniel M-T, Flandrin G, Galton DAG, Gralnick HR, Sultan C. A variant form of hypergranular promyelocytic leukemia (M3). Br J Haematol 1980;44:169-170.

Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021-1028.

Lengfelder E, Reichert A, Schoch C, Haase D, Haferlach T, Löffler H et al. Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. Leukemia 2000;14:1362-1370.

Schoch C, Schnittger S, Kern W, Lengfelder E, Löffler H, Hiddemann W, Haferlach T. Rapid diagnostic approach to PML-RARalpha-positive acute promyelocytic leukemia. Hematol J 2002;3:259-263.

Schoch C, Schnittger S, Kern W, Dugas M, Hiddemann W, Haferlach T. Acute myeloid leukemia with recurring chromosome abnormalities as defined by the WHO-classification: incidence of subgroups, additional genetic abnormalities, FAB subtypes and age distribution in an unselected series of 1,897 patients with acute myeloid leukemia. Haematologica 2003;88:351-352.

Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S. Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Haematol 2005;130:196-202.

Brunning RD, Matutes E, Harris NL, Flandrin G, Vardiman J, Bennett JM, Head DR. WHO histological classification of acute myeloid leukaemias. World Health Organization of Tumors, Pathology & Genetics, Tumors of haematopoietic and lymphoid tissues, editors: Jaffe ES, Harris NL, Stein H, Vardiman J. Lyon, IARC Press Chapter 4, page: 75-108.

This article should be referenced as such: Schoch C. M3/M3v acute non lymphocytic leukemia (M3-ANLL); M3/M3v acute myeloid leukemia (AML M3/M3v); Acute promyelocytic leukemia (APL). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):184-185.





t(10;11)(p11.2;q23) Cristina Morerio, Claudio Panarello

Dipartimento di Ematologia ed Oncologia Pediatrica, IRCCS Istituto Giannina Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1011ID1178.html DOI: 10.4267/2042/38326

This article is an update of: Huret JL. t(10;11)(p11.2;q23). Atlas Genet Cytogenet Oncol Haematol.2000;4(2):71. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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/M5.

Epidemiology Only three cases reported to date: all infants (2M/1F).

Clinics Two boys aged 2 and 8 months respectively, achieved complete remission (1 years+, 5 years+), the newborn girl died soon for infection during induction.

Cytogenetics

A. Partial Q-banded karyotype showing the t(10;11)(p11.2;q23), derivative chromosomes are on the right. B. FISH using RP13-31H8 (ABI1) shows one signal on the normal chromosome 10 and the another one split between the p arm of der(10) (arrowheads) and the q arm of der(11) (arrow). The BAC clone was provided by Prof. M.Rocchi.

t(10;11)(p11.2;q23) Morerio C, Panarello C


Genes involved and Proteins ABI-1 Location: 10p11.2

DNA / RNA Different splicings.

Protein Possesses a SH3 domain; cell growth inhibitor.

MLL Location: in 11q23

DNA / RNA 13-15 kb mRNA.

Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation.

Results of the chromosomal anomaly Hybrid gene Description 5' MLL - 3' ABI1; fusion at MLL exon 6-7. The breakpoint of ABI1 gene is the same in the two

cases studied (nucleotide 433), while the breakpoint of MLL can be located either in exon 6 or 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;92:1125-1130.

Shibuya N, Taki T, Mugishima H, Chin M, Tsuchida M, Sako M, Kawa K, Ishii E, Miura I, Yanagisawa M, Hayashi Y. t(10;11)-acute leukemias with MLL-AF10 and MLL-ABI1 chimeric transcripts: specific expression patterns of ABI1 gene in leukemia and solid tumor cell lines. Genes Chromosomes Cancer 2001;32:1-10.

Morerio C, Rosanda C, Rapella A, Micalizzi C, Panarello C. Is t(10;11)(p11.2;q23) involving MLL and ABI-1 genes associated with congenital acute monocytic leukemia?. Cancer Genet Cytogenet 2002;139:57-59.

This article should be referenced as such: Morerio C, Panarello C. t(10;11)(p11.2;q23). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):186-187.

Leukaemia Section Short Communication




t(5;14)(q33;q32) PDGFRB/KIAA1509 Jean-Loup Huret



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0514q33q32ID1379.html DOI: 10.4267/2042/38327


Clinics and pathology Disease Atypical chronic myeloid leukemia (a-CML).

Epidemiology Only one case to date with ascertainment of the genes involved (another case was a 18 year old female patient with a M2 acute non lymphocytic leukemia (ANLL) and a t(7;11)(p15;p15) ; the t(5;14) appeared at relapse, 5 months before death, 27 months after diagnosis).

Clinics The sole case of t(5;14)(q33;q32) with certain PDGFRB/KIAA1509 involvement was a 42 year old male patient, BCR-ABL negative, treatad with imatinib, and maintained in complete remission 18 mths after diagnosis.

Genes involved and Proteins PDGFRB Location: 5q33

Protein PDGFRB is the receptor for PDGFB (platelet-derived growth factor-b); Ig like, transmembrane and tyrosine kinase domains; membrane tyrosine kinase; can homodimerize.

KIAA1509 Location: 14q32

Protein Poorly known; 1935 amino acids; possess a coiled coil domain.

Results of the chromosomal anomaly Hybrid gene Description 5' KIAA1509 - 3' PDGFRB; breakpoint in PDGFRB intron 10, identical to most PDGFRB breakpoints.

Fusion protein Description 934 amino acids composed of the 355 amino acids from KIAA1506 in N-term and 579 amino acids from PDGFRB C-term.

Oncogenesis The coiled coil domain may mediate PDGFRB homodimerization and constitutive activation.

References Abe A, Tanimoto M, Towatari M, Matsuoka A, Kitaori K, Kato H, Toyozumi H, Takeo T, Adachi K, Emi N, Kawashima K, Saito H. Acute myeloblastic leukemia (M2) with translocation (7;11) followed by marked eosinophilia and additional abnormalities of chromosome 5. Cancer Genet Cytogenet 1995;83:37-41.

Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, Galinsky I, Stone RM, DeAngelo DJ, Gilliland DG, Cools J. KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). Leukemia 2005;19:27-30.

This article should be referenced as such: Huret JL. t(5;14)(q33;q32) PDGFRB/KIAA1509. Atlas Genet Cytogenet Oncol Haematol.2006;10(3):188.





t(5;15)(q33;q22) Jean-Loup Huret





Clinics and pathology Disease Atypical chronic myelogenous leukemia (a-CML) (BCR-ABL negative chronic myeloproliferative disease).

Epidemiology Only one case to date, a 79 year old male patient.

Prognosis The disease was sensitive to imatinib, but the patient developped resistance to imatinib and died 14 months after diagnosis.

Genes involved and Proteins PDGFRB Location: 5q33

Protein PDGFRB is the receptor for PDGFB (platelet-derived growth factor-b); Ig like, transmembrane and tyrosine kinase domains; membrane tyrosine kinase; can homodimerize.

TP53BP1 Location: 15q22

Protein Component of the cellular response to DNA damage.

Results of the chromosomal anomaly Hybrid gene Description 5' TP53BP1 - 3' PDGFRB; breakpoint in PDGFRB intron 10, identical to most PDGFRB breakpoints; exon

23 of TP53BP1 fused in frame to PDGFRB exon 11; reciprocal product not detectable. Fusion protein Description 247 kDa; composed of the N-term TP53BP1 including the coiled coil domains and the kinetochore binding domain from TP53BP1 fused to the transmembrane and the tyrosine kinase domains of PDGFRB C-term.

Oncogenesis The coiled coil domains from TP53BP1 may mediate PDGFRB homodimerization and constitutive activation of its tyrosine kinase activity; on the other hand, the DNA damage response of TP53BP1 may be perturbed.

References Rappold I, Iwabuchi K, Date T, Chen J. Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage-signaling pathways. J Cell Biol 2001;153:613-620.

Charier G, Couprie J, Alpha-Bazin B, Meyer V, Quéméneur E, Guérois R, Callebaut I, Gilquin B, Zinn-Justin S. The Tudor tandem of 53BP1: a new structural motif involved in DNA and RG-rich peptide binding. Structure 2004;12:1551-1562.

Grand FH, Burgstaller S, Kühr T, Baxter EJ, Webersinke G, Thaler J, Chase AJ, Cross NC. p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. Cancer Res 2004;64:7216-7219.

Ward IM, Difilippantonio S, Minn K, Mueller MD, Molina JR, Yu X, Frisk CS, Ried T, Nussenzweig A, Chen J. 53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice. Mol Cell Biol 2005;25:10079-10086.

