Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Databa&àse/Text-Book. TABLE OF CONTENTS Volume 10, Number 3, Jul-Sep 2006 Previous Issue / Next Issue Genes HMGA2 (high mobility group AT-hook 2) (12q15) - updated . Karin Brober. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 290-305. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/HMGICID82.html JJAZ1 (joined to JAZF1) (17q11.2). Hildegard Kehrer-Sawatzki. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 306-310. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/JJAZ1ID41039ch17q11.html MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3 (8p11). Jean Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 311-316. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MYST3ID25ch8p11.html PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)) (20p12.3). Matilde Y. Follo, Vincenza Rita Lo Vasco, Giovanni Martinelli, Giandomenico Palka, Lucio Cocco. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 317-323. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PLCB1ID41742ch20p12.html PMS1 (PMS1 postmeiotic segregation increased 1 (S. cerevisiae)) (2q31-33). Enric Domingo, Simo Schwartz Jr. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 324-328. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PMS1ID345ch2q31.html PKD1 (Protein Kinase D1) (14q11). Cheng Du, KC Balaji. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 329-335. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 I URL : http://AtlasGeneticsOncology.org/Genes/PRKCMID41860ch14q11.html THBS2 (thrombospondin-2) (6q27). Elizabeth M. Perruccio, David . Roberts. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 336-350. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/THBS2ID42549ch6q27.html BAALC (brain and acute leukemia, cytoplasmic) (8q22.3). Jean Loup Huret, Sylvie Senon. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 351-355. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/BAALCID739ch8q22.html MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase)) (20q11.2-q13.1). Deepak Pralhad Patil, Gopal Chandra Kundu. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 356-362. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MMP9ID41408ch20q11.html NF1 (neurofibromin 1) (17q11.2) - updated. Katharina Wimmer. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 363-369. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/NF1ID134.html PSAP (Prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)) (10q22.1). Shahriar Koochekpour. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 370-384. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PSAPID42980ch10q22.html RCHY1 (ring finger and CHY domain containing 1) (4q21.1). Wenrui Duan, Miguel A. Villalona-Calero. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 385-390. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RCHY1ID43012ch04q21.html Leukaemias Follicular lymphoma (FL) - updated. Antonio Cuneo, Antonella Russo Rossi and Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 391-394. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/FollLymphomID2075.html Mucosa-associated lymphoid tissue (MALT) lymphoma. Antonio Cuneo, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 395-401. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/MALTlymphID2095.html Marginal Zone B-cell lymphoma - updated. Antonio Cuneo, Gianluigi Castoldi.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 II Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 402-409. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/MarginalZoneBID2078.html Acute promyelocytic leukemia (APL); M3/M3v acute myeloid leukemia (AML M3/M3v). Claudia Schoch. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 410-413. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/M3ANLLID1240.html t(10;11)(p11.2;q23) - updated. Cristina Morerio, Claudio Panarello. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 414-416. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1011ID1178.html t(5;14)(q33;q32) PDGFRB/KIAA1509. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 417-418. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0514q33q32ID1379.html t(5;15)(q33;q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 419-421. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0515q33q22ID1326.html t(1;21)(p36;q22) - updated. Marian Stevens-Kroef. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 422-426. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0121ID1186.html t(3;16)(q27;p13). Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 427-428. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0316q27p13ID2089.html t(4;16)(q26;p13). Jean Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 429-430. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0416q26p13ID1358.html t(11;20)(q23;q11). JF Fu, LY Shih. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 431-433. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t1120q23q11ID1415.html Solid Tumours Liver adenoma. Jessica Zucman-Rossi.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 III Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 434-437. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/LiverAdenomID5420.html Cancer Prone Diseases Birt-Hogg-Dubé Syndrome (BHD). Benedetta Toschi, Maurizio Genuardi. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 438-443. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/BirtHoggDubeID10091.html Neurofibromatosis type 1 (NF1) - updated. Katharina Wimmer. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 444-447. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/NF1ID10006.html Familial liver adenomatosis. Jessica Zucman-Rossi. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 448-450. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/FamLiverAdenomID10130.html Deep Insights Ethical issues in cancer genetics. Robert Roger Lebel. Atlas Genet Cytogenet Oncol Haematol 2006; 10 (3): 451-459. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/EthicCancerGenetID20054.html Case Reports Educational Items

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Atlas Genet Cytogenet Oncol Haematol 2006; 3 IV Atlas of Genetics and Cytogenetics in Oncology and Haematology

HMGA2 (high mobility group AT-hook 2)

Identity Other HMGIC (High mobility group isoform I-C) names Hugo HMGA2 Location 12q15 telomeric to CDK4, centromeric to MDM2 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 3¹UTR 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -290- 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 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 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 Entity MESENCHYMAL BENIGN TUMORS as follows:

Entity Lipoma Disease benign adipocyte tumor Prognosis good Cytogenetics various rearrangements involving 12q15 (translocations, inversions, deletions...); reciprocal translocations involve 12q15 with different partners such as 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 for t(3;12): HMGIC-LPP (LPP: lipoma preferred partner; 3q27-28); a Gene 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 HMGIC-LPP; the three AT hook domains at the aminoterminal of Protein HMGIC are fused to the LIM domain of LPP; another fusion protein

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -291- 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 is 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

Entity 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 in a majority of cases, there is no fusion gene: the breakpoint is Gene 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 HMGIC-ALDH2: ALDH2 contribution was only 10 amino acids; Protein 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

Entity Pleomorphic adenoma of the salivary gland (or mixed salivary gland tumor)

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -292- 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 in t(9;12): HMGIC-NFIB fusion; another type of fusion HMGIC-FHIT Gene (3p14.2) has also been described

Entity 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 in two cases with apparently normal karyotypes, exon 3 of HMGIC Gene 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;

Entity 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

Entity Myofibroblastic inflammatory tumor Disease benign mesenchymal tumors Prognosis good Cytogenetics in one case, a complex rearrangement involving chromosomes 12 (in

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -293- 12q15), 4 and 21 was described Hybrid/Mutated an aberrant transcript was produced by the fusion of HMGIC exon 3 Gene to an ectopic sequence originating from the third intron of HMGIC

Entity 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.

Entity 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.

Entity Hyaline vascular Castleman's disease Cytogenetics one case with der(6)t(6;12)(q23;q15)del(12)(q15) is described. Hybrid/Mutated a combined immunologic-cytogenetic approach demonstrated Gene HMGA2 rearrangement in follicular dendritic cells

Entity Prolactinoma Disease prolactin-secreting pituary adenoma, non-metastasizing Cytogenetics trisomy 12 nonrandom finding in pituary adenomas Hybrid/Mutated HMGA2 locus amplified in 7/8 prolactinomas Gene

Entity 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 FISH demonstrated a breakpoint 3' of the gene, the tumour Gene expressed HMGA2

Entity MALIGNANT TUMORS as follows:

Entity Well-differentiated liposarcoma

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -294- 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 ectopic sequences from 12q14-15, 1q24, 11q14, and Gene was shown to be fused to HMGA2 exon 2 or 3

Entity Uterine leiomyosarcoma Disease malignant counterpart of uterine leiomyoma Prognosis poor Cytogenetics 12q13-15 region is recurrently amplified Hybrid/Mutated HMGA2 amplified within this region Gene

Entity Osteosarcoma Disease malignant tumor Hybrid/Mutated in one osteosarcoma cell line (OsA-Cl) the three DNA binding Gene 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

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

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

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -295-

External links Nomenclature Hugo HMGA2 GDB HMGA2 Entrez_Gene HMGA2 8091 high mobility group AT-hook 2 Cards Atlas HMGICID82 GeneCards HMGA2 Ensembl HMGA2 Genatlas HMGA2 GeneLynx HMGA2 eGenome HMGA2 euGene 8091 Genomic and cartography HMGA2 - 12q15 chr12:64504507-64646335 + 12q14.3 (hg18- GoldenPath Mar_2006) Ensembl HMGA2 - 12q14.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene HMGA2 Gene and transcription

Genbank AB209853 [ ]

Genbank AF533651 [ ENTREZ ]

Genbank AF533652 [ ENTREZ ]

Genbank AF533653 [ ENTREZ ]

Genbank AF533654 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -296- RefSeq NM_003483 [ SRS ] NM_003483 [ ENTREZ ]

RefSeq NM_003484 [ SRS ] NM_003484 [ ENTREZ ] AceView HMGA2 AceView - NCBI TRASER HMGA2 Traser - Stanford

Unigene Hs.505924 [ SRS ] Hs.505924 [ NCBI ] HS505924 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P52926 [ SRS] P52926 [ EXPASY ] P52926 [ INTERPRO ]

Prosite PS00354 HMGI_Y [ SRS ] PS00354 HMGI_Y [ Expasy ] Interpro IPR000637 AT_hook_DNA_bd [ SRS ] IPR000637 AT_hook_DNA_bd [ EBI ]

Interpro IPR000116 Highmoblty_IY [ SRS ] IPR000116 Highmoblty_IY [ EBI ] CluSTr P52926 Pfam PF02178 AT_hook [ SRS ] PF02178 AT_hook [ Sanger ] pfam02178 [ NCBI-CDD ]

Smart SM00384 AT_hook [EMBL]

Prodom PD005593 Highmoblty_IY[INRA-Toulouse] Prodom P52926 HMGA2_HUMAN [ Domain structure ] P52926 HMGA2_HUMAN [ sequences sharing at least 1 domain ] Blocks P52926 HPRD P52926 Protein Interaction databases DIP P52926 IntAct P52926 Polymorphism : SNP, mutations, diseases OMIM 151900;600698 [ map ] GENECLINICS 151900;600698

SNP HMGA2 [dbSNP-NCBI]

SNP NM_003483 [SNP-NCI]

SNP NM_003484 [SNP-NCI]

SNP HMGA2 [GeneSNPs - Utah] HMGA2] [HGBASE - SRS]

HAPMAP HMGA2 [HAPMAP] General knowledge Family HMGA2 [UCSC Family Browser] Browser SOURCE NM_003483 SOURCE NM_003484 SMD Hs.505924 SAGE Hs.505924 Amigo chromatin Amigo DNA binding

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -297- Amigo AT DNA binding Amigo nucleus Amigo chromosome Amigo establishment and/or maintenance of chromatin architecture Amigo transcription Amigo regulation of transcription, DNA-dependent Amigo regulation of transcription, DNA-dependent Amigo chromosome organization and biogenesis (sensu Eukaryota) Amigo development PubGene HMGA2 Other databases Probes Probe Cancer Cytogenetics (Bari) Probe HMGA2 Related clones (RZPD - Berlin) PubMed PubMed 48 Pubmed reference(s) in LocusLink Bibliography Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Ashar HR, Schoenberg Fejzo M, Tkachenko A, Zhou X, Fletcher JA, et al. Cell 1995; 82: 57-65. Medline 7606786

Description of a novel fusion transcript between HMGI-C, a gene encoding for a member of the high mobility group , and the mitochondrial aldehyde dehydrogenase gene. Kazmierczak B, Hennig Y, Wanschura S, Rogalla P, Bartnizke S, Van de Ven WJM, et al. Cancer Res 1995; 55: 6038-6039. Medline 8521389

Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumors. Schoenmakers EFPM, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJM. Nature Genet 1995; 10: 436-444. Medline 7670494

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -298- Medline 7651535

Fusion transcripts between the HMGIC gene and RTVL-H related sequences in mesenchymal tumors without cytogenetic aberrations. Kazmierczak B, Pohnke Y, Bullerdiek J. Genomics 1996; 38: 223-226. Medline 8954805