Zgheib O, Huyen Y, DiTullio RA Jr, Snyder A, Venere M, Stavridi ES, Halazonetis TD. ATM signaling and 53BP1. Radiother Oncol 2005;76:119-122.

This article should be referenced as such: Huret JL. t(5;15)(q33;q22). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):189.





t(7;8)(q34;p11) Elena Belloni, Francesco Lo Coco, Pier Giuseppe Pelicci

IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, and IEO, Istituto Europero di Oncologia, Milan, Italy


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0708q34p11ID1409.html DOI: 10.4267/2042/38329


Clinics and pathology Disease Acute myeloid leucemia (AML) and 8p11 myeloproliferative syndrome (EMS). Chromosome band 8p11 has been implicated in recurrent chromosome rearrangements associated either with acute myeloid leukemia (AML) or with a peculiar myeloproliferative disorder named 8p11 myeloproliferative syndrome (EMS). The latter is characterized by generalized lymphadenopathy and marked eosinophilia, rapid evolution to AML, and frequent association with non-Hodgkin lymphoma. The FGFR1 gene is constantly involved in EMS, often evolving to AML.

Phenotype / cell stem origin AML-M4 (EMS).

Clinics 1 case to date, a female patient aged 49 yrs. The differential WBC count suggested a chronic MPD. Examination of a bone marrow smear showed 44% blasts, hypoplasia, and eosinophilia. The immunophenotypic characterization revealed the coexistence of two distinct components, a myelomonocytic part along with a lymphoid population. A diagnosis of AML-M4 was established.

Treatment Induction therapy was started with daunorubicin, cytosine arabinoside, and etoposide.

Evolution The patient died of sepsis during aplasia on day 20.

Cytogenetics Probes See figure below

Additional anomalies None

Genes involved and Proteins TRIM24 Location: 7q34 Note: Alias TIF1

DNA / RNA See figure a. Transcript: 2 variants. For details see the specific NCBI page.

Protein TIF1 encodes a nuclear protein, transcription intermediary factor 1a displaying an RBCC motif (RING finger, B-BOX, and coiled-coil domains, also called tripartite motif, TRIM) in its N-terminus and PHD and bromo domains at the C-terminus (figure b).

FGFR1 Location: 8p11

DNA / RNA See figure c. Transcript: various isoforms. For details see the specific NCBI page. Protein The FGFR1 gene encodes the fibroblast growth factor receptor 1, a transmembrane receptor with a tyrosine kinase (TK) domain in the intracellular C-terminus, a transmembrane (TM) domain, and 3 immunoglobulin-like C-2 type extracellular domains.

t(7;8)(q34;p11) Belloni E et al.


Genomic clones and genes in the FGFR1 (8p11) and TIF1 (7q34) regions. To the left are shown the positions of the RPCI11- 350N15 at 8p11 and of the 2 adjacent genomic clones, RPCI11-513D5 and 675F6 (vertical white bars, genes in the genomic region of interest). On the right are the positions of the 4 clones that span the TIF1 locus (indicated by a vertical white bar) at 7q34 (RPCI11-18L16, 256C24, 199L18, and 269N18).

Genomic structure (not drawn to scale) of the TIF1 loci (numbered black boxes, exons) in figure a. The corresponding protein are represented in figure b.

Genomic structure (not drawn to scale) of the FGFR1 loci (numbered black boxes, exons) in figure c. The corresponding proteins are represented in figure d.



Results of the chromosomal anomaly Hybrid gene Note: TIF1-FGFR1 and FGFR1-TIF1: see figure e.

Fusion protein Note: TIF1-FGFR1 and FGFR1-TIF1: see figure f.

References Bench AJ, Nacheva EP, Champion KM, Green AR. Molecular genetics and cytogenetics of myeloproliferative disorders. Baillieres Clin Haematol 1998;11(4):819-848.

Reiter A, Sohal J, Kulkarni S, Chase A, Macdonald DH, Aguiar RC, Gonçalves C, Hernandez JM, Jennings BA, Goldman JM, Cross NC. Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome. Blood 1998;92(5):1735-1742.

Kulkarni S, Reiter A, Smedley D, Goldman JM, Cross NC. The genomic structure of ZNF198 and location of breakpoints in the t(8;13)myeloproliferative syndrome. Genomics 1999;55(1):118-121.

Reither A, Hehlmann R, Goldman JM, Cross NC. The 8p11 myeloproliferative syndrome. Med Klin (Munich) 1999; 94(4):207-10. (Review). German.

Smedley D, Demiroglu A, Abdul-Rauf M, Heath C, Cooper C, Shipley J, Cross NC. ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5. Neoplasia 1999;1(4):349-355.

Bench AJ, Cross NC, Huntly BJ, Nacheva EP, Green AR. Myeloproliferative disorders. Best Pract Res Clin Haematol 2001;14(3):531-551.

Sohal J, Chase A, Mould S, Corcoran M, Oscier D, Iqbal S, Parker S, Welborn J, Harris RI, Martinelli G, Montefusco V, Sinclair P, Wilkins BS, van den Berg H, Vanstraelen D,

Goldman JM, Cross NC. Identification of four new translocations involving FGFR1 in myeloid disorders. Genes Chromosomes Cancer 2001;32(2):155-163.

Macdonald D, Reiter A, Cross NC. The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol 2002;107(2):101-107.

Grand EK, Grand FH, Chase AJ, Ross FM, Corcoran MM, Oscier DG, Cross NC. Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome. Genes Chromosomes Cancer 2004;40(1):78-83.

Heath C, Cross NC. Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1. J Biol Chem 2004;279(8):6666-6673.

Roumiantsev S, Krause DS, Neumann CA, Dimitri CA, Asiedu F, Cross NC, Van Etten RA. Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. Cancer Cell 2004;5(3):287-298.

Vizmanos JL, Hernández R, Vidal MJ, Larráyoz MJ, Odero MD, Marín J, Ardanaz MT, Calasanz MJ, Cross NC. Clinical variability of patients with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion: two further cases. Hematol J 2004;5(6):534-537.

Belloni E, Trubia M, Gasparini P, Micucci C, Tapinassi C, Confalonieri S, Nuciforo P, Martino B, Lo-Coco F, Pelicci PG, Di Fiore PP. 8p11 myeloproliferative syndrome with a novel



t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes. Genes Chromosomes Cancer 2005;42(3):320-325.

Gotlib J. Molecular classification and pathogenesis of eosinophilic disorders: 2005 update. Acta Haematol 2005;114(1):7-25.

Tefferi A. Modern diagnosis and treatment of primary eosinophilia. Acta Haematol 2005;114(1):52-60.

Walz C, Chase A, Schoch C, Weisser A, Schlegel F, Hochhaus A, Fuchs R, Schmitt-Gräff A, Hehlmann R, Cross NC, Reiter A. The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1. Leukemia 2005 ;19(6):1005-1009.

Gotlib J, Cross NC, Gilliland DG. Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy. Best Pract Res Clin Haematol 2006;19(3):535-569.

Gu TL, Goss VL, Reeves C, Popova L, Nardone J, Macneill J, Walters DK, Wang Y, Rush J, Comb MJ, Druker BJ, Polakiewicz RD. Phosphotyrosine profiling identifies the KG-1

cell line as a model for thestudy of FGFR1 fusions in acute myeloid leukemia. Blood 2006;[Epub ahead of print].

Wong WS, Cheng KC, Lau KM, Chan NP, Shing MM, Cheng SH, Chik KW, Li CK, Ng MH. Clonal evolution of 8p11 stem cell syndrome in a 14-year-old Chinese boy: A review of literature of t(8;13) associated myeloproliferative diseases. Leuk Res 2006;[Epub ahead of print].

Yamamoto K, Kawano H, Nishikawa S, Yakushijin K, Okamura A, Matsui T. A biphenotypic transformation of 8p11 myeloproliferative syndrome with CEP1/FGFR1 fusion gene. Eur J Haematol 2006; 77(4):349-354.

This article should be referenced as such: Belloni E, Lo Coco F, Pelicci PG. t(7;8)(q34;p11). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):190-193.





t(1;21)(p36;q22) Marian Stevens-Kroef

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0121ID1186.html DOI: 10.4267/2042/38330

This article is an update of: Huret JL. t(1;21)(p36;q22). Atlas Genet Cytogenet Oncol Haematol.2000;4(1):30. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Note: Subtle cytogenetic abnormality, easy to confuse with a del(21)(q22), may be missed in poor quality metaphases.

Partial GTG-banded karyotype of t(1;21)(p36;q22).

t(1;21)(p36;q22) Stevens-Kroef M


Clinics and pathology Disease Acute non lymphocytic leukemia (ANLL or AML: acute myeloid leukemia) and myelodysplastic syndromes (MDS); 2 of 5 cases at least are secondary to toxic exposure. Note: Only 5 cases described so far one with features identical to a case of TXT t(18;21)(q21;q22), and a case of t(19;21)(q13.4;q22).

Etiology Two of the reported cases are therapy-related, in

another case, ANLL occurred about 50 years after radiation exposure from nuclear explosions.

Prognosis Poor; median survival 6 months.

Cytogenetics Probes AML1/ETO dual-color, dual-fusion probe.

Additional anomalies -7, del(7q).

FISH analysis using RUNX1 (red) probe. Three signals for RUNX1 are observed; on the normal chromosome 21, and on the derivative chromosomes 1 and 21.

t(1;21)(p36;q22) Stevens-Kroef M


Schematic representation of RUNX1 and PRDM16 (fusion) genes. Upper panel: normal genomic structures of PRDM16 and RUNX1 (non-coding parts in bleu). A cryptic exon, residing within intron 1 of PRDM16, is indicated in green (speckled). Lower panel: structure of RUNX1-PRDM16 fusion transcripts. Exons are numbered on the basis of consensus gene sequences. Exon sizes are not to scale.

Genes involved and Proteins PRDM16 Location: 1p36 Note: This gene is also involved in the t(1;3)(p36;q21) (AML/MDS).

Protein Zinc-finger protein, containing two DNA binding domains and a PRDI-BF1 (positive regulatory domain I binding factor 1/ RIZ (retinoblastoma-interacting zinc finger protein) homologous (PR) domain at the N-terminus.

RUNX1/AML1 Location: 21q22

DNA / RNA Transcription is from telomere to centromere.

Protein Contains a Runt domain and, in the C-term, a transactivation domain; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes.

Results of the chromosomal anomaly Hybrid gene Note: Two different chimeric transcripts have been identified. One contains the exon 1 to 6 of RUNX1 including the runt domain, fused to sequences derived

from intron 1 of PRDM16. The other fusion transcript contains exons 1 to 6 of RUNX1 and almost the entire PRDM16 coding region (see figure above).

Description 5' RUNX1 - 3' PRDM16.

References Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD. CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Blood 1998;92:2879-2885.

Webb DKH, Passmore SJ, Hann IM, Harrison G, Wheatley K, Chessells JM. Results of treatment of children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt) in Great Britain 1990-99. Br. J. Haematol 2002;117:33-39.

Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K. A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations. Blood 2000;95:4011-4013.

Sakai I, Tamura T, Narumi H, Uchida N, Yakushijin Y, Hato T, Fujita S, Yasukawa M. Novel RUNX1-PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22). Genes Chromosomes Cancer 2005;44:265-270.

Stevens-Kroef MJPL, Schoenmakers EFPM, van Kraaij M, Huys E, Vermeulen S, van der Reijden B, Geurts van Kessel A. Identification of truncated RUNX1 and RUNX1-PRDM16 fusion transcripts in a case of t(1;21)(p36;q22)-positive therapy-related AML. Leukemia 2006;20:1187-1189.

This article should be referenced as such: Stevens-Kroef M. t(1;21)(p36;q22). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):194-196.





t(3;16)(q27;p13) Jean-Loup Huret



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0316q27p13ID2089.html DOI: 10.4267/2042/38331


Clinics and pathology Disease B cell non Hodgkin lymphoma (NHL).

Epidemiology Only 3 cases so far.

Clinics The 3 patients had diffuse large B cell lymphoma (DLBCL); 2 of 2 patients were male patients, one presented with a history of follicular small cleaved cell lymphoma 15 years ago, when aged 47 year. This patient died 6 months later of progressive disease.

Cytogenetics Additional anomalies 2 out of 2 cases had a t(14;18)(q32;q21) and both patients presented with MAKA (major karyotypic anomalies).

Genes involved and Proteins BCL6 Location: 3q27

DNA / RNA Spans on 25 kb;. 11 exons.

Protein Sequence-specific DNA binding transcriptional repressor.

MHC2TA Location: 16p13

Protein Non-DNA-binding transcriptional coactivator; transactivator of the major histocompatibility complex (MHC) class II genes.

Results of the chromosomal anomaly Hybrid gene Description 5'-MHC2TA/BCL6-3' fusion transcripts but also the 5'-BCL6/MHC2TA-3' fusion transcripts.

References Au WY, Gascoyne RD, Viswanatha DS, Skinnider BF, Connors JM, Klasa RJ, Horsman DE. Concurrent chromosomal alterations at 3q27, 8q24 and 18q21 in B-cell lymphomas. Br J Haematol 1999;105:437-440.

Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M. Identification of heterologous translocation partner genes fused to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE and LA - PCR analyses of biopsy samples. Oncogene 1999;18:7994-7999.

Sanchez-Izquierdo D, Siebert R, Harder L, Marugan I, Gozzetti A, Price HP, Gesk S, Hernandez-Rivas JM, Benet I, Solé F, Sonoki T, Le Beau MM, Schlegelberger B, Dyer MJ, Garcia-Conde J, Martinez-Climent JA. Detection of translocations affecting the BCL6 locus in B cell non-Hodgkin's lymphoma by interphase fluorescence in situ hybridization. Leukemia 2001;15:1475-1484.

Kaneita Y, Yoshida S, Ishiguro N, Sawada U, Horie T, Mori S, Moriyama M. Detection of reciprocal fusion 5'-BCL6/partner-3' transcripts in lymphomas exhibiting reciprocal BCL6 translocations. Br J Haematol 2001;113:803-806.

This article should be referenced as such: Huret JL. t(3;16)(q27;p13). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):197.





t(4;16)(q26;p13) Jean-Loup Huret



Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0416q26p13ID1358.html DOI: 10.4267/2042/38332 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Disease T-cell lymphoma of the small intestine of low grade malignancy.

Phenotype / cell stem origin CD3, CD4, TCR A-B phenotype.

Epidemiology Only 1 case to date, a 28 year old male patient.

Cytogenetics Cytogenetics morphological Sole anomaly.

Genes involved and Proteins IL2 Location: 4q26

DNA / RNA 6 exons.

Protein Role in mediation of the immune system; member of the IL2 family of cytokines; binds to and signals through a receptor complex consisting of IL2Ralpha, IL2Rbeta, and gamma chain; T-cell growth factor.

TNFRSF17 Location: 16p13.1

DNA / RNA 3 exons. Protein Role in mediation of the immune system; member of the TNF-receptor superfamily; binds to TNFSF13B/BAFF/BLys and TNFSF13/APRIL; promotes B-cell survival.

Results of the chromosomal anomaly Hybrid gene Description 5' IL2 - 3' TNFRSF17; breakpoint in intron 3 of IL2.

References Laâbi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, Larsen CJ, Tsapis A. A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma. EMBO J 1992;11:3897-3904.

Carbonnel F, Lavergne A, Messing B, Tsapis A, Berger R, Galian A, Nemeth J, Brouet JC, Rambaud JC. Extensive small intestinal T-cell lymphoma of low-grade malignancy associated with a new chromosomal translocation. Cancer 1994;73:1286-1291.

This article should be referenced as such: Huret JL. t(4;16)(q26;p13). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):198.





t(11;20)(q23;q11) Jen-Fen Fu, Lee-Yung Shih

Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, 199 Tung-Hwa North Road, Taipei 105, Taiwan




Clinics and pathology Disease pro-B acute lymphoblastic leukemia (L2).

Epidemiology One case described (42 years); male.

Clinics The patient presented with fever and chills for 10 days. He had multiple 0.5 to 1.0 cm lymph nodes on bilateral necks, axillary and inguinal areas. He had no hepatosplenomegaly. His initial blood counts were HB 10.3 gm/dL, WBC 579.0 x 109L with 97% blasts, and platelet 37.0 x 109L.

Cytology Bone marrow smear showed 99% blasts (FAB L2), which were negative for myeloperoxidase and exhibited diffuse fine granular patterns for PAS and acid phosphatase stains. Immunophenotypic analysis showed that the blasts were positive for CD19, CD33, CD34, HLA-DR and cyCD79; and negative for CD10, CD7, CD2, CD13, and cyMPO.

Treatment The patient refused chemotherapy.

Cytogenetics Cytogenetics morphological Cytogenetic analysis was not performed.

Genes involved and Proteins MLL Location: 11q23

Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyltransferase motif, and a SET [Su(var)3-9, enhancer of Zeste, and trithorax] doamin.