Amplification of a rearranged form of the high mobility group protein gene HMGIC in OSA-Cl osteosarcoma cells. Kools PF, Van de Ven JM. Cancer Genet Cytogenet 1996; 911-917. Medline 8908160

LPP, the preferred fusion partner gene of HMGI-C in lipomas, is a novel member of the LIM protein gene family. Petit MMR, Mols R, Schoenmakers EFPM, Mandahl N, Van de Ven WJM. Genomics 1996; 36: 118-129. Medline 8812423

Translocation breakpoints upstream of the HMGIC gene in uterine leiomyomata suggest dysregulation of this gene by a mechanism different from that in lipomas. Schoenberg Fejzo M, Ashar HR, Krauter KS Powell WL, Rein MS, Weremowicz S, et al Genes Chromosomes Cancer 1996; 17: 1-6. Medline 8889500

Hidden paracentric inversions of chromosome arm 12 q affecting the HMGIC gene. Wanschura S, Dal Cin P, Kazmierczak B, Barnitzke S, Van den berghe H, Bullerdiek J.REFERENCE Genes Chromosomes Cancer 1997; 18: 322-323. Medline 9087575

Chromosomal translocations in benign tumors. The HMGI proteins. Hess JL. Am J Clin Pathol 1998; 109: 251-261 (Review). Medline 9495195

The t(3;12)(q27 ;q14-15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype. Rogalla P, Kazmierczak B, Meyer-Bolte K, tran KH, Bullerdiek J. Genes Chromosomes Cancer 1998; 22: 100-104. Medline 9598796

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -299- HMGIC expression in human adult and fetal tissues and in uterine leiomyomata. Gattas GJ, Quade BJ, Nowak RA, Morton CC. Genes Chromosomes Cancer 1999; 254: 316-322.

Inflammatory myofibroblastic tumor with HMGIC rearrangement. Kazmierczak B, Dal Cin P, Sciot R, Van den Berghe H, Bullerdiek J. Cancer Genet Cytogenet 1999; 112: 156-160. Medline 10686944

Allelic knokout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas. Schoenmakers EFPM, Huysmans C, Van de Ven WJM. Cancer Res 1999; 59: 19-23. Medline 9892177

In vivo modulation of Hmgic reduces obesity. Anand A, Chada K. Nat Genet 2000; 24: 377-380. Medline 10742101

Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas. Arlotta P, Tai AK, Manfioletti G. et al. J Biol Chem 2000; 275: 14394-1400. Medline 10747931

Novel gene fusion of COX6C at 8q22-23 to HMGIC at 8q22-23 to HMGIC in a uterine leiomyoma. Kurose K, Mine N, Doi D, Ota Y, Yoneyama K, Konoshi H, Araki T, Emi M. Genes Chromosomes Cancer 2000; 27: 303-307. Medline 10679920

The expression of HMGA genes is regulated by their 3'UTR. Borrmann L, Wilkening S, Bullerdiek J. Oncogene 2001; 20: 4537-4541. Medline 11494149

Chromosomal rearrangements leading to abnormal splicing within intron 4 of HMGIC? Hauke S, Rippe V, Bullerdiek J. Genes Chromosomes Cancer 2001; 30: 302-304. Medline 11170289

Three aberrant splicing variants of the HMGIC gene transcribed in uterine leiomyomas.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -300- Kurose K, Mine N, Iida A. et al. Genes Chromosomes Cancer 2001; 30: 212-217. Medline 11135440

Ectopic sequences from truncated HMGIC in liposarcomas are derived from various amplified chromosomal regions. Meza-Zepeda LA, Berner JM, Henriksen J. Genes Chromosomes Cancer 2001; 31: 264-273. Medline 11391797

Fusion of a sequence from HEI10 (14q11) to the HMGIC gene at 12q15 in a uterine leiomyoma. Mine N, Kurose K, Konishi H. et al. Jpn J Cancer Res 2001; 92: 135-139. Medline 11223542

Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. Nucci MR,Weremowicz S, Neskey DM. et al. Genes Chromosomes Cancer 2001; 32: 172-176. Medline 11550285

Evidence for RAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma. Takahashi T, Nagai N, Oda H. et al. Genes Chromosomes Cance 2001; 30: 196-201. Medline 11135437

Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15. Broberg K, Zhang M, Strömbeck B. et al. Int J Oncol 2002; 21: 321-326. Medline 12118328

HMGA1 and HMGA2 protein expression in mouse spermatogenesis. Chieffi P, Battista S, Barchi M. et al. Oncogene 2002; 21: 3644-3650. Medline 12032866

Hyaline vascular Castleman's disease with HMGIC rearrangement in follicular dendritic cells: molecular evidence of mesenchymal tumorigenesis. Cokelaere K, Debiec-Rychter M, De Wolf-Peeters C. et al. Am J Surg Pathol 2002; 26: 662-669. Medline 11979097

Overexpression of the HMGA2 gene in transgenic mice leads to the onset of

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -301- pituitary adenomas. Fedele M, Battista S, Kenyon L. et al. Oncogene 2002; 21: 3190-3198. Medline 12082634

The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas. Finelli P, Pierantoni GM, Giardino D. et al. Cancer Res 2002; 62: 2398-2405. Medline 11956103

Sequencing of intron 3 of HMGA2 uncovers the existence of a novel exon. Hauke S, Flohr AM, Rogalla P. et al. Genes Chromosomes Cancer 2002; 34: 17-23. Medline 11921278

Expression of the HMGA2-LPP fusion transcript in only 1 of 61 karyotypically normal pulmonary chondroid hamartomas. Lemke I, Rogalla P, Grundmann F. Et al. Cancer Genet Cytogenet 2002; 138: 160-164. Medline 12505264

Absence of HMGIC-LHFP fusion in pulmonary chondroid hamartomas with aberrations involving chromosomal regions 12q13 through 15 and 13q12 through q14. Rogalla P, Lemke I, Bullerdiek J. Cancer Genet Cytogenet 2002; 133: 90-93. Medline 11890997

Translocation of the HMGI-C ( HMGA2) gene in a benign mesenchymoma (chondrolipoangioma). Van Dorpe J, Dal Cin P,Weremowicz S. et al. Virchows Arch 2002; 440: 485-490. Medline 12021922

An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue. Abe N, Watanabe T, Suzuki Y. et al. Br J Cancer 2003; 89: 2104-2109. Medline 14647145

Human HMGA2 promoter is coregulated by a polymorphic dinucleotide (TC)- repeat. Borrmann L, Seebeck B, Rogalla P. et al. Oncogene 2003; 22: 56-60. Medline 12569368

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -302-

Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Dahlen A, Mertens F, Rydholm A. et al. Mod Pathol 2003; 16: 1132-1140. Medline 14614053

HMGA2 locus rearrangement in a case of acute lymphoblastic leukemia. Pierantoni GM, Santulli B, Caliendo I. et al. Int J Oncol 2003; 23: 363-367. Medline 12851685

Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Quade BJ, Weremowicz S, Neskey DM. Et al. Cancer Res 2003; 63: 1351-1358. Medline 12649198

High mobility group I-C protein in astrocytoma and glioblastoma. Akai T, Ueda Y, Sasagawa Y. et al. Pathol Res Pract 2004; 200: 619-624. Medline 15497774

Dysregulation and overexpression of HMGA2 in myelofibrosis with myeloid metaplasia. Andrieux J, Demory JL, Dupriez B. et al. Genes Chromosomes Cancer 2004; 39: 82-87. Medline 14603445

HMGA molecules in neuroblastic tumors. Cerignoli F, Ambrosi C, Mellone M. Ann N Y Acad Sci 2004; 1028: 122-132. Medline 15650238

Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Miyazawa J, Mitoro A, Kawashiri S. et al. Cancer Res 2004; 64: 2024-2029. Medline 15026339

Array comparative genomic hybridization analysis of uterine leiomyosarcoma. Cho YL, Bae S, Koo MS. Et al. Gynecol Oncol 2005; 99: 545-551. Medline 16125217

Transactivation functions of the tumor-specific HMGA2/LPP fusion protein are

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -303- augmented by wild-type HMGA2. Crombez KR, Vanoirbeek EM, Van de Ven WJ. et al. Mol Cancer Res 2005; 3: 63-70. Medline 15755872

HMGA proteins in malignant peripheral nerve sheath tumor and synovial sarcoma: preferential expression of HMGA2 in malignant peripheral nerve sheath tumor. Hui P, Li N, Johnson C. et al. Mod Pathol 2005; 18: 1519-1526. Medline 16056249

Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. Ligon AH, Moore SD, Parisi MA. Am J Hum Genet 2005; 76: 340-348. Medline 15593017

Fusion of the HMGA2 and NFIB genes in lipoma. Nilsson M, Panagopoulos I, Mertens F. et al. Virchows Arch 2005; 447: 855-858. Medline 16133369

Frequent deletions at 12q14.3 chromosomal locus in adult acute lymphoblastic leukemia. Patel HS, Kantarjian HM, Bueso-Ramos CE. Et al. Genes Chromosomes Cancer 2005; 42: 87-94. Medline 15495192

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Florence Pedeutour 2000 Updated 12- Karin Brober 2005

Citation This paper should be referenced as such : Pedeutour F . HMGA2 (high mobility group AT-hook 2). Atlas Genet Cytogenet Oncol Haematol. May 2000 . URL : http://AtlasGeneticsOncology.org/Genes/HMGICID82.html

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -304- Brober K . HMGA2 (high mobility group AT-hook 2). Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Genes/HMGICID82.html

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Atlas Genet Cytogenet Oncol Haematol 2006; 3 -305- Atlas of Genetics and Cytogenetics in Oncology and Haematology

JJAZ1 (joined to JAZF1)

Identity Other KIAA0160, names CHET9 Hugo SUZ12 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -306- 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 Entity endometrial stromal neoplasms with classic histology Cytogenetics nonrandom t(7;17)(p15; q21) in endometrial stromal neoplasms Hybrid/Mutated JJAZ1/JAZF1 fusion gene Gene Abnormal unknown Protein Oncogenesis unknown

External links Nomenclature Hugo SUZ12 GDB SUZ12 Entrez_Gene SUZ12 23512 suppressor of zeste 12 homolog (Drosophila) Cards Atlas JJAZ1ID41039ch17q11 GeneCards SUZ12 Ensembl SUZ12 Genatlas SUZ12 GeneLynx SUZ12 eGenome SUZ12 euGene 23512 Genomic and cartography SUZ12 - 17q11.2 chr17:27288185-27352162 + 17q11.2 (hg18- GoldenPath Mar_2006) Ensembl SUZ12 - 17q11.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene SUZ12 Gene and transcription

Genbank AK074333 [ ENTREZ ]

Genbank BC015704 [ ENTREZ ]

Genbank BC018583 [ ENTREZ ]

Genbank D63881 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -307- RefSeq NM_015355 [ SRS ] NM_015355 [ ENTREZ ] AceView SUZ12 AceView - NCBI TRASER SUZ12 Traser - Stanford

Unigene Hs.462732 [ SRS ] Hs.462732 [ NCBI ] HS462732 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q15022 [ SRS] Q15022 [ EXPASY ] Q15022 [ INTERPRO ]

PS00028 ZINC_FINGER_C2H2_1 [ SRS ] PS00028 Prosite ZINC_FINGER_C2H2_1 [ Expasy ]

PS50157 ZINC_FINGER_C2H2_2 [ SRS ] PS50157 Prosite ZINC_FINGER_C2H2_2 [ Expasy ]