MAPRE1 Location: 20q11.2

Protein MAPRE1 encoding EB1 which contains a microtubule-binding domain, a dynactin-binding domain (DBD), and an APC-binding domain that is overlapped to DBD; localized at cytoplasmic microtubule tips, centrosomes, and spindle microtubules, and interacts with APC or dynein/dynactin complex to regulate microtubule dynamics, cell polarity, and chromosomal stability.

Results of the chromosomal anomaly Hybrid gene Description 5' MLL - 3' MAPRE1, with fusion of MLL exon 6 to MAPRE1 exon 5; the reciprocal in-frame MAPRE1-MLL is also transcribed.

t(11;20)(q23;q11) Fu JF, Shih LY


Partial nucleotide and deduced amino acid sequence of the break junctions of MLL-MAPRE1 and MAPRE1-MLL fusion transcripts. Vertical lines indicate break junctions.

Schematic representation of MLL-EB1 and EB1-MLL fusion proteins. AT-H, AT hooks; MT, DNA methyltansferase motif; Zn-F, zinc finger domain; SET, [Su(var]3-9, enhancer of zeste, and trithorax] domain; En, microtubule-binding domain; ABD, APC-binding domain;

numbers indicate amino acids of each protein.

Detection protocole cDNA panhandle PCR.

Fusion protein Description NH2-AT hook and DNA methyltransferase motif from MLL fused to APC-binding domain of EB1.

References Fu JF, Hsu HC, Shih LY. MLL is fused to EB1 (MAPRE1), which encodes a microtubule-associated protein, in a patient with acute lymphoblastic leukemia. Genes Chromosomes Cancer 2005;43:206-210.

This article should be referenced as such: Fu JF, Shih LY. t(11;20)(q23;q11). Atlas Genet Cytogenet Oncol Haematol.2006; 10(3):199-200.

Solid Tumour Section Mini Review




Liver adenoma Jessica Zucman-Rossi

Inserm U674, Génomique Fonctionnelle des tumeurs solides, 27 rue Juliette Dodu, 75010 Paris, France


Online updated version: http://AtlasGeneticsOncology.org/Tumors/LiverAdenomID5420.html DOI: 10.4267/2042/38335


Identity Other names: Hepatocellular adenoma; Liver cell adenoma

Clinics and pathology Disease Hepatocellular adenomas (HA) are rare benign liver tumors, most frequently occurring in women using oral contraception. HA are single or more rarely multiple nodules; the presence of more than ten nodules in the liver indicates a specific nosological entity: liver adenomatosis.

Etiology In 90% of the cases, adenomas are sporadic and only rare cases are developed in a familial context (Familial liver adenomatosis). Patients with an inherited mutation in one allele of TCF1/HNF1a may develop maturity onset diabetes of the young type 3 (MODY3) and familial liver adenomatosis, when the second allele is inactivated in hepatocytes by somatic mutation or chromosome deletion.

Epidemiology Hepatocellular adenomas are usually related to oral contraceptive use. The other risk factors are: glycogen storage diseases and the androgen therapy. HA are rare tumours: their estimated incidence in France is approximately one case per 100,000 women. Over the past fifteen years, their incidence has seen a sustained decline in industrialised countries; this trend is probably linked to the reduction in ethinylestradiol doses in oral contraceptives.

Pathology These tumours result from a benign proliferation of hepatocytes which destroy the normal architecture of the liver. They are usually hyper-vascularised and

typical adenoma corresponds to a proliferation of benign hepatocytes, intermingled with numerous thin-walled vessels, without portal tracts.

Treatment Surgery is usually proposed for lesion of more than 3 cm.

Evolution Hepatocellular adenoma may bleed, or rarely, undergo malignant transformation.

Prognosis The molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Genetics Note: Germline TCF1/HNF1A mutation can predispose to familial liver adenomatosis.

Genes involved and Proteins Note: Half of the adenoma cases are mutated for TCF1 gene encoding HNF1a. These mutations are inactivating and both allele are mutated in tumors. Patients with an inherited mutation in one allele of HNF1a may develop maturity onset diabetes of the young type 3 (MODY3) and familial liver adenomatosis, when the second allele is inactivated in hepatocytes by somatic mutation or chromosome deletion. Mutations of CTNNB1 activating the beta-catenin was also found in 15% of the HA cases. The molecular and pathological classification of hepatocellular adenomas permited the identification of strong genotype-phenotype correlations and suggested that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Liver adenoma Zucman-Rossi J


TCF1 Location: 12q24.31 Note: Alias: HNF1A, hepatocyte nuclear factor 1 alpha, HNF1, LFB1, M57732, MODY3. More than 50 different HNF1a mutations have been identified in HA. These mutations are distributed mainly from exon 1 to 6. Point mutations, small deletions and insertions were identified. Gene deletions are less frequent.

CTNNB1 Location: 3p22.1 Note: Description: catenin (cadherin-associated protein), beta 1. Activating mutations are amino-acid substitution in exon 3 or in-frame deletion including part or all exon 3.

Protein Beta-catenin is an adherens junction protein. Adherens junctions are critical for the establishment and maintenance of epithelial layers, cells adhesion, signal communication, anchorage of the actin cytoskeleton. CTNNB1 has important functions in the E-cadherin-mediated cell-cell adhesion system and also as a dowstream signaling molecule in the Wnt pathway. Cytoplasmic accumulation of b catenin allows it to translocate to the nucleus to form complexes with transcription factors of the T cell factor-lymphoid enhancer factor (Tcf-Lef) family. b-catenin is assumed to transactivate mostly unknown target genes, which may stimulate cell proliferation (acts as an oncogene) or inhibit apoptosis. The b-catenin level in the cell is regulated by its association with the adenomatous polyposis coli (APC) tumor suppressor protein, axin and GSK-3b. Phosphorylation of b-catenin by the APC-axin-GSK-3b complex leads to its degradation by the ubiquitin-proteasome system.

References Edmondson HA, Henderson B, Benton B. Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med 1976;294:470-472.

Foster JH, Donohue TA, Berman MM. Familial liver-cell adenomas and diabetes mellitus. N Engl J Med 1978;299:239-241.

Flejou JF, Barge J, Menu Y, Degott C, Bismuth H, Potet F, et al. Liver adenomatosis. An entity distinct from liver adenoma?. Gastroenterology 1985;89:1132-1138.

Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996 Dec 5;384(6608):455-458.

Chiche L, Dao T, Salamé E, Galais MP, Bouvard N, Schmutz G, Rousselot P, Bioulac-Sage P, Ségol P, Gignoux M. Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature. Ann Surg 2000;231:74-81.

Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet 2002;32:312-315.

Chen YW, Jeng YM, Yeh SH, Chen PJ. P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology 2002;36:927-935.

Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, Laurent C, Bourlier P, Pariente D, de Muret A, Fabre M, Bioulac-Sage P, Zucman-Rossi J. Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation. Gastroenterology 2003;125:1470-1475.

Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, Rousselot P, Fabre M, Oberti F, Fatome A, Zucman-Rossi J, Bellanne-Chantelot C. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families. J Clin Endocrinol Metab 2004;89:1476-1480.

Zucman-Rossi J, Jeannot E, Van Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, Bacq Y, Leteurtre E, Paradis V, Michalak S, Wendum D, Chiche L, Fabre M, Mellottee L, Laurent C, Partensky C, Castaing D, Zafrani ES, Laurent-Puig P, Balabaud C, Bioulac-Sage P. Genotype-phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC. Hepatology 2006;43:515-524.

This article should be referenced as such: Zucman-Rossi J. Liver adenoma. Atlas Genet Cytogenet Oncol Haematol.2006;10(3):201-202.

Cancer Prone Disease Section Mini Review




Birt-Hogg-Dubé Syndrome (BHD) Benedetta Toschi, Maurizio Genuardi

Department of Clinical Pathophysiology, University of Florence, Viale Gaetano Pieraccini 6, 50139 Firenze, Italy


Online updated version: http://AtlasGeneticsOncology.org/Kprones/BirtHoggDubeID10091.html DOI: 10.4267/2042/38336


Identity Note: Birt-Hogg-Dubé syndrome (BHDS) is characterized by renal oncocytic tumors, benign skin tumors (fibrofolliculomas and trichodiscomas), and spontaneous pneumothorax. The first description of an affected family was provided by Birt, Hogg, and Dubé in 1977. Inheritance: Autosomal Dominant with variable expressivity. Prevalence is estimated at about 1/200,000.

Clinics Phenotype and clinics BHDS is a genodermatosis characterized by the triad of benign tumors of the hair follicle, spontaneous pneumothorax and kidney tumors. These manifestations do not have to be simultaneously present in the same individual in order to establish a diagnosis of BHDS, since the phenotype is variable and penetrance is not complete. Patients may also suffer from colonic polyps and colorectal cancer. Cutaneous tumors are fibrofolliculomas, trichodiscomas and/or acrochordons. Fibrofolliculomas and trichodiscomas tend to appear in the third or fourth decade of life as small white or skin-colored multiple papules on the face, neck and upper trunk. Acrochordon is a non specific designation for small and soft skin tags. Multiple angiofibromas, lipomas and collagenomas have also been reported. Affected individuals have a high chance of developing cysts in the lungs and spontaneous pneumothorax. Although almost all patients who have BHDS have lung blebs (90%), but only a fifth will have spontaneous pneumothorax. The

strong association of spontaneous pneumothorax with BHDS suggests that the presence of spontaneous pneumothorax in a member of a BHDS family could be used as a criterion for the diagnosis of BHDS.

Neoplastic risk Approximately 27% of BHDS patients develop renal tumors of different histological type: - chromophobe (34%), - hybrid chromophobe/oncocytic (50%), - oncocytoma (5%), and - clear cell renal carcinoma (9%). Hybrid tumors are most characteristic of this condition, and several lesions initially diagnosed as oncocytomas or chromofobe tumors have been defined as hybrid tumors upon reappraisal. Multiple histological types of kidney tumors can be found in the same BHDS family, in the same patient or even in the same kidney. Although colonic tumors have been observed in some families, it is not clear whether they represent a manifestation of BHDS.

Treatment No specific medical treatment exists for the cutaneous lesions of BHDS. Surgical removal has provided definitive treatment of solitary perifollicular fibromas and electrodesiccation may be helpful in removal of multiple lesions, but these can recur.· High-resolution CT scan is required in order to identify lung cysts. Individuals at risk or affected by BHDS should be radiographically screened for renal tumors at periodic intervals and they are best treated with nephron sparing surgical approaches. Colonoscopy should be considered.

Birt-Hogg-Dube Syndrome (BHD) Toschi B, Genuardi M


Multiple trichodiscomas of the neck.

Prognosis Prognosis depends on the number, type and age at diagnosis of kidney tumors. Hybrid and chromophobe tumors have malignant potential, while pure renal oncocytomas are benign. Mean age at diagnosis of kidney tumors is 50.7 years.

Genes involved and Proteins FLCN Location: 17p11.2

DNA/RNA Description: Total gene size: 24971 bp. Transcription: Alternative splicing results in two transcript variants encoding different isoforms. mRNA is expressed in a variety of tissues, including the skin, the kidney, the lung, the pancreas, parotid gland, and the brain. Tissues with reduced expression of FLCN mRNA include heart, muscle and liver. FLCN mRNA is not expressed in renal tumors from BHDS patients.

Protein Folliculin. Description: The protein contains a conserved SLS potential phosphorylation site, a glutamic acid-rich coiled-coil domain, an N-glycosylation site, and 3 myristoylation sites. Its function is yet unknown.

Mutations Cytosine insertions or deletions in a mononucleotide repeat tract containing 8 cytosines within exon 11 are

the most frequent constitutional mutations found, being detected in approximately 50% of BHDS families. These mutations result in an abnormally small, non functional folliculin protein. Other mutations located elsewhere in the coding sequence are heterogeneous. Overall, point mutations in the FLCN gene are found in approximately 80% of BHDS cases.

References Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Derm 1977;113:1674-1677.

Weintraub R, Pinkus H. Multiple fibrofolliculomas (Birt-Hogg-Dubé) associated with a large connective tissue nevus. J Cutan Pathol 1977;4:289-299.

Fujita WH, Barr RJ, Headley JL. Multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Derm 1981;117:32-35.

Starink TM, Kisch LS, Meijer CJLM. Familial multiple trichodiscomas: a clinicopathologic study. Arch Derm 1985;121:888-891.

Ubogy-Rainey Z, James WD, Lupton GP, Rodman OG. Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dubé syndrome. J Am Acad Derm 1987;16:452-457.

Rongioletti F, Hazini R, Gianotti G, Rebora A. Fibrofolliculomas, tricodiscomas and acrochordons (Birt-Hogg-Dubé) associated with intestinal polyposis. Clin Exp Derm 1989;14:72-74.

Shapiro PE, Kopf, AW. Familial multiple desmoplastic trichoepitheliomas. Arch Derm 1991;127:83-87.

Roth JS, Rabinowitz AD, Benson M, Grossman ME. Bilateral renal cell carcinoma in the Birt-Hogg-Dubé syndrome. J Am Acad Derm 1993;29:1055-1056.

Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F. Multiple lipomas, angiolipomas, and parathyroid adenomas in a

Birt-Hogg-Dube Syndrome (BHD) Toschi B, Genuardi M


patient with Birt-Hogg-Dubé syndrome. Int J Dermatol 1996;35:365-367.

Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Störkel S, Van Den Berg E, Zbar B. The Heidelberg classification of renal cell tumors. J Path 1997;183:131-133.

Le Guyadec T, Dufau J.-P, Poulain J.-F, Vaylet F, Grossin M, Lanternier G. Multiple trichodiscomas associated with intestinal polyposis. Ann Derm Venereol 1998;125:717-719.

Weirich G, Glenn G, Junker, K, Merino M, Störkel S, Lubensky I, Choyke P, Pack S, Amin M, Walther MM, Linehan WM, Zbar B. Familial renal oncocytoma: clinicopathological study of 5 families. J Urol 1998;160:335-340.

Liu V, Kwan T, Page EH. Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. J Am Acad Dermatol 2000;43:1120-1122.

Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene 2001;20:5239-5242.

Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR, Turner ML, Duray P, Merino M, Hewitt S, Pavlovich CP, Glenn G, Greenberg CR, Linehan WM, Zbar B. Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 2001;69:876-882.

Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Lévy R, Ferlicot S, Wolkenstein P, Hammel P. Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjold M, Richard S. Clinical and genetic studies of Birt-Hogg-Dubé syndrome. J Med Genet 2002;39:906-912.

Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg

C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2002;2:157-164.

Pavlovich CP, Walther MW, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ. Renal tumors in the Birt-Hogg-Dubé syndrome. Am J Surg Path 2002;26:1542-1552.

Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol. Biomarkers Prev 2002;11:393-400.

Warren MB, Torres-Cabala CA, Turner ML, Merino MJ, Matrosova VY, Nickerson ML, Ma W, Linehan WM, Zbar B, Schmidt LS. Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues. Mod Pathol 2004;17:998-1011.

Pavlovich CP, Grubb RL 3rd, Hurley K, Glenn GM, Toro J, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P, Walther MM, Linehan WM. Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol 2005;173:1482-1486. Erratum in J Urol 2005;174:796.

Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J, Morrison P, Maher ER, Walther MM, Zbar B, Linehan WM. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet 2005;76:1023-1033.

This article should be referenced as such: Toschi B, Genuardi M. Birt-Hogg-Dubé Syndrome (BHD). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):203-205.

Cancer Prone Disease Section Mini Review




Neurofibromatosis type 1 (NF1) Katharina Wimmer

Abteilung Humangenetik des Klinischen Instituts für Medizinische und Chemische Labordiagnostik (KIMCL), Medizinische Universität Wien, Wien, Austria


Online updated version: http://AtlasGeneticsOncology.org/Kprones/NF1ID10006.html DOI: 10.4267/2042/38337

This article is an update of: Huret JL. Neurofibromatosis type 1 (NF1). Atlas Genet Cytogenet Oncol Haematol.1997;1(1):36-37. This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2006 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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

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

Phenotype and clinics Diagnosis is made on the ground of at least 2 of the following: - café-au-lait spots (no 6 or more with 0.5 cm of diameter (in pre-puberty)); - 2 neurofibromas or 1 plexiform neurofibromas (mainly cutaneous); - 2 Lisch nodules (melanocytic hamartomas of the iris); - freckling in the axillary/inguinal region (Crowe's sign); - glioma of the optic nerve; - distintive bone anomalies (scoliosis, pseudoarthroses, bony defects (orbital wall)...); - positive family history. Other features:

- macrocephaly; - epilepsy; - mental retardation in 10 %; learning diabilities in half patients; - sexual precocity and other endocrine anomalies; - hypertension (renal artery stenosis).

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

Treatment Early diagnosis, lifetime monitoring and surgery are essential

Cytogenetics Inborn condition No special feature.

Neurofibromatosis type 1 (NF1) Wimmer K


Cancer cytogenetics According to the cancer type in most cases JMML: monosomy 7.

Genes involved and Proteins NF1 Location: 17q11.2

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

Mutations Germinal: mainly nucleotide substitutions (splicing defects, nonsense mutations, missense mutations) and frameshift alterations, microdeletions (5-10%), some intragenic copy number changes on one allele. Somatic: the second allele is often lost in the neoplatic cell owing to copy number loss and mitotic recombination events, but also minor lesion mutations are found.