Interpro IPR007087 Znf_C2H2 [ SRS ] IPR007087 Znf_C2H2 [ EBI ] CluSTr Q15022 Blocks Q15022 HPRD Q15022 Protein Interaction databases DIP Q15022 IntAct Q15022 Polymorphism : SNP, mutations, diseases OMIM 606245 [ map ] GENECLINICS 606245

SNP SUZ12 [dbSNP-NCBI]

SNP NM_015355 [SNP-NCI]

SNP SUZ12 [GeneSNPs - Utah] SUZ12] [HGBASE - SRS]

HAPMAP SUZ12 [HAPMAP] General knowledge Family SUZ12 [UCSC Family Browser] Browser SOURCE NM_015355 SMD Hs.462732 SAGE Hs.462732 Amigo nucleic acid binding Amigo intracellular Amigo nucleus Amigo transcription Amigo regulation of transcription, DNA-dependent Amigo zinc ion binding Amigo chromatin modification Amigo metal ion binding BIOCARTA The PRC2 Complex Sets Long-term Gene Silencing Through

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -308- Modification of Histone Tails [Genes] PubGene SUZ12 Other databases Probes Probe SUZ12 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography JAZF1/JJAZ1 gene fusion in endometrial stromal sarcomas: molecular analysis by reverse transcriptase-polymerase chain reaction optimized for paraffin- embedded tissue. Hrzenjak A, Moinfar F, Tavassoli FA, Strohmeier B, Kremser ML, Zatloukal K, Denk H. J Mol Diagn 2005; 7(3): 388-395. Review. Medline 16049311

High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF. Am J Hum Genet 2004; 75(3): 410-423. Epub 2004 Jul 15. Medline 15257518

Molecular detection of JAZF1-JJAZ1 gene fusion in endometrial stromal neoplasms with classic and variant histology: evidence for genetic heterogeneity. Huang HY, Ladanyi M, Soslow RA. Am J Surg Pathol 2004; 28(2): 224-232. Medline 15043312

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). Micci F, Walter CU, Teixeira MR, Panagopoulos I, Bjerkehagen B, Saeter G, Heim S. Cancer Genet Cytogenet 2003; 144(2): 119-124. Medline 12850374

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. Petek E, Jenne DE, Smolle J, Binder B, Lasinger W, Windpassinger C, Wagner K, Kroisel PM, Kehrer-Sawatzki H. J Med Genet 2003; 40(7): 520-525. Medline 12843325

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -309- Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Cin PD, Fletcher JA, Sklar J. Proc Natl Acad Sci U S A 2001; 98(11): 6348-6353. Medline 11371647

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- Hildegard Kehrer-Sawatzki 2005 Citation This paper should be referenced as such : Kehrer-Sawatzki H . JJAZ1 (joined to JAZF1). Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Genes/JJAZ1ID41039ch17q11.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3

Identity Other MOZ (monocytic leukemia zinc finger) names ZNF220 RUNXBP2 Hugo MYST3 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -311- factor), a transcription regulator with positive and negative domains and activities Implicated in Entity t(2;8)(p23;p11) in therapy related myelodysplastic syndrome --> MYST3 / ? Disease only 1 case to date, a boy aged 6 yrs

Entity 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 5' MYST3 - 3' NCOA2 Gene Abnormal The fusion product retains the zinc fingers, the the histone acetyl Protein transferase (HAT) domain of MYST3 and the HAT domains and CREBBP interacting domain of NCOA2

Entity 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 5¹ MYST3 - 3¹ CREBBP Gene Abnormal The fusion product retains the zinc fingers, the HAT domain of Protein MYST3 and most of CREBBP, including the CREBBP interacting domain and the HAT domain; the fusion protein may repressRUNX1- dependant gene expression£.

Entity 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -312-

To be noted 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 External links Nomenclature Hugo MYST3 GDB MYST3 MYST3 7994 MYST histone acetyltransferase (monocytic leukemia) Entrez_Gene 3 Cards Atlas MYST3ID25ch8p11 GeneCards MYST3 Ensembl MYST3 Genatlas MYST3 GeneLynx MYST3 eGenome MYST3 euGene 7994 Genomic and cartography MYST3 - 8p11 chr8:41907427-42028635 - 8p11.21 (hg18- GoldenPath Mar_2006) Ensembl MYST3 - 8p11.21 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MYST3 Gene and transcription

Genbank AK027361 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -313- Genbank AK128323 [ ENTREZ ]

Genbank BC018011 [ ENTREZ ]

Genbank U47742 [ ENTREZ ]

RefSeq NM_006766 [ SRS ] NM_006766 [ ENTREZ ] AceView MYST3 AceView - NCBI TRASER MYST3 Traser - Stanford

Unigene Hs.591848 [ SRS ] Hs.591848 [ NCBI ] HS591848 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q6ZRC7 [ SRS] Q6ZRC7 [ EXPASY ] Q6ZRC7 [ INTERPRO ]

Interpro IPR002717 MOZ_SAS [ SRS ] IPR002717 MOZ_SAS [ EBI ]

IPR011991 Wing_hlx_DNA_bd [ SRS ] IPR011991 Interpro Wing_hlx_DNA_bd [ EBI ] CluSTr Q6ZRC7

PF01853 MOZ_SAS [ SRS ] PF01853 MOZ_SAS [ Sanger Pfam ] pfam01853 [ NCBI-CDD ] Blocks Q6ZRC7 HPRD Q6ZRC7 Protein Interaction databases DIP Q6ZRC7 IntAct Q6ZRC7 Polymorphism : SNP, mutations, diseases OMIM 601408 [ map ] GENECLINICS 601408

SNP MYST3 [dbSNP-NCBI]

SNP NM_006766 [SNP-NCI]

SNP MYST3 [GeneSNPs - Utah] MYST3] [HGBASE - SRS]

HAPMAP MYST3 [HAPMAP] General knowledge Family MYST3 [UCSC Family Browser] Browser SOURCE NM_006766 SMD Hs.591848 SAGE Hs.591848 Amigo nucleosome Amigo DNA binding Amigo histone acetyltransferase activity Amigo nucleus Amigo DNA packaging Amigo nucleosome assembly

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -314- Amigo transcription Amigo regulation of transcription, DNA-dependent Amigo transcription factor binding Amigo zinc ion binding Amigo acetyltransferase activity Amigo negative regulation of transcription Amigo chromatin modification Amigo histone acetylation Amigo transferase activity Amigo myeloid cell differentiation Amigo positive regulation of transcription Amigo metal ion binding PubGene MYST3 Other databases Probes Probe MYST3 Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography Three cases of translocation t(8 ;16)(p11 ;p13) observed in acute myelomonocytic leukaemia : a new specific subgroup? Lai JL, Zandecki M, Jouet JP, Savary KB, Lambiliotte A, Bauters F, Cosson A, Deminatti M. Cancer Genet Cytogenet 1987; 27: 101-109. Medline 3472640

The 8p11 anomaly in "monoblastic" leukaemia Brizard A, Guilhot F, Huret JL, Benz-Lemoine E, Tanzer J. Leuk Res 1988; 12: 693-697. Medline 89038614

The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein Borrow J, Stanton VP Jr, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dube I, Frischauf AM, Horsman D, Mitelman F, Volinia S, Watmore AE, Housman DE. Nat Genet 1996; 14: 33-41. Medline 96376968

Abnormalities of chromosome band 8p11 in leukemia: two clinical syndromes can be distinguished on the basis of MOZ involvement. Aguiar R, Chase A, Coulthard S, Macdonald D, Carapeti M, Reiter A, Sohal J,

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -315- Lennard A, Goldman J, Cross N. Blood 1997; 90: 3130-3135. Medline 9376594

A novel fusion between MOZ and the nuclear receptor coactivator TIF-2 in acute myeloid leukemia. Carapeti M, Aguiar R, Goldman JM, Cross N. Blood 1998; 91: 3127-313 Medline 9558366

Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11). Imamura T, Kakazu N, Hibi S, Morimoto A, Fukushima Y, Ijuin I, Hada S, Kitabayashi I, Abe T, Imashuku S. Genes Chromosomes Cancer 2003; 36: 413-419 Medline 12619166 moz regulates Hox expression and pharyngeal segmental identity in zebrafish. Miller CT, Maves L, Kimmel CB. Development 2004; 131: 2443-2461. Medline 15128673

The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Yang XJ. Nucleic Acids Res 2004; 32: 959-976. Medline 14960713

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Contributor(s) Written 12- Jean Loup Huret, Sylvie Senon 2005 Citation

This paper should be referenced as such : Huret JL, Senon S . MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3. Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Genes/MYST3ID25ch8p11.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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PLCB1 (phospholipase C, beta 1 (phosphoinositide- specific))

Identity Other PLC-I names PI-PLC PLC-154 Hugo PLCB1 Location 20p12.3 between the markers D20S917 and D20S177 DNA/RNA

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 49.

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -317- was identified, which gives a smaller isoform, and another PLCB1b isoform, which is produced by using an alternative 3¹-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 , 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%

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -318- homologous among all mammalian isozymes. Mutations Note Until now only deletions have been relevated by using FISH analysis. Implicated in Entity 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 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.

External links Nomenclature Hugo PLCB1 GDB PLCB1 Entrez_Gene PLCB1 23236 phospholipase C, beta 1 (phosphoinositide-specific) Cards

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -319- Atlas PLCB1ID41742ch20p12 GeneCards PLCB1 Ensembl PLCB1 Genatlas PLCB1 GeneLynx PLCB1 eGenome PLCB1 euGene 23236 Genomic and cartography PLCB1 - 20p12.3 chr20:8061296-8813545 + 20p12.3 (hg18- GoldenPath Mar_2006) Ensembl PLCB1 - 20p12.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PLCB1 Gene and transcription

Genbank AB011153 [ ENTREZ ]

Genbank AJ278313 [ ENTREZ ]

Genbank AJ278314 [ ENTREZ ]

Genbank AK023689 [ ENTREZ ]

Genbank AK127693 [ ENTREZ ]

RefSeq NM_015192 [ SRS ] NM_015192 [ ENTREZ ]

RefSeq NM_182734 [ SRS ] NM_182734 [ ENTREZ ] AceView PLCB1 AceView - NCBI TRASER PLCB1 Traser - Stanford

Unigene Hs.431173 [ SRS ] Hs.431173 [ NCBI ] HS431173 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q5JXN4 [ SRS] Q5JXN4 [ EXPASY ] Q5JXN4 [ INTERPRO ]

Prosite PS50004 C2_DOMAIN [ SRS ] PS50004 C2_DOMAIN [ Expasy ] Prosite PS50007 PIPLC_X_DOMAIN [ SRS ] PS50007 PIPLC_X_DOMAIN [ Expasy ] Prosite PS50008 PIPLC_Y_DOMAIN [ SRS ] PS50008 PIPLC_Y_DOMAIN [ Expasy ]

Interpro IPR000008 C2_Ca-dep [ SRS ] IPR000008 C2_Ca-dep [ EBI ]

Interpro IPR008973 C2_CaLB [ SRS ] IPR008973 C2_CaLB [ EBI ]

Interpro IPR001192 PI_PLC [ SRS ] IPR001192 PI_PLC [ EBI ]

Interpro IPR000909 PI_PLC_X [ SRS ] IPR000909 PI_PLC_X [ EBI ]

Interpro IPR001711 PI_PLC_Y [ SRS ] IPR001711 PI_PLC_Y [ EBI ] CluSTr Q5JXN4

Pfam PF00168 C2 [ SRS ] PF00168 C2 [ Sanger ] pfam00168 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -320- Pfam PF00388 PI-PLC-X [ SRS ] PF00388 PI-PLC-X [ Sanger ] pfam00388 [ NCBI-CDD ] Pfam PF00387 PI-PLC-Y [ SRS ] PF00387 PI-PLC-Y [ Sanger ] pfam00387 [ NCBI-CDD ]

Smart SM00239 C2 [EMBL]

Smart SM00149 PLCYc [EMBL]

Prodom PD001202 PI_PLC_Y[INRA-Toulouse] Prodom Q5JXN4 Q5JXN4_HUMAN [ Domain structure ] Q5JXN4 Q5JXN4_HUMAN [ sequences sharing at least 1 domain ] Blocks Q5JXN4 HPRD Q5JXN4 Protein Interaction databases DIP Q5JXN4 IntAct Q5JXN4 Polymorphism : SNP, mutations, diseases OMIM 607120 [ map ] GENECLINICS 607120

SNP PLCB1 [dbSNP-NCBI]

SNP NM_015192 [SNP-NCI]

SNP NM_182734 [SNP-NCI]

SNP PLCB1 [GeneSNPs - Utah] PLCB1] [HGBASE - SRS]

HAPMAP PLCB1 [HAPMAP] General knowledge Family PLCB1 [UCSC Family Browser] Browser SOURCE NM_015192 SOURCE NM_182734 SMD Hs.431173 SAGE Hs.431173 Amigo regulation of progression through cell cycle Amigo phosphoinositide phospholipase C activity Amigo phosphoinositide phospholipase C activity Amigo signal transducer activity Amigo calcium ion binding Amigo nucleus Amigo cytoplasm Amigo lipid metabolism Amigo intracellular signaling cascade Amigo lipid catabolism Amigo hydrolase activity

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -321- KEGG Inositol Phosphate Metabolism KEGG Phosphatidylinositol Signaling System PubGene PLCB1 Other databases Probes Probe PLCB1 Related clones (RZPD - Berlin) PubMed PubMed 31 Pubmed reference(s) in LocusLink Bibliography 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. Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. DNA Res 1998; 5: 31-39. Medline 9628581

Cloning and characterization of the human phosphoinositide-specific phospholipase C-beta 1 (PLC-beta 1). Caricasole A, Sala C, Roncarati R, Formenti E, Terstappen GC. Biochim Biophys Acta 2000; 1517: 63-72. Medline 11118617

Identification and chromosomal localisation by fluorescence in situ hybridisation of human gene of phosphoinositide-specific phospholipase C beta-1. Peruzzi D, Calabrese G, Faenza I, Manzoli L, Matteucci A, Gianfrancesco F, Billi AM, Stuppia L, Palka G, Cocco L. Biochim Biophys Acta 2000; 1484: 175-182. Medline 10760467

Molecular characterization of the human PLC beta-1 gene Peruzzi D, Aluigi M, Manzoli L, Billi AM, Di Giorgio FP, Morleo M, Martelli AM, Cocco L. Biochim Biophys Acta 2002; 1584: 46-54. Medline 12213492

Inositide-specific phospholipase c beta-1 gene deletion in the progression of myelodysplastic syndrome to acute myeloid leukemia. Lo Vasco VR, Calabrese G, Manzoli L, Palka G, Spadano A, Morizio E, Guanciali- Franchi P, Fantasia D, Cocco L. Leukemia 2004; 18: 1122-1126. Medline 15085153

REVIEW articles automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -322- Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- Matilde Y. Follo, Vincenza Rita Lo Vasco, Giovanni Martinelli, 2005 Giandomenico Palka, Lucio Cocco Citation This paper 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. December 2005 . URL : http://AtlasGeneticsOncology.org/Genes/PLCB1ID41742ch20p12.html

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Atlas Genet Cytogenet Oncol Haematol 2006; 3 -323- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PMS1 (PMS1 postmeiotic segregation increased 1 (S. cerevisiae))

Identity Other HNPCC3 names PMSL1 Hugo PMS1 Location 2q31-33 DNA/RNA

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.

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 MLH1/PMS1 heterodimer in the mismatch repair process, despite that the

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -324- 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. External links Nomenclature Hugo PMS1 GDB PMS1 PMS1 5378 PMS1 postmeiotic segregation increased 1 (S. Entrez_Gene cerevisiae) Cards Atlas PMS1ID345ch2q31 GeneCards PMS1 Ensembl PMS1 Genatlas PMS1 GeneLynx PMS1 eGenome PMS1 euGene 5378 Genomic and cartography PMS1 - chr2:190357355-190450599 + 2q32.2 (hg18- GoldenPath Mar_2006) Ensembl PMS1 - 2q32.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PMS1 Gene and transcription

Genbank AB102869 [ ENTREZ ]

Genbank AB102870 [ ENTREZ ]

Genbank AB102871 [ ENTREZ ]

Genbank AB102872 [ ENTREZ ]

Genbank AB102873 [ ENTREZ ]

RefSeq NM_000534 [ SRS ] NM_000534 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -325- AceView PMS1 AceView - NCBI TRASER PMS1 Traser - Stanford

Unigene Hs.111749 [ SRS ] Hs.111749 [ NCBI ] HS111749 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P54277 [ SRS] P54277 [ EXPASY ] P54277 [ INTERPRO ]

PS00058 DNA_MISMATCH_REPAIR_1 [ SRS ] PS00058 Prosite DNA_MISMATCH_REPAIR_1 [ Expasy ]

Prosite PS50118 HMG_BOX_2 [ SRS ] PS50118 HMG_BOX_2 [ Expasy ] Interpro IPR003594 ATP_bd_ATPase [ SRS ] IPR003594 ATP_bd_ATPase [ EBI ]

Interpro IPR002099 DNA_mis_repair [ SRS ] IPR002099 DNA_mis_repair [ EBI ]

IPR013507 DNA_mis_repair_C [ SRS ] IPR013507 Interpro DNA_mis_repair_C [ EBI ]

Interpro IPR009071 HMG-box [ SRS ] IPR009071 HMG-box [ EBI ]

Interpro IPR000910 HMG_1/2_box [ SRS ] IPR000910 HMG_1/2_box [ EBI ] CluSTr P54277

PF01119 DNA_mis_repair [ SRS ] PF01119 DNA_mis_repair [ Sanger Pfam ] pfam01119 [ NCBI-CDD ]

PF02518 HATPase_c [ SRS ] PF02518 HATPase_c [ Sanger Pfam ] pfam02518 [ NCBI-CDD ] Pfam PF00505 HMG_box [ SRS ] PF00505 HMG_box [ Sanger ] pfam00505 [ NCBI-CDD ]

Smart SM00398 HMG [EMBL] Blocks P54277

PDB 2CS1 [ SRS ] 2CS1 [ PdbSum ], 2CS1 [ IMB ] 2CS1 [ RSDB ] HPRD P54277 Protein Interaction databases DIP P54277 IntAct P54277 Polymorphism : SNP, mutations, diseases OMIM 600258 [ map ] GENECLINICS 600258

SNP PMS1 [dbSNP-NCBI]

SNP NM_000534 [SNP-NCI]

SNP PMS1 [GeneSNPs - Utah] PMS1] [HGBASE - SRS]

HAPMAP PMS1 [HAPMAP] General knowledge Family PMS1 [UCSC Family Browser] Browser SOURCE NM_000534

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -326- SMD Hs.111749 SAGE Hs.111749 Amigo DNA binding Amigo ATP binding Amigo nucleus Amigo mismatch repair Amigo mismatch repair Amigo regulation of transcription, DNA-dependent Amigo cell cycle Amigo negative regulation of progression through cell cycle PubGene PMS1 Other databases Probes Probe PMS1 Related clones (RZPD - Berlin) PubMed PubMed 19 Pubmed reference(s) in LocusLink Bibliography Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. 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. Nature 1994 Sep 1; 371(6492): 75-80. Medline 8072530

Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair. 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. Nat Genet 1998; 18: 276-279. Medline 9500552

Isolation and characterization of the 5' region of the human mismatch repair gene hPMS1. Yanagisawa Y, Ito E, Iwahashi Y, Akiyama Y, Yuasa Y, Maruyama K. Biochem Biophys Res Commun 1998; 243: 738-743. Medline 9500994

Identification of hMutLbeta, a heterodimer of hMLH1 and hPMS1 Raschle M, Marra G, Nystrom-Lahti M, Schar P, Jiricny J. J Biol Chem 1999; 274: 32368-32375. Medline 10542278

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -327- The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Kondo E, Horii A, Fukushige S. Nucleic Acids Res 2001; 29: 1695-1702. Medline 11292842

The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. 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. Cancer Res 2001; 61: 7798-7802. Medline 11691795

DNA mismatch repair defects: role in colorectal carcinogenesis. Jacob S, Praz F. Biochimie 2002; 84: 27-47. (REVIEW) Medline 11900875

Lynch syndrome genes. Peltomaki P. Fam Cancer 2005; 4: 227-232. Medline 16136382

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 12- Enric Domingo, Simo Schwartz Jr 2005 Citation This paper should be referenced as such : Domingo E, Schwartz SJr . PMS1 (PMS1 postmeiotic segregation increased 1 (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Genes/PMS1ID345ch2q31.html

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Atlas Genet Cytogenet Oncol Haematol 2006; 3 -328- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PKD1 (Protein Kinase D1)

Identity Other PKCmu names PRKCM Hugo PRKD1 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -329- Homology Homologues present in mouse and rat. Implicated in Entity 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.

Entity 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.

External links Nomenclature Hugo PRKD1 GDB PRKD1 Entrez_Gene PRKD1 5587 protein kinase D1 Cards Atlas PRKCMID41860ch14q11 GeneCards PRKD1 Ensembl PRKD1 Genatlas PRKD1 GeneLynx PRKD1 eGenome PRKD1 euGene 5587 Genomic and cartography PRKD1 - 14q11 chr14:29115440-29466652 - 14q12 (hg18- GoldenPath Mar_2006) Ensembl PRKD1 - 14q12 [CytoView]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -330- NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PRKD1 Gene and transcription

Genbank X75756 [ ENTREZ ]

RefSeq NM_002742 [ SRS ] NM_002742 [ ENTREZ ] AceView PRKD1 AceView - NCBI TRASER PRKD1 Traser - Stanford

Unigene Hs.508999 [ SRS ] Hs.508999 [ NCBI ] HS508999 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q15139 [ SRS] Q15139 [ EXPASY ] Q15139 [ INTERPRO ]

Prosite PS50003 PH_DOMAIN [ SRS ] PS50003 PH_DOMAIN [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 Prosite PROTEIN_KINASE_ST [ Expasy ]

Prosite PS00479 ZF_DAG_PE_1 [ SRS ] PS00479 ZF_DAG_PE_1 [ Expasy ]

Prosite PS50081 ZF_DAG_PE_2 [ SRS ] PS50081 ZF_DAG_PE_2 [ Expasy ]

Interpro IPR002219 DAG_PE_bd [ SRS ] IPR002219 DAG_PE_bd [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR001849 PH [ SRS ] IPR001849 PH [ EBI ]

Interpro IPR011993 PH_type [ SRS ] IPR011993 PH_type [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ]

Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ] CluSTr Q15139

Pfam PF00130 C1_1 [ SRS ] PF00130 C1_1 [ Sanger ] pfam00130 [ NCBI-CDD ]

Pfam PF00169 PH [ SRS ] PF00169 PH [ Sanger ] pfam00169 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00109 C1 [EMBL]

Smart SM00233 PH [EMBL]

Smart SM00220 S_TKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom Q15139 KPCD1_HUMAN [ Domain structure ] Q15139 KPCD1_HUMAN [ sequences sharing at least 1 domain ] Blocks Q15139