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

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

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

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

De Raedt T, Brems H, Wolkenstein P, Vidaud D, Pilotti S, Perrone F, Mautner V, Frahm S, Sciot R, Legius E. Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet 2003 May;72(5):1288-1292.

This article should be referenced as such: Wimmer K. Neurofibromatosis type 1 (NF1). Atlas Genet Cytogenet Oncol Haematol.2006;10(3):206-207.

Cancer Prone Disease Section Short Communication




Familial liver adenomatosis Jessica Zucman-Rossi

Inserm U674, Génomique Fonctionnelle des tumeurs solides, 27 rue Juliette Dodu, 75010 Paris, France


Online updated version: http://AtlasGeneticsOncology.org/Kprones/FamLiverAdenomID10130.html DOI: 10.4267/2042/38338


Identity Other names: Familial hepatic adenomas Note: Liver adenomatosis is a rare disease defined by the presence of multiple adenomas within an otherwise normal hepatic parenchyma. In 2002, frequent bi-allelic inactivation of TCF1 /HNF-1alpha, was identified in hepatocellular adenomas. In 80% of the cases both mutations were of somatic origin. However, in the remaining cases, one heterozygous germline mutation has been found in patients revealing a relation between liver adenomatosis and maturity-onset diabetes of the young (MODY3). MODY3 is a rare dominantly inherited subtype of non-insulin-dependent diabetes mellitus characterized by early onset, usually before the age of 25, and a primary defect in insulin secretion. In 1996, heterozygous germline mutations of TCF1/HNF1a have been linked to the occurrence of MODY3 in humans. Inheritance: autosomal dominant disorder with low penetrance.

Clinics Phenotype and clinics To date, all familial liver adenomatosis cases described are related to TCF1/HFN1a constitutional mutation. Genotype-phenotype correlation analysis showed that TCF1/HNF1a benign lesions were steatotic.

Neoplastic risk Among MODY3 patients only a very small minority will develop liver adenomatosis. Cases of malignant transformation are uncommon.

Evolution Patients presenting TCF1/HNF1a mutated adenomatosis are at risk of tumor hemorrhagic rupture.

Genes involved and Proteins Note: HNF1a is a homeodomain containing transcription factor that is implicated in hepatocyte differentiation and is required for the liver-specific expression of several genes, including ß-fibrinogen, albumin and a1-antitrypsin.

TCF1 Location: 12q24.31

DNA/RNA Description: 10 coding exons.

Protein Description: hepatocyte nuclear factor 1 alpha, HNF1A Function: transcription factor. Homology: Homeodomain, pou family.

Mutations Germinal: at least 6 different mutations were found in familial adenomatosis: R229X, R272S, P291fs (2 cases), G55fs, IVS2 +1 G>T. Somatic: inactivation of the second allele in adenoma tumors is by gene deletion or mutation.

References Foster JH, Donohue TA, Berman MM. Familial liver-cell adenomas and diabetes mellitus. N Engl J Med 1978; 299:239-241.

Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996 Dec 5; 384(6608):455-458.

Chiche L, Dao T, Salamé E, Galais MP, Bouvard N, Schmutz G, Rousselot P, Bioulac-Sage P, Ségol P, Gignoux M. Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature. Ann Surg 2000;231:74-81.

Familial liver adenomatosis Zucman-Rossi J


Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet 2002;32:312-315.

Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, Laurent C, Bourlier P, Pariente D, de Muret A, Fabre M, Bioulac-Sage P, Zucman-Rossi J. Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation. Gastroenterology 2003;125:1470-1475.

Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, Rousselot P, Fabre M, Oberti F, Fatome A, Zucman-Rossi J, Bellanne-Chantelot C. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the

young (MODY)3 families. J Clin Endocrinol Metab 2004;89:1476-1480.

Zucman-Rossi J, Jeannot E, Van Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, Bacq Y, Leteurtre E, Paradis V, Michalak S, Wendum D, Chiche L, Fabre M, Mellottee L, Laurent C, Partensky C, Castaing D, Zafrani ES, Laurent-Puig P, Balabaud C, Bioulac-Sage P. Genotype-phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC. Hepatology 2006 Feb 22;43(3):515-524.

This article should be referenced as such: Zucman-Rossi J. Familial liver adenomatosis. Atlas Genet Cytogenet Oncol Haematol.2006;10(3):208-209.

Deep Insight Section




Ethical issues in cancer genetics Robert Roger Lebel

Greenwood Genetic Center, 101 Gregor Mendel Circle, Greenwood, SC 29649, USA


Online updated version: http://AtlasGeneticsOncology.org/Deep/EthicCancerGenetID20054.html DOI: 10.4267/2042/38339


Abstract The history of medical ethics has provided, at various junctures, focus on major principles such as justice, fidelity, autonomy, beneficence, etc. When deontological (rule-based) perspectives received competition from utilitarian (results-based) methods of analysis in the 19th century, changes in emphasis helped pave the way for ethical assessment of the Darwinian, Mendelian, Freudian and Einsteinian revolutions. Modern frameworks in medical ethics have returned to principalism (which has its roots in the ancient Greek philosophical tradition that directs our attention to the Good, the True and the Beautiful). This in turn has conditioned much of the underpinning of genetics counseling, with emphases on justice, beneficence and autonomy. The recent opening up of oncogenetics offers an opportunity to revisit the insights of the past and refine them for clinical oncology settings. There are important problems and issues which arise in several contexts: intrafamilial dynamics, economic concerns, professional qualifications, research settings, and most recently reproductive decision-making.

Introduction As modern scientific insights deepen and strengthen our abilities to discover and apply knowledge of the fundamental biological processes involved in malignant neoplasia, there is a concurrent need for us to mine the humanistic and philosophical meaning of the cancer experience and its social context. This essay will explore some philosophical and theological foundations, and modern applications, of medical ethics. The descriptive aspects of oncogenetics (e.g. tumor-suppressor genes, proto-oncogenes, DNA mismatch repair genes, autosomal dominant inheritance patterns with incomplete penetrance and variable expressivity, genetic heterogeneity) are discussed elsewhere in the encyclopedia, and a basic knowledge of those scientific materials is presumed in this treatment.

Historical overview of ethics Ethics is the systematic study of norms and practices governing interactions between persons, who are moral agents with rights and obligations. The ethicist asks how people should act. While it may seem ideal to articulate timeless answers to these questions, the

process of addressing them is usually conditioned by cultural and social context of the inquiring philosopher, so that practical results typically are expressed in ways that reflect the religious traditions and foundational assumptions of the writer. The roots of modern ethics can be traced to early religious traditions that began to take form in written documents nearly 3000 years ago. During what has been called the “axial age”, a relatively short period of several centuries, leading thinkers independently reached very similar new insights regarding the role of the human agent, the conscience, and the notions of duty, honor and responsibility. They rejected the animistic magical explanation of events and the notion that divine agencies are capricious or vindictive. They promoted the notion that individuals are obliged to maintain a relationship axis by which they experience and participate in creativity and righteousness. Thus the Hebrew prophets (Isaiah, ca. 770-685 BC; Micah, ca. 760-700; Jeremiah, ca. 650-580 BC; Ezekiel, ca. 620-570 BC, etc.) in the Mediterranean basin, Siddhartha Gautama (ca. 563-483 BC) in the Indian subcontinent, and Han Fei-Tzu (ca. 551-483 BC) in China expressed convergent ideas without having had any opportunity to know of each others’ teachings.