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -331- HPRD Q15139 Protein Interaction databases DIP Q15139 IntAct Q15139 Polymorphism : SNP, mutations, diseases OMIM 605435 [ map ] GENECLINICS 605435

SNP PRKD1 [dbSNP-NCBI]

SNP NM_002742 [SNP-NCI]

SNP PRKD1 [GeneSNPs - Utah] PRKD1] [HGBASE - SRS]

HAPMAP PRKD1 [HAPMAP] General knowledge Family PRKD1 [UCSC Family Browser] Browser SOURCE NM_002742 SMD Hs.508999 SAGE Hs.508999

2.7.11.13 [ Enzyme-SRS ] 2.7.11.13 [ Brenda-SRS ] 2.7.11.13 [ KEGG Enzyme ] 2.7.11.13 [ WIT ] Amigo nucleotide binding Amigo protein serine/threonine kinase activity Amigo atypical protein kinase C activity Amigo protein binding Amigo ATP binding Amigo Golgi apparatus Amigo cytosol Amigo plasma membrane Amigo integral to plasma membrane Amigo protein amino acid phosphorylation Amigo intracellular signaling cascade Amigo zinc ion binding Amigo cell proliferation Amigo transferase activity Amigo diacylglycerol binding Amigo metal ion binding PubGene PRKD1 Other databases Probes

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -332- Probe PRKD1 Related clones (RZPD - Berlin) PubMed PubMed 60 Pubmed reference(s) in LocusLink Bibliography PKCu is a novel, atypical member of the protein kinase C family. Johannes FJ, Prestle J, Eis S, Oberhagemann P, Pfizenmaier K. J Biol Chem 1994; 269(8): 6140-6148. Medline 8119958

Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain. Valverde AM, Sinnett-Smith J, Van Lint J, Rozengurt E. Proc Natl Acad Sci USA 1994; 91(18): 8572-8576. Medline 8078925

Expression and characterization of PKD, a phorbol ester and diacylglycerol- stimulated serine protein kinase. Van Lint JV, Sinnett-Smith J, Rozengurt E. J Biol Chem 1995; 270(3): 1455-1461. Medline 7836415

Protein kinase C mu (PKC mu) associates with the B cell antigen receptor complex and regulates lymphocyte signaling. Sidorenko SP, Law CL, Klaus SJ, Chandran KA, Takata M, Kurosaki T, Clark EA. Immunity 1996; 5(4): 353-363. Medline 8885868

Protein kinase D (PKD) activation in intact cells through a protein kinase C- dependent signal transduction pathway. Zugaza JL, Sinnett-Smith J, Van Lint J, Rozengurt E. EMBO J 1996 Nov 15; 15(22): 6220-6230. Medline 8947045

An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation. Bowden ET, Barth M, Thomas D, Glazer RI, Mueller SC. Oncogene 1999; 18(31): 4440-4449. Medline 10442635

Protein kinase C mu is negatively regulated by 14-3-3 signal transduction proteins. Hausser A, Storz P, Link G, Stoll H, Liu YC, Altman A, Pfizenmaier K, Johannes FJ. J Biol Chem 1999; 274(14): 9258-9264. Medline 10092600

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -333- Phosphorylation-dependent protein kinase D activation. Waldron RT, Iglesias T, Rozengurt E. Electrophoresis 1999; 20(2): 382-390. Review. Medline 10197446

Protein kinase D. A selective target for antigen receptors and a downstream target for protein kinase C in lymphocytes. Matthews SA, Rozengurt E, Cantrell D. J Exp Med 2000; 191(12): 2075-2082. Medline 10859332

Regulation of protein kinase D by multisite phosphorylation. Identification of phosphorylation sites by mass spectrometry and characterization by site- directed mutagenesis. Vertommen D, Rider M, Ni Y, Waelkens E, Merlevede W, Vandenheede JR, Van Lint J. J Biol Chem 2000; 275(26): 19567-19576. Medline 10867018

Regulated nucleocytoplasmic transport of protein kinase D in response to G protein-coupled receptor activation. Rey O, Sinnett-Smith J, Zhukova E, Rozengurt E. J Biol Chem 2001; 276(52): 49228-49235 Medline 11641411

Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo. Waldron RT, Rey O, Iglesias T, Tugal T, Cantrell D, Rozengurt E. J Biol Chem 2001; 276(35): 32606-32615. Epub 2001 Jun 15. Medline 11410586

Structural requirements for localization and activation of protein kinase C mu (PKC mu) at the Golgi compartment. Hausser A, Link G, Bamberg L, Burzlaff A, Lutz S, Pfizenmaier K, Johannes FJ. J Cell Biol 2002; 156(1): 65-74. Medline 11777941

Getting to know protein kinase D. Lint JV, Rykx A, Vantus T, Vandenheede JR. Int J Biochem Cell Biol 2002; 34(6): 577-581. Review. Medline 11943587

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -334- Medline 12829240

Protein kinase C phosphorylates protein kinase D activation loop Ser744 and Ser748 and releases autoinhibition by the pleckstrin homology domain. Waldron RT, Rozengurt E. J Biol Chem 2003; 278(1): 154-163. Medline 12407104

E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer. Jaggi M, Rao PS, Smith DJ, Wheelock MJ, Johnson KR, Hemstreet GP, Balaji KC. Cancer Res 2005; 65(2): 483-492. Medline 15695390

Protein kinase D signaling. Rozengurt E, Rey O, Waldron RT. J Biol Chem 2005; 280(14): 13205-13208. Review. Medline 15701647

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- C Du, M Jaggi , W Zhang, KC Balaji 2006 Citation This paper should be referenced as such : Du C, Zhang W, Balaji KC . PKD1 (Protein Kinase D1). Atlas Genet Cytogenet Oncol Haematol. January 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PRKCMID41860ch14q11.html

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Atlas Genet Cytogenet Oncol Haematol 2006; 3 -335- Atlas of Genetics and Cytogenetics in Oncology and Haematology

THBS2 (thrombospondin-2)

Identity Other TSP2, names CISP (corticotropin-induced secreted protein) Hugo THBS2 Location 6q27 Telomeric to SMOC2 (SPARC related modular calcium binding 2),

centromeric to LOC442278 DNA/RNA

Intron-exon organization of the THBS2 gene.

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 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. 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,, Myc-CF1, Sp1, CF-1,GATA and AP-1. Pseudogene none described Protein

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -336-

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.

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -337- 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -338- 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 Entity 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -339- angiogenesis.

External links Nomenclature Hugo THBS2 GDB THBS2 Entrez_Gene THBS2 7058 thrombospondin 2 Cards Atlas THBS2ID42549ch6q27 GeneCards THBS2 Ensembl THBS2 Genatlas THBS2 GeneLynx THBS2 eGenome THBS2 euGene 7058 Genomic and cartography THBS2 - 6q27 chr6:169357801-169396062 - 6q27 (hg18- GoldenPath Mar_2006) Ensembl THBS2 - 6q27 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene THBS2 Gene and transcription

Genbank AA853383 [ ENTREZ ]

Genbank AA853654 [ ENTREZ ]

Genbank AI130835 [ ENTREZ ]

Genbank AL603377 [ ENTREZ ]

Genbank BX390187 [ ENTREZ ]

RefSeq NM_003247 [ SRS ] NM_003247 [ ENTREZ ] AceView THBS2 AceView - NCBI TRASER THBS2 Traser - Stanford

Unigene Hs.371147 [ SRS ] Hs.371147 [ NCBI ] HS371147 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P35442 [ SRS] P35442 [ EXPASY ] P35442 [ INTERPRO ]

Prosite PS00022 EGF_1 [ SRS ] PS00022 EGF_1 [ Expasy ]

Prosite PS01186 EGF_2 [ SRS ] PS01186 EGF_2 [ Expasy ]

Prosite PS50026 EGF_3 [ SRS ] PS50026 EGF_3 [ Expasy ]

Prosite PS50092 TSP1 [ SRS ] PS50092 TSP1 [ Expasy ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -340- Prosite PS01208 VWFC_1 [ SRS ] PS01208 VWFC_1 [ Expasy ]

Prosite PS50184 VWFC_2 [ SRS ] PS50184 VWFC_2 [ Expasy ] Interpro IPR008985 ConA_like_lec_gl [ SRS ] IPR008985 ConA_like_lec_gl [ EBI ]

Interpro IPR006210 EGF [ SRS ] IPR006210 EGF [ EBI ]

Interpro IPR000742 EGF_3 [ SRS ] IPR000742 EGF_3 [ EBI ]

Interpro IPR013091 EGF_Ca_bd_2 [ SRS ] IPR013091 EGF_Ca_bd_2 [ EBI ]

Interpro IPR006209 EGF_like [ SRS ] IPR006209 EGF_like [ EBI ]

Interpro IPR013032 EGF_like_reg [ SRS ] IPR013032 EGF_like_reg [ EBI ]

IPR003129 Laminin_G_TSP_N [ SRS ] IPR003129 Interpro Laminin_G_TSP_N [ EBI ]

Interpro IPR000884 TSP1 [ SRS ] IPR000884 TSP1 [ EBI ]

Interpro IPR008085 TSP_1 [ SRS ] IPR008085 TSP_1 [ EBI ]

Interpro IPR003367 tsp_3 [ SRS ] IPR003367 tsp_3 [ EBI ]

Interpro IPR008859 TSP_C [ SRS ] IPR008859 TSP_C [ EBI ]

Interpro IPR001007 VWF_C [ SRS ] IPR001007 VWF_C [ EBI ] CluSTr P35442

Pfam PF00008 EGF [ SRS ] PF00008 EGF [ Sanger ] pfam00008 [ NCBI-CDD ] Pfam PF07645 EGF_CA [ SRS ] PF07645 EGF_CA [ Sanger ] pfam07645 [ NCBI-CDD ] Pfam PF00090 TSP_1 [ SRS ] PF00090 TSP_1 [ Sanger ] pfam00090 [ NCBI- CDD ] Pfam PF02412 TSP_3 [ SRS ] PF02412 TSP_3 [ Sanger ] pfam02412 [ NCBI- CDD ] Pfam PF05735 TSP_C [ SRS ] PF05735 TSP_C [ Sanger ] pfam05735 [ NCBI- CDD ]

Pfam PF00093 VWC [ SRS ] PF00093 VWC [ Sanger ] pfam00093 [ NCBI-CDD ]

Smart SM00181 EGF [EMBL]

Smart SM00209 TSP1 [EMBL]

Smart SM00210 TSPN [EMBL]

Smart SM00214 VWC [EMBL] Blocks P35442

PDB 1YO8 [ SRS ] 1YO8 [ PdbSum ], 1YO8 [ IMB ] 1YO8 [ RSDB ] HPRD P35442 Protein Interaction databases DIP P35442 IntAct P35442 Polymorphism : SNP, mutations, diseases OMIM 188061 [ map ] GENECLINICS 188061

SNP THBS2 [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -341- SNP NM_003247 [SNP-NCI]

SNP THBS2 [GeneSNPs - Utah] THBS2] [HGBASE - SRS]

HAPMAP THBS2 [HAPMAP] General knowledge Family THBS2 [UCSC Family Browser] Browser SOURCE NM_003247 SMD Hs.371147 SAGE Hs.371147 Amigo structural molecule activity Amigo calcium ion binding Amigo protein binding Amigo extracellular region Amigo extracellular matrix (sensu Metazoa) Amigo cell adhesion Amigo heparin binding PubGene THBS2 Other databases Probes Probe THBS2 Related clones (RZPD - Berlin) PubMed PubMed 24 Pubmed reference(s) in LocusLink Bibliography Corticotropin-induced secreted protein, an ACTH-induced protein secreted by adrenocortical cells, is structurally related to thrombospondins. Pellerin S, Lafeuillade B, Scherrer N, Gagnon J, Shi DL, Chambaz EM, Feige JJ. J Biol Chem 1993 Feb 25; 268(6): 4304-4310. Medline 8382699

Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice. Zhang Y, Deng Y, Luther T, Muller M, Ziegler R, Waldherr R, Stern DM, Nawroth PP. J Clin Invest 1994 Sep; 94(3): 1320-1327. Medline 7521887

Analysis of the promoter and transcription start sites of the human thrombospondin 2 gene (THBS2). Adolph KW, Liska DJ, Bornstein P. Gene 1997 Jul 1; 193(1): 5-11. Medline 9249061

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -342- Thrombospondin-1 and -2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and fibroblastic desmoplasia. Bertin N, Clezardin P, Kubiak R, Frappart L. Cancer Res 1997 Feb 1; 57(3): 396-399. Medline 9012463

Myb-dependent regulation of thrombospondin 2 expression. Role of mRNA stability. Bein K, Ware JA, Simons M. J Biol Chem 1998 Aug 14; 273(33): 21423-21429. Medline 9694906

Thrombospondin 2 gene expression is correlated with decreased vascularity in non-small cell lung cancer. Oshika Y, Masuda K, Tokunaga T, Hatanaka H, Kamiya T, Abe Y, Ozeki Y, Kijima H, Yamazaki H, Tamaoki N, Ueyama Y, Nakamura M. Clin Cancer Res 1998 Jul; 4(7): 1785-1788. Medline 9676856

Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays. Zhu H, Cong JP, Mamtora G, Gingeras T, Shenk T. Proc Natl Acad Sci U S A 1998 Nov 24; 95(24): 14470-14475. Medline 9826724

Expression of members of the thrombospondin family by human skeletal tissues and cultured cells. Carron JA, Bowler WB, Wagstaff SC, Gallagher JA. Biochem Biophys Res Commun 1999 Sep 24; 263(2): 389-391. Medline 10491303

Thrombospondin-2 (TSP2) expression is inversely correlated with vascularity in glioma. Kazuno M, Tokunaga T, Oshika Y, Tanaka Y, Tsugane R, Kijima H, Yamazaki H, Ueyama Y, Nakamura M. Eur J Cancer 1999 Mar; 35(3): 502-506. Medline 10448307

Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Streit M, Riccardi L, Velasco P, Brown LF, Hawighorst T, Bornstein P, Detmar M. Proc Natl Acad Sci U S A 1999 Dec 21; 96(26): 14888-14893. Medline 10611308

Expression of angiostatic factors in colorectal cancer.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -343- Yoshida Y, Oshika Y, Fukushima Y, Tokunaga T, Hatanaka H, Kijima H, Yamazaki H, Ueyama Y, Tamaoki N, Miura S, Nakamura M. Int J Oncol 1999 Dec; 15(6): 1221-1225. Medline 10568831

Angiogenesis modulators expression in culture cell lines positives for HPV-16 oncoproteins. Bequet-Romero M, Lopez-Ocejo O. Biochem Biophys Res Commun 2000 Oct 14; 277(1): 55-61. Medline 11027639

Thrombospondins: multifunctional regulators of cell interactions. Adams JC. Annu Rev Cell Dev Biol 2001; 17: 25-51. Review. Medline 11687483

Thrombospondins and tumor angiogenesis. de Fraipont F, Nicholson AC, Feige JJ, Van Meir EG. Trends Mol Med 2001 Sep; 7(9): 401-407. Review. Medline 11530335

Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. Hawighorst T, Velasco P, Streit M, Hong YK, Kyriakides TR, Brown LF, Bornstein P, Detmar M. EMBO J 2001 Jun 1; 20(11): 2631-2640. Medline 11387198

Gene expression profiling in human esophageal cancers using cDNA microarray. Kan T, Shimada Y, Sato F, Maeda M, Kawabe A, Kaganoi J, Itami A, Yamasaki S, Imamura M. Biochem Biophys Res Commun 2001 Aug 31; 286(4): 792-801. Medline 11520067

Thrombospondin-1 and -2 messenger RNA expression in epithelial ovarian tumor. Kodama J, Hashimoto I, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T. Anticancer Res 2001 Jul-Aug; 21(4B): 2983-2987. Medline 11712798

Thrombospondin-1 and -2 messenger RNA expression in invasive cervical cancer: correlation with angiogenesis and prognosis. Kodama J, Hashimoto I, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T. Clin Cancer Res 2001 Sep; 7(9): 2826-2831. Medline 11555600

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -344-

Comparative study of angiostatic and anti-invasive gene expressions as prognostic factors in gastric cancer. Lee JH, Koh JT, Shin BA, Ahn KY, Roh JH, Kim YJ, Kim KK. Int J Oncol 2001 Feb; 18(2): 355-361. Medline 11172604

Transcription factor ATF3 partially transforms chick embryo fibroblasts by promoting growth factor-independent proliferation. Perez S, Vial E, van Dam H, Castellazzi M. Oncogene 2001 Mar 1; 20(9): 1135-1141. Medline 11314051

Thrombospondin-1 and -2 messenger RNA expression in normal and neoplastic endometrial tissues: correlation with angiogenesis and prognosis. Seki N, Kodama J, Hashimoto I, Hongo A, Yoshinouchi M, Kudo T. Int J Oncol. 2001 Aug;19(2):305-10. Medline 11445843

The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Agah A, Kyriakides TR, Lawler J, Bornstein P. Am J Pathol 2002 Sep; 161(3): 831-839. Medline 12213711

Corneal stromal cells (keratocytes) express thrombospondins 2 and 3 in wound repair phenotype. Armstrong DJ, Hiscott P, Batterbury M, Kaye S. Int J Biochem Cell Biol 2002 Jun; 34(6): 588-593. Medline 11943589

Gene expression profiling in silico: relative expression of candidate angiogenesis associated genes in renal cell carcinomas. Gerritsen ME, Peale FV Jr, Wu T. Exp Nephrol 2002; 10(2): 114-119. Review. Medline 11937758

Thrombospondin expression in aldosterone-producing adenomas. Hatakeyama H, Nishizawa M, Nakagawa A, Nakano S, Kigoshi T, Miyamori I, Uchida K. Hypertens Res 2002 Jul; 25(4): 523-527. Medline 12358136

Differential expression of thrombospondin 2 in primary and metastatic malignant melanoma. Kunz M, Koczan D, Ibrahim SM, Gillitzer R, Gross G, Thiesen HJ.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -345- Acta Derm Venereol 2002; 82(3): 163-169. Medline 12353704

Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2--deficient mice. Lange-Asschenfeldt B, Weninger W, Velasco P, Kyriakides TR, von Andrian UH, Bornstein P, Detmar M. Blood 2002 Jan 15; 99(2): 538-545. Medline 11781236

Expression and localization of thrombospondin-1 and -2 and their cell-surface receptor, CD36, during rat follicular development and formation of the corpus luteum. Petrik JJ, Gentry PA, Feige JJ, LaMarre J. Biol Reprod 2002 Nov; 67(5): 1522-1531. Medline 12390884

Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy. Streit M, Stephen AE, Hawighorst T, Matsuda K, Lange-Asschenfeldt B, Brown LF, Vacanti JP, Detmar M. Cancer Res 2002 Apr 1; 62(7): 2004-2012. Medline 11929817

Thrombospondins 1 and 2 function as inhibitors of angiogenesis. Armstrong LC, Bornstein P. Matrix Biol 2003 Mar; 22(1): 63-71. Review. Medline 12714043

Molecular mechanism of the anti-cancer activity of cerivastatin, an inhibitor of HMG-CoA reductase, on aggressive human breast cancer cells. Denoyelle C, Albanese P, Uzan G, Hong L, Vannier JP, Soria J, Soria C. Cell Signal 2003 Mar; 15(3): 327-338. Medline 12531431

Loss of heterozygosity on chromosome 6q correlates with decreased thrombospondin-2 expression in human salivary gland carcinomas. Kishi M, Nakamura M, Nishimine M, Ishida E, Shimada K, Kirita T, Konishi N. Cancer Sci 2003 Jun; 94(6): 530-535. Medline 12824879

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -346- Medline 12511771

Thrombospondin 2 regulates cell proliferation induced by Rac1 redox- dependent signaling. Lopes N, Gregg D, Vasudevan S, Hassanain H, Goldschmidt-Clermont P, Kovacic H. Mol Cell Biol 2003 Aug; 23(15): 5401-5408. Medline 12861025

Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression. Sadoun E, Reed MJ. J Histochem Cytochem 2003 Sep; 51(9): 1119-1130. Medline 12923237

Frequent HOXA11 and THBS2 promoter methylation, and a methylator phenotype in endometrial adenocarcinoma. Whitcomb BP, Mutch DG, Herzog TJ, Rader JS, Gibb RK, Goodfellow PJ. Clin Cancer Res 2003 Jun; 9(6): 2277-2287. Medline 12796396

The thrombospondins. Adams JC, Lawler J. Int J Biochem Cell Biol 2004 Jun; 36(6): 961-968. Review. Medline 15094109

Thrombospondin 2 levels are increased in aged mice: consequences for cutaneous wound healing and angiogenesis. Agah A, Kyriakides TR, Letrondo N, Bjorkblom B, Bornstein P. Matrix Biol 2004 Jan; 22(7): 539-547. Medline 14996433

Proteomic analysis of exosomes isolated from human malignant pleural effusions. Bard MP, Hegmans JP, Hemmes A, Luider TM, Willemsen R, Severijnen LA, van Meerbeeck JP, Burgers SA, Hoogsteden HC, Lambrecht BN. Am J Respir Cell Mol Biol 2004 Jul; 31(1): 114-121. Medline 14975938

The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Bornstein P, Agah A, Kyriakides TR. 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. Medline 15094126

Regulation of VEGF-A, VEGFR-I, thrombospondin-1, -2, and -3 expression in a

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -347- human pituitary cell line (HP75) by TGFbeta1, bFGF, and EGF. Horiguchi H, Jin L, Ruebel KH, Scheithauer BW, Lloyd RV. Endocrine 2004 Jul; 24(2): 141-146. Medline 15347840

Decreased expressions of thrombospondin 2 in cyclosporin A-induced gingival overgrowth. Koh JT, Kim OJ, Park YS, Kim SH, Kim WJ, Chung HJ, Lee SE, Jeong BC, Jung JY, Kim KK. J Periodontal Res 2004 Apr; 39(2): 93-100. Medline 15009516

Thrombospondin 2 deficiency in pregnant mice results in premature softening of the uterine cervix. Kokenyesi R, Armstrong LC, Agah A, Artal R, Bornstein P. Biol Reprod 2004 Feb; 70(2): 385-390. Epub 2003 Oct 15. Medline 14561659

Tumor progression: the effects of thrombospondin-1 and -2. Lawler J, Detmar M. Int J Biochem Cell Biol 2004 Jun; 36(6): 1038-1045. Review. Medline 15094119

Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis. Park YW, Kang YM, Butterfield J, Detmar M, Goronzy JJ, Weyand CM. Am J Pathol 2004 Dec; 165(6): 2087-2098. Medline 15579451

Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. 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. Int J Cancer 2004 Oct 20; 112(1): 14-25. Medline 15305371

Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy. 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. Circ Res 2004 Sep 3; 95(5): 515-522. Medline 15284191