Ethical issues in cancer genetics Lebel RR


Soon thereafter, in another region of the Mediterranean basin, Socrates (ca. 470-399 BC), his student Plato (429-347 BC), and his student Aristotle (384-322 BC) developed strong intellectual foundations for ethical thinking, probably without having any awareness of the teachings of those earlier thinkers. The more religiously motivated teachings of Jesus (ca. 4 BC-29 AD) and Mohammad (570-632 AD) were founded largely on the same cultural tradition to which Isaiah and the other Hebrew prophets had made their contributions. As Europe languished in relative intellectual quiescence, the Islamists preserved and treasured ancient Greek philosophical writings. Then, while their culture was slipping into fundamentalism, Aristotle’s works were “rediscovered”. The Jewish scholar/scientist/physician Moses Maimonides (1135-1204) conducted seminal study and reflection on these materials. A conscious and systematic effort to incorporate them into a Christian hermeneutic was undertaken by several people at about that time, most importantly Thomas Aquinas (1225-1274). He and Maimonides were, however, still unaware of the Buddhist and Confucian lines of thought. Rene Descartes (1596-1650) posited, as a starting point in his search for a reliable method in moral philosophy, that all persons believe themselves to enter every debate with an adequate deposit of common sense. In other words, we can and should assume that on entering any debate, each participant begins with good will and an interest in reaching a well reasoned and “correct” conclusion. When we find this difficult to achieve, he believes, it is not due to ill will or poor motivation, but rather to differences in perspective. A modern reader might be tempted to think that Descartes was expressing cynicism, but apparently he took this presupposition seriously. It is intriguing to contemplate how different much human discourse might be if we all genuinely and habitually employed this as a starting point for familial, professional and political interactions! Immanuel Kant (1724-1804) is the supreme adherent to deontology, the normative ethical framework which is based on adherence to universal rules of behavior, often received as religious revelation or dogma. He perceived two things that consistently inspire awe and respect: the starry heavens above, and the moral law within. He derived for us the “categorical imperative” whereby a moral agent should never engage in any activity unless s/he is convinced that all moral agents should always choose the same course of action. This lofty expectation is, of course, not lightly achieved. Yet none of the serious thinkers in religious or philosophical arenas has ever offered us easy virtue. Plato’s eternal search for the Good, True and Beautiful is always demanding. Gautama Buddha requires that the yogin, having achieved enlightenment, return from blissful contemplation to the marketplace and manifest compassion on others by teaching them to enjoy the

same accomplishment. Jesus demands self-sacrificial love. Mohammad mandates inclusiveness and a radical option for the poor and oppressed. Nineteenth century utilitarianism incorporated into the mainstream of ethical dialogue some of the practical religious thinking embodied in the tradition of “casuistry” that had been employed by 17th and 18th century Jesuits (an order of Roman Catholic priests famed for scholarship) to meet the challenges of the confessional. Casuistry has to do with discerning probable, but not always certain, approximations of virtue in the application of ethical principles to daily ongoing decision-making. The utilitarians evolved an ethical analysis in which the greatest good for the greatest number became the ruling principle. Seeking the greatest pleasure and the least pain (not for the agent personally [hedonism], but for the whole population of those involved in the decision and its outcomes) became the normative heuristic. Out of this emerged the notion that the ends might justify the means, a formula that is not attractive to most deontologists. However, consistent utilitarianism also makes demands on the individual, who may be called upon for great personal sacrifice. Popular 20th century American culture found this expressed dramatically and explicitly in Mr. Spock’s suicidal actions to save the entire crew of the Enterprise in the movie Star Trek II: Revenge of Khan. It has, however, long been part of the high lore of warfare and chivalry, whenever one soldier lays down his life to preserve the lives of his comrades. A broadly based perspective that can take advantage of all these traditions was possible only in the past century, when syncretistic approaches to diverse cultural traditions could be achieved as a result of improved transportation and communication. Albert Schweitzer (1874-1964), a giant of theological and scientific scholarship as well as professional and personal sacrifice, proposed an overall ethic of reverence for life that sought to incorporate the strengths of a wide variety of preceding thinkers. Syncretism always hazards being criticized for failing to adhere to or achieve the highest purity in any given system of thought. Twentieth century popes, theologians, and philosophers of many religious and secular schools, and sincere secular-minded practitioners of health care with strong interest in seeking the Good, have elaborated a broad and deep literature addressing the challenges of ethics in a world imbued with techno-scientific instruments and opportunities. Many of them strive to avoid any attenuation of their specific cultural and religious contexts in that process. Principalism has offered, in this context, a modern reconsideration of normative ethical foundations applied to apparently new problems posed by technology. The mantra of the principalist is “beneficence, non-malfeasance, justice and respect for



autonomy (the right to know about one’s risk factors, and the right not to know things that one prefers not to address)”. This heuristic has achieved broad acceptance in the community engaged in “bioethics”. These four pillars for ethical analysis have found an important application in genetic counseling, a paramedical profession which arose during the third quarter of the century and which is focused on genetic decision making processes. Today most professionals engaged in genetic counseling are masters-level people with training in both psychosocial fields and applied genetics; most others are medical geneticists (most MD, some PhD, some both).

Counseling Someone once noted facetiously that genetic counseling has been with us as long as there have been in-laws anxious to assert “that never happened in our family.” The more subtle, and so more readily overlooked, errors in application of science to human challenges will often take a form such as “the risk is only 6%, so you should not waste any sleep over it.” If the empiric risk for some adverse event is “only 6%”, the meaning (medical, social, psychological, spiritual) for the person at risk remains a function of the relative impact of the problem in question. A 6% risk for a fractured finger is not equivalent to a 6% risk for metastatic ovarian tumor. A 6% risk for male breast cancer associated with carrier status of a mutation in the BRCA2 gene may be a matter of great concern because such tumors often blind-side the patient who assumes his risk to be essentially zero, so that he may have advanced disease before appreciating a need for medical attention. Consequently, effective genetic counseling must not only quote the most scientifically based risk factors and explain the technical aspects of heredity, but also travel the notoriously complex passages of self-image, religious conviction, social obligation, and reproductive goals. All of these can inhabit the psyche of the person at risk for (or already affected by) such a distressing health problem as cancer. The effective genetic counselor knows of all these hazards and develops the skills to assist patients in navigating the troubled waters between them. Always and everywhere, the genetic counselor maintains the self-discipline to avoid directing the decisions to those that might best manifest his or her worldview, helping the patient to express personal perspective and values in the process. The question “What would you do in my situation?” is consistently met with the response “I do not know, but let us explore how you might express your own views and needs in a decision that fits your life.” Few physicians and nurses have had the training opportunities to develop this peculiar skill, which is central to the training of the genetic counselor and helps define that specific profession. It also requires

serious investment of time for the conversation, so that it can occur in the full context of explicitly appreciating the patient’s courage in facing the challenges involved. Avoiding directiveness in genetic counseling is motivated by dedication to the principle of autonomy, but it represents a utilitarian bias because it eschews adherence to any pre-existing dictum or moral rule by which decisions must be reached. So, a deontologist finds it difficult to provide genetic counseling in the form that most modern medical professionals have learned to perceive it. The closest most geneticists will allow ourselves to come to directives and deontologic paradigms is that we will not perform any action that appears to us to be malevolent or unjust. For example, seldom will be agree to test minors for conditions that have late adult onset and lack preventive strategies. Further, we are fairly strict in following protocols for consultation and testing. For example, an unaffected person concerned about risk for inheriting mutations in BRCA1 or BRCA2 will be urged to first engage an affected relative in the process, to maximize the chance of identifying a specific mutation in the family, but also minimize the risk that the affected person might later learn of risk factors that s/he preferred not to address. Thus, we always approach the issues at hand as being familial rather than only individual matters; this has the advantage of building a communal context for the conversation, but the dangers of being embroiled in long-standing familial disputes.

Family dynamics A woman with a strong personal and family history of breast and/or ovarian cancer, who has already undergone bilateral mastectomy and/or oophorectomy to manage her personal risks, will sometimes present for genetic counseling and testing in order to provide useful information to her daughter, sister, or other relative at risk of inheriting the same predisposing mutation (if, in fact, such a mutation is demonstrable). The genetics professional, having noticed that her personal management has been well directed and thorough, does not repel her questions, but honors her stated interests. Meanwhile, s/he makes it a habit to focus first on the patient’s own medical care, and then derivatively on the potential benefits to those beloved relatives. Thus beneficence and justice are honored along with respect for autonomy. The core material of all ethical discourse is interpersonal relationships. This has been paradigmatic since the axial age, when the early sages taught that the quality of relations among persons is the foundation of upright living, and reflects the stance an individual assumes before a loving but demanding deity. It is not surprising, then, that genetic counseling for cancer risk factors is directed often and intently on intrafamilial communication. Principalism can be encountered as a bland recitation of four intuitively apparent truths about