Coronary artery disease and the thrombospondin single nucleotide

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -348- polymorphisms. Stenina OI, Byzova TV, Adams JC, McCarthy JJ, Topol EJ, Plow EF. Int J Biochem Cell Biol 2004 Jun; 36(6): 1013-1030. Review. Medline 15094117

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. Ahtiainen P, Rulli SB, Shariatmadari R, Pelliniemi LJ, Toppari J, Poutanen M, Huhtaniemi IT. Oncogene 2005 Nov 10; 24(49): 7301-7309. Medline 16007123

Novel integrin antagonists derived from thrombospondins. Calzada MJ, Roberts DD. Curr Pharm Des 2005; 11(7): 849-866. Review. Medline 15777239

Structure of the calcium-rich signature domain of human thrombospondin-2. Carlson CB, Bernstein DA, Annis DS, Misenheimer TM, Hannah BL, Mosher DF, Keck JL. Nat Struct Mol Biol 2005 Oct; 12(10): 910-914. Medline 16186819

Suppression of thrombospondin 1 and 2 production by herpes simplex virus 1 infection in cultured keratocytes. Choudhary A, Hiscott P, Hart CA, Kaye SB, Batterbury M, Grierson I. Mol Vis 2005 Mar 2; 11: 163-168. Medline 15761388

Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development. Greenaway J, Gentry PA, Feige JJ, LaMarre J, Petrik JJ. Biol Reprod 2005 May; 72(5): 1071-1078. Medline 15616224

Mice lacking thrombospondin 2 show an atypical pattern of endocortical and periosteal bone formation in response to mechanical loading. Hankenson KD, Ausk BJ, Bain SD, Bornstein P, Gross TS, Srinivasan S. Bone 2005 Nov 11. Medline 16290255

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. Lindert S, Wickert L, Sawitza I, Wiercinska E, Gressner AM, Dooley S, Breitkopf K.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -349- Matrix Biol 2005 May; 24(3): 198-207. Medline 15905080

A role for Hox A5 in regulating angiogenesis and vascular patterning. Rhoads K, Arderiu G, Charboneau A, Hansen SL, Hoffman W, Boudreau N. Lymphat Res Biol 2005; 3(4): 240-252. Medline 16379594

The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein. Simantov R, Febbraio M, Silverstein RL. Matrix Biol 2005 Feb; 24(1): 27-34. Medline 15748999

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Elizabeth M. Perruccio, David D. Roberts 2006 Citation This paper should be referenced as such : Perruccio EM, Roberts DD . THBS2 (thrombospondin-2). Atlas Genet Cytogenet Oncol Haematol. January 2006 . URL : http://AtlasGeneticsOncology.org/Genes/THBS2ID42549ch6q27.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -350- Atlas of Genetics and Cytogenetics in Oncology and Haematology

BAALC (brain and acute leukemia, cytoplasmic)

Identity Other FLJ12015 names LOC79870 Hugo BAALC 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 leukemias Implicated in Entity 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -351- 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 overexpression in ANLL cases: at 3 yrs, 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.

Entity Glioblastoma Note BAALC in also upregulated in normal astrocytes

External links Nomenclature Hugo BAALC GDB BAALC Entrez_Gene BAALC 79870 brain and acute leukemia, cytoplasmic Cards Atlas BAALCID739ch8q22 GeneCards BAALC Ensembl BAALC Genatlas BAALC GeneLynx BAALC eGenome BAALC euGene 79870 Genomic and cartography BAALC - 8q22.3 chr8:104222097-104311706 + 8q22.3 (hg18- GoldenPath Mar_2006) Ensembl BAALC - 8q22.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BAALC Gene and transcription

Genbank AF371319 [ ENTREZ ]

Genbank AF371323 [ ENTREZ ]

Genbank AK022077 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -352- Genbank AK093819 [ ENTREZ ]

Genbank BC011517 [ ENTREZ ]

RefSeq NM_001024372 [ SRS ] NM_001024372 [ ENTREZ ]

RefSeq NM_024812 [ SRS ] NM_024812 [ ENTREZ ] AceView BAALC AceView - NCBI TRASER BAALC Traser - Stanford

Unigene Hs.533446 [ SRS ] Hs.533446 [ NCBI ] HS533446 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q8WXS3 [ SRS] Q8WXS3 [ EXPASY ] Q8WXS3 [ INTERPRO ]

Interpro IPR009728 BAALC_N [ SRS ] IPR009728 BAALC_N [ EBI ] CluSTr Q8WXS3 Pfam PF06989 BAALC_N [ SRS ] PF06989 BAALC_N [ Sanger ] pfam06989 [ NCBI-CDD ] Blocks Q8WXS3 HPRD Q8WXS3 Protein Interaction databases DIP Q8WXS3 IntAct Q8WXS3 Polymorphism : SNP, mutations, diseases OMIM 606602 [ map ] GENECLINICS 606602

SNP BAALC [dbSNP-NCBI]

SNP NM_001024372 [SNP-NCI]

SNP NM_024812 [SNP-NCI]

SNP BAALC [GeneSNPs - Utah] BAALC] [HGBASE - SRS]

HAPMAP BAALC [HAPMAP] General knowledge Family BAALC [UCSC Family Browser] Browser SOURCE NM_001024372 SOURCE NM_024812 SMD Hs.533446 SAGE Hs.533446 PubGene BAALC Other databases Probes Probe BAALC Related clones (RZPD - Berlin) PubMed

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -353- PubMed 9 Pubmed reference(s) in LocusLink Bibliography BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Tanner SM, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K, Mrozek K, Sill H, Knuutila S, Kolitz JE, Archer KJ, Caligiuri MA, Bloomfield CD, de La Chapelle A. Proc Natl Acad Sci U S A 2001; 98: 13901-1396. Medline 11707601

BAALC, a novel marker of human hematopoietic progenitor cells. Baldus CD, Tanner SM, Kusewitt DF, Liyanarachchi S, Choi C, Caligiuri MA, Bloomfield CD, de la Chapelle A. Exp Hematol 2003; 31: 1051-1056. Medline 14585369

BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study 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. Blood 2003; 102: 1613-1618. Medline 12750167

Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. Marcucci G, Mrozek K, Bloomfield CD. Curr Opin Hematol 2005; 12: 68-75. Medline 15604894

Baalc, a marker of mesoderm and muscle. Satoskar AA, Tanner SM, Weinstein M, Qualman SJ, de la Chapelle A. Gene Expr Patterns 2005; 5: 463-473. Medline 15749074

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. Wang X, Tian QB, Okano A, Sakagami H, Moon IS, Kondo H, Endo S, Suzuki T. J Neurochem 2005; 92: 647-659. Medline 15659234

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -354- Medline 16418499

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

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Jean Loup Huret, Sylvie Senon 2006 Citation This paper should be referenced as such : Huret JL, Senon S . BAALC (brain and acute leukemia, cytoplasmic). Atlas Genet Cytogenet Oncol Haematol. February 2006 . URL : http://AtlasGeneticsOncology.org/Genes/BAALCID739ch8q22.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -355- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MMP9 (matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase))

Identity Other CLG4 (Collagenase Type IV), names CLG4B (Collagenase Type IV-B), GELB (Gelatinase B) Hugo MMP9 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

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.

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -356- 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. 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 Entity 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,

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -357- 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.

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

External links Nomenclature Hugo MMP9 GDB MMP9 MMP9 4318 matrix metallopeptidase 9 (gelatinase B, 92kDa Entrez_Gene gelatinase, 92kDa type IV collagenase) Cards Atlas MMP9ID41408ch20q11 GeneCards MMP9 Ensembl MMP9 Genatlas MMP9 GeneLynx MMP9 eGenome MMP9 euGene 4318 Genomic and cartography MMP9 - chr20:44070954-44078606 + 20q13.12 (hg18- GoldenPath Mar_2006) Ensembl MMP9 - 20q13.12 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MMP9 Gene and transcription

Genbank AW468235 [ ENTREZ ]

Genbank BC006093 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -358- Genbank CN288579 [ ENTREZ ]

Genbank J05070 [ ENTREZ ]

RefSeq NM_004994 [ SRS ] NM_004994 [ ENTREZ ] AceView MMP9 AceView - NCBI TRASER MMP9 Traser - Stanford

Unigene Hs.297413 [ SRS ] Hs.297413 [ NCBI ] HS297413 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P14780 [ SRS] P14780 [ EXPASY ] P14780 [ INTERPRO ]

PS00546 CYSTEINE_SWITCH [ SRS ] PS00546 Prosite CYSTEINE_SWITCH [ Expasy ]

Prosite PS00023 FN2_1 [ SRS ] PS00023 FN2_1 [ Expasy ]

Prosite PS51092 FN2_2 [ SRS ] PS51092 FN2_2 [ Expasy ]

Prosite PS00024 HEMOPEXIN [ SRS ] PS00024 HEMOPEXIN [ Expasy ] Prosite PS00142 ZINC_PROTEASE [ SRS ] PS00142 ZINC_PROTEASE [ Expasy ] Interpro IPR000562 FN_type2_col_bd [ SRS ] IPR000562 FN_type2_col_bd [ EBI ]

Interpro IPR000585 Hemopexin [ SRS ] IPR000585 Hemopexin [ EBI ]

IPR001818 Pept_M10A_M12B [ SRS ] IPR001818 Interpro Pept_M10A_M12B [ EBI ]

Interpro IPR006025 Pept_M_Zn_BS [ SRS ] IPR006025 Pept_M_Zn_BS [ EBI ]

Interpro IPR006026 Peptidase_M [ SRS ] IPR006026 Peptidase_M [ EBI ]

Interpro IPR002477 PGBD_1 [ SRS ] IPR002477 PGBD_1 [ EBI ]

Interpro IPR009070 PGBD_like [ SRS ] IPR009070 PGBD_like [ EBI ]

Interpro IPR006970 PT [ SRS ] IPR006970 PT [ EBI ] CluSTr P14780

Pfam PF00040 fn2 [ SRS ] PF00040 fn2 [ Sanger ] pfam00040 [ NCBI-CDD ]

PF00045 Hemopexin [ SRS ] PF00045 Hemopexin [ Sanger Pfam ] pfam00045 [ NCBI-CDD ]

PF00413 Peptidase_M10 [ SRS ] PF00413 Peptidase_M10 [ Sanger Pfam ] pfam00413 [ NCBI-CDD ]

PF01471 PG_binding_1 [ SRS ] PF01471 PG_binding_1 [ Sanger Pfam ] pfam01471 [ NCBI-CDD ]

Pfam PF04886 PT [ SRS ] PF04886 PT [ Sanger ] pfam04886 [ NCBI-CDD ]

Smart SM00059 FN2 [EMBL]

Smart SM00120 HX [EMBL]

Smart SM00235 ZnMc [EMBL]

Prodom PD000995 FN_Type_II[INRA-Toulouse] Prodom P14780 MMP9_HUMAN [ Domain structure ] P14780 MMP9_HUMAN [ sequences sharing at least 1 domain ] Blocks P14780

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -359- PDB 1GKC [ SRS ] 1GKC [ PdbSum ], 1GKC [ IMB ] 1GKC [ RSDB ]

PDB 1GKD [ SRS ] 1GKD [ PdbSum ], 1GKD [ IMB ] 1GKD [ RSDB ]

PDB 1ITV [ SRS ] 1ITV [ PdbSum ], 1ITV [ IMB ] 1ITV [ RSDB ]

PDB 1L6J [ SRS ] 1L6J [ PdbSum ], 1L6J [ IMB ] 1L6J [ RSDB ]