human interaction, but in the pursuit of one principle the counselor sometimes encounters collisions with the others. Personal autonomy enshrines the right of the individual to ask questions for whatever reason she wishes (as noted above), and also to keep confidential the fact that s/he carries a deleterious mutation posing high probability of tumorigenesis. However, the principle of justice motivates informing relatives who are at risk for inheriting the same factor. Counselors sometimes experience moral dissonance. As a prime example, a proband may refuse to contact, or to grant permission for others to contact, relatives with whom s/he has been at odds over a family dispute. The path of wisdom is not always evident to the casual observer, but it is essential to find a balance between nondirectiveness on the one hand and an instinctive sense of obligation to invite an anger-harboring consultand to contemplate the larger contexts of benevolence. In their monumental documentation of geneticists’ attitudes around the world, Wertz and Fletcher (2004) surveyed many hundreds of practicing medical geneticists and genetics counselors in 36 countries. They found (pp. 54 and 393) that 47% of American respondents would respect autonomy in the setting of a mutation for Li-Fraumeni cancer-family syndrome and remain silent, while 30% would divulge to at-risk relatives without permission of the proband if asked, and 12% even if not asked. Worldwide, the results were 36%, 32% and 17%, respectively. Genetic counseling then overlaps with psychological counseling, as the notions of forgiveness and the healing of relationships become a part of the discussion that began with explanation of the technical significance of frame-shift mutations and probabilistic analysis of variable expressivity with incomplete phenotypic penetrance. So we learn to uphold and acknowledgement the patient’s suffering, insight and foresight, generosity and creativity in seeking knowledge that may better inform her own care and also the decisions faced by her relatives. Another challenge in this arena arises when familial relations are strained in regard to the desire to investigate risk factors. A woman anxious to know her status for an important mutation that has been documented in her maternal aunt may find that her mother (who biologically attaches her to that aunt) wants nothing to do with genetic testing. If the consultand is tested and found to harbor the mutation, its route to her must have passed through her non-consenting mother, whose blindness to the testing outcome is almost impossible to achieve if the two have any contact. So the daughter’s autonomy violates the mother’s and an injustice is perpetrated. A woman preparing to determine whether she carries a predisposing mutation, having grasped the importance of alerting the extended family to the risk factor, asked what she ought to do about a cousin who is not actually

at risk since he was adopted…but does not know this detail of his own origins and so presumes himself to be at risk. This is, of course, a special case of the broader problem of non-paternity which is sometimes inadvertently exposed when extended families are subjected to genetic testing in the pursuit of risk factors. Aside from leaving him to continue behaving as though his risk is elevated, it is difficult to discern what course of action could be chosen justly and beneficently but still honor his autonomy. Personal autonomy (the right to know about one’s risk factors, and the right not to know things that one prefers not to address), the demands of justice, the allure of beneficence, all converge in this arena and challenge the counselor who confronts hard realities of individuals with psychosocial difficulties, and families broken by old wounds. Thus, directiveness prevails in our custom of arguing vigorously for communication with at-risk relatives when a person has learned of a mutation but expressed disinclination to advise siblings or others who are clearly at risk. We do this in the hope of escaping the conflict of simultaneous dedication to the principles of autonomy and justice.

Economics In venues that do not have universal health care coverage as a right of citizenship, the cost of molecular testing in search of mutations that place their carriers at high risk for malignancy is very significant. Even when universal coverage is afforded, this may be adumbrated by policy decisions which set the bar fairly high for determining eligibility. The problem is exacerbated in those situations which involve patents or other proprietary aspects of the testing process. The ethical debate over appropriateness of patenting human genes or the processes for testing them is not addressed in this essay, but is clearly worthy of considerable attention; the present author considers such patents highly inappropriate and contrary to the public good. Significant efforts are sometimes demanded, from patients and caregivers, to secure authorization under third party (insurance) payers. Absent reliable insurance coverage of some kind, or unusual disposable income that obviates concern about cost, there are important economic barriers to seeking the presumably useful information that may be available in the laboratory. Every time such a barrier exists, it constitutes a violation of the foundational ethical principle of justice, since it prevents access of the poor to benefits of technology enjoyed by the well endowed. Overcoming such injustice has innumerable practical as well as theoretical challenges, but no ethical analysis is complete without acknowledging this problem. Such problems are not specific to cancer genetics, however, but are found in every aspect of health care. Indeed, distributive justice is an arena of concern in all settings



where there are populations or individuals facing disadvantage in enjoyment of the world’s resources.

Professionalism As in any highly specialized area of medical practice, consultations for discussion and testing pertaining to genetic risk factors associated with high probability of developing cancer should be undertaken only by persons who have a thorough background in the field, and also the ability to maintain familiarity with ongoing changes in that field. Change and growth of pertinent materials in this area are unusually rapid. Consequently, such consultations should not be undertaken by general practitioners, just as one would not wish to have an appendectomy or cesarean section performed by someone who only has occasion to do them once or twice annually. Board certification by national or regional examination, with appropriate continuing education, should be considered essential. A specialist in clinical genetics, working with a nurse or counselor with expertise in genetics or oncology or both, should be considered the highest standard. A counselor or nurse with genetics credentials, collaborating with an oncologist, would be the next best. Accepting less might flirt with the principles of non-malfeasance and justice, whereby professionals have a duty to provide the best reasonably possible care; in this setting that calls for a high level of familiarity with the field and its ongoing developments. There are several reasons for the above perspective. One is the importance of thorough and insightful documentation of family history; without a background in genetics, many would overlook the significance of an endometrial tumor in a member of a family with several cases of colon carcinoma. Another is the adequate preparation of the patient for testing, since a wide range of emotional states may accompany results which reveal elevated personal health risks and/or material that should be communicated to relatives. Yet another is the complexity of the testing itself, and the delicacy of explaining test results when they are confusing, technically complex, or anxiety-provoking. Such considerations revolve around the fact that genetic tests for cancer predisposition are highly complex not only in terms of laboratory expertise (as reflected by their high cost) but also in terms of their impact on the patient and the patient’s family. Thus the preparation for these tests is proportionately more painstaking, whereas a routine blood count, or monitoring serum level of antibiotics of anticonvulsants, calls for very little advance discussion.

Research The usual issues of informed consent apply to this field of investigation, as do the usual safeguards of privacy and of guarded access to results that have not been certified by a licensed clinical laboratory. The special

case of inadvertent exposure of non-paternity is vexing but has already been considered in other genetics arenas. Ethical issues that pertain specially to cancer genetics research are not numerous. It is difficult to imagine, for example, any committee for the protection of human subjects to allow any genetics research to interfere with or postpone appropriate therapeutic interventions. Existing literature and ongoing debate about the use of archived specimens applies in the cancer genetics arena, but this arena does not introduce new ethical concerns that are not already under consideration from other avenues of discussion. Probably the greatest danger of inappropriate professional action in the cancer-genetics field is the premature release of new information which might mislead the general public about availability of predictive, diagnostic, or therapeutic modalities based on molecular genetic factors. Again, however, this is not unique to cancer genetics.

Reproductive decisions Many middle-aged and elderly persons are seen for consultation and testing to determine whether a predisposing mutation is associated with their tumors. Often they express their interest as being motivated by concern for clarification of risk factors facing their sons and daughters (though the clinician’s first interest must always be the utility of this kind of information to guide treatment and surveillance decisions for the patient him/herself). When those offspring learn that they have 50% risk of having inherited a genetic risk factor, or when the proband is a person still in the reproductive age range, one encounters the opportunity to apply the new information to decisions about child bearing. Some people faced with such materials will opt to forego offspring; some might turn to gamete “donors” and/or surrogate parents. Few will give serious consideration to termination of pregnancy after prenatal diagnosis of transmission of the mutation (since such a termination involves an otherwise presumably normal fetus whose risk for ill health is remote and poorly defined). Some who have the resources and the motivation might employ in vitro fertilization followed by preimplantation genetic diagnosis so that only embryos lacking the mutation are transferred; this cleanly moves around the problem of termination for many people concerned about maximizing the health of future children, but it still opens the window on potential abuse of technology for election of traits that have nothing to do with disease risks (“designer babies”). Personal autonomy, which is always a central concern in seeking informed consent for testing and for treatment, is especially important when reproductive decisions are at issue. The beneficent practice of medicine might motivate professionals to guide patients



into decisions deemed of higher moral content by the professional, but genetic counseling has a consistent emphasis on autonomy as the overarching principle in such settings. This emphasis beckons us into troubling territory when families elect to test a pregnancy for mutations that pose an increased risk for cancer in the fourth and fifth decades of life; All of these considerations are highly personal and sensitive. They open the entire field of potentially controversial use of high technology and seeking to control health risks by selecting genetic features in planned offspring. This does not absolve professionals working in the cancer genetics arena from introducing patients to the questions and working with them to achieve answers compatible with their values and

goals. In fact, the delicacy of this material highlights the importance of all the other ethics concerns in cancer genetics being treated with respect.

ACKNOWLEDGMENTS I am grateful for critical readings of drafts by CA Gennuso, GF Guzauskas, PA Lebel, K Lee, RA Saul, RE Stevenson, and DL Van Dyke. Their comments helped strengthen the final product but of course they should not be held accountable for any of its weaknesses.

This article should be referenced as such: Lebel RR. Ethical issues in cancer genetics. Atlas Genet Cytogenet Oncol Haematol.2006;10(3):210-215.



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