PDB 1LKG [ SRS ] 1LKG [ PdbSum ], 1LKG [ IMB ] 1LKG [ RSDB ] HPRD P14780 Protein Interaction databases DIP P14780 IntAct P14780 Polymorphism : SNP, mutations, diseases OMIM 120361 [ map ] GENECLINICS 120361

SNP MMP9 [dbSNP-NCBI]

SNP NM_004994 [SNP-NCI]

SNP MMP9 [GeneSNPs - Utah] MMP9] [HGBASE - SRS]

HAPMAP MMP9 [HAPMAP] General knowledge Family MMP9 [UCSC Family Browser] Browser SOURCE NM_004994 SMD Hs.297413 SAGE Hs.297413

3.4.24.35 [ Enzyme-SRS ] 3.4.24.35 [ Brenda-SRS ] 3.4.24.35 [ KEGG Enzyme ] 3.4.24.35 [ WIT ] Amigo peptidoglycan metabolism Amigo gelatinase B activity Amigo calcium ion binding Amigo collagen binding Amigo extracellular matrix (sensu Metazoa) Amigo extracellular space Amigo proteolysis Amigo collagenase activity Amigo zinc ion binding Amigo macrophage differentiation Amigo collagen catabolism BIOCARTA Inhibition of Matrix Metalloproteinases [Genes] PubGene MMP9 Other databases

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -360- Probes Probe MMP9 Related clones (RZPD - Berlin) PubMed PubMed 316 Pubmed reference(s) in LocusLink Bibliography An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides. Hangauer D G, Monzingo AF and Matthews BW. Biochemistry 1984; 23: 5730-5741. Medline 6525336

Activity of type IV collagenase in benign and malignant breast tissue. Davies B, Miles DW, Happerfield MLC et al. Br J Cancer 1993; 67: 1126-1131. Medline 8494711

Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. Stetler-Stevenenson W. J Clin Invest 1999; 103:1237-1241. (REVIEW) Medline 10225966

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. Zeng ZS, Cohen AM and Guillem JG. Carcinogenesis 1999; 20(5):749-755. Medline 10334190

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

Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF- beta and promotes tumor invasion and angiogenesis. Yu Q, Stamenkovic I. Genes Dev 2000; 14: 163-176. Medline 10652271

The Role of Matrix Metalloproteinases in Tumor Angiogenesis and Tumor Metastasis. John A and Tuszynski G. Path. Onco. Research 2001; 7(1): 14-23. (REVIEW) Medline 11349215

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -361- How matrix metalloproteinases regulate cell behavior. Sternlicht MD, Werb Z. Annu Rev Cell Dev Biol 2001; 17: 463-516 (REVIEW). Medline 11687497

Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials. Bloomston M, Zervos EE and Rosemurgy AS. Annals of Surgical Oncology 2002, 9(7): 668-674. (REVIEW) Medline 12167581

Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Matsuyama A, Sakai N, Ishigami M, Hiraoka H, Kashine S, Hirata A, Nakamura T, Yamashita S and Matsuzawa Y. Circulation 2003, 108: 1469-1473. Medline 12952836

Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkBa kinase-dependent nuclear factor kB-mediated promatrix metalloproteinase-9 activation. Rangaswami H, Bulbule A and Kundu GC. J Biol Chem 2004; 279(37): 38921-38935. Medline 15247285

JNK1 differentially regulates osteopontin-induced NIK/MEKK1-dependent AP1- mediated promatrix metalloproteinase-9 activation. Rangaswami H, Bulbule A and Kundu GC. J Biol Chem 2005; 280(19): 19381-19392. Medline 15757900

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Deepak Pralhad Patil, Gopal Chandra Kundu 2006 Citation This paper 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. February 2006 . URL : http://AtlasGeneticsOncology.org/Genes/MMP9ID41408ch20q11.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -362- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NF1 ()

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 Entity 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -363- Entity 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.

External links Nomenclature Hugo NF1 GDB NF1 NF1 4763 neurofibromin 1 (neurofibromatosis, von Recklinghausen Entrez_Gene disease, Watson disease) Cards Atlas NF1ID134 GeneCards NF1 Ensembl NF1 Genatlas NF1 GeneLynx NF1 eGenome NF1 euGene 4763 Genomic and cartography NF1 - 17q11.2 chr17:26446243-26725590 + 17q11.2 (hg18- GoldenPath Mar_2006) Ensembl NF1 - 17q11.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NF1 Gene and transcription

Genbank AB209336 [ ENTREZ ]

Genbank AF055023 [ ENTREZ ]

Genbank AF086346 [ ENTREZ ]

Genbank AK026658 [ ENTREZ ]

Genbank BP271334 [ ENTREZ ]

RefSeq NM_000267 [ SRS ] NM_000267 [ ENTREZ ]

RefSeq NM_001042492 [ SRS ] NM_001042492 [ ENTREZ ] AceView NF1 AceView - NCBI TRASER NF1 Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -364- Unigene Hs.567266 [ SRS ] Hs.567266 [ NCBI ] HS567266 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P21359 [ SRS] P21359 [ EXPASY ] P21359 [ INTERPRO ]

Prosite PS50191 CRAL_TRIO [ SRS ] PS50191 CRAL_TRIO [ Expasy ]

PS00509 RAS_GTPASE_ACTIV_1 [ SRS ] PS00509 Prosite RAS_GTPASE_ACTIV_1 [ Expasy ]

PS50018 RAS_GTPASE_ACTIV_2 [ SRS ] PS50018 Prosite RAS_GTPASE_ACTIV_2 [ Expasy ]

IPR001251 CRAL_bd_TRIO_C [ SRS ] IPR001251 Interpro CRAL_bd_TRIO_C [ EBI ]

Interpro IPR001936 RasGAP [ SRS ] IPR001936 RasGAP [ EBI ]

Interpro IPR008936 Rho_GAP [ SRS ] IPR008936 Rho_GAP [ EBI ] CluSTr P21359 Pfam PF00616 RasGAP [ SRS ] PF00616 RasGAP [ Sanger ] pfam00616 [ NCBI-CDD ]

Smart SM00323 RasGAP [EMBL]

Smart SM00516 SEC14 [EMBL] Blocks P21359

PDB 1NF1 [ SRS ] 1NF1 [ PdbSum ], 1NF1 [ IMB ] 1NF1 [ RSDB ] HPRD P21359 Protein Interaction databases DIP P21359 IntAct P21359 Polymorphism : SNP, mutations, diseases OMIM 162200;162210;193520;601321;607785 [ map ] GENECLINICS 162200;162210;193520;601321;607785

SNP NF1 [dbSNP-NCBI]

SNP NM_000267 [SNP-NCI]

SNP NM_001042492 [SNP-NCI]

SNP NF1 [GeneSNPs - Utah] NF1] [HGBASE - SRS]

HAPMAP NF1 [HAPMAP] General knowledge Family NF1 [UCSC Family Browser] Browser SOURCE NM_000267 SOURCE NM_001042492 SMD Hs.567266 SAGE Hs.567266 Amigo biological process unknown

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -365- Amigo enzyme inhibitor activity Amigo Ras GTPase activator activity Amigo molecular function unknown Amigo intracellular Amigo cytoplasm Amigo cell cycle Amigo Ras protein signal transduction Amigo negative regulation of cell proliferation Amigo cellular component unknown Amigo negative regulation of progression through cell cycle Amigo regulation of small GTPase mediated signal transduction Chromatin Remodeling by hSWI/SNF ATP-dependent BIOCARTA Complexes [Genes] PubGene NF1 Other databases Probes Probe NF1 Related clones (RZPD - Berlin) PubMed PubMed 118 Pubmed reference(s) in LocusLink Bibliography A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, et al. Cell 1990 Jul 13; 62(1): 193-201. Published erratum appears in Cell 1990 Aug 10; 62(3): following 608. Medline 90304909

Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, et al. Cell 1990 Jul 13; 62(1): 187-192. Medline 90304908

Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, et al. Science 1990 Jul 13; 249(4965): 181-186. Published erratum appears in Science 1990 Dec 21; 250(4988): 1749. Medline 90319792

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -366-

Watson syndrome: is it a subtype of type 1 neurofibromatosis? Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. J Med Genet 1991 Nov; 28(11): 752-756. Medline 92122296

Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome. Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R, Thakker N. Am J Hum Genet 1993 Jul; 53(1): 90-95. Medline 93304433

Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Legius E, Marchuk DA, Collins FS, Glover TW. Nat Genet 1993 Feb; 3(2): 122-126. Medline 8499945

Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, McCormick F. N Engl J Med 1994 Mar 3; 330(9): 597-601. Medline 94134142

Genomic organization of the neurofibromatosis 1 gene (NF1). Li Y, O'Connell P, Breidenbach HH, Cawthon R, Stevens J, Xu G, Neil S, Robertson M, White R, Viskochil D. Genomics 1995 Jan 1; 25(1): 9-18. Medline 95293414

Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I. Metheny LJ, Cappione AJ, Skuse GR. J Neuropathol Exp Neurol 1995 Nov; 54(6): 753-760. Medline 96067328

A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors. Cappione AJ, French BL, Skuse GR. Am J Hum Genet 1997 Feb; 60(2): 305-312. Medline 97164596

Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N,

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -367- Speleman F, Paepe AD. Hum Mutat 2000; 15(6): 541-555. Medline 10862084

Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner VF. Hum Mutat 2004 Feb; 23(2): 111-116. Medline 14722914

Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglbock H, Maertens O, Messiaen L. Genes Chromosomes Cancer 2006 Mar; 45(3): 265-276 Medline 16283621

Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations. Serra E, Rosenbaum T, Winner U, Aledo R, Ars E, Estivill X, Lenard HG, Lazaro C. Hum Mol Genet 2000 Dec 12; 9(20): 3055-3064 Medline 11115850

Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas. Serra E, Rosenbaum T, Nadal M, Winner U, Ars E, Estivill X, Lazaro C. Nat Genet 2001 Jul; 28(3): 294-296. Medline 11431704

High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. Kehrer-Sawatzki H, Kluwe L, Sandig C, Kohn M, Wimmer K, Krammer U, Peyrl A, Jenne DE, Hansmann I, Mautner VF. Am J Hum Genet 2004 Sep; 75(3): 410-423. Medline 15257518

NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. 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. Am J Hum Genet 2005 Dec; 77(6): 1092-1101. Medline 16380919

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -368-

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 09- Jean-Loup Huret 1997 Updated 02- Katharina Wimmer 2006 Citation This paper should be referenced as such : Huret JL . NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol Haematol. September 1997 . URL : http://AtlasGeneticsOncology.org/Genes/NF1ID134.html Wimmer K . NF1 (neurofibromin 1). Atlas Genet Cytogenet Oncol Haematol. February 2006 . URL : http://AtlasGeneticsOncology.org/Genes/NF1ID134.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -369- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PSAP (Prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy))

Identity Other FLJ00245 names GLBA MGC110993 SAP1 Hugo PSAP Location 10q22.1 Between CDH23 (cadherin-like 23; centromeric) and Carbohydrate

(chondroitin 6) sulfotransferase 3 (CST3; telomeric). DNA/RNA

Schematic diagram of the human PSAP gene (A) and cDNA (B). Open squares are exons 2-15 and shaded boxes correspond to untranslated 5' and 3' regions. The signal sequence is located adjacent to ATG and will be removed during transit in the edoplasmic reticulum. Exon 8 of the saposin B domain of prosaposin contain a 9-bp alternate splicing site that might generate three different cDNAs: a) a complete exon 8 (CAG GAT CAG; 3 amino acids), b) no exon 8, and c) exon 8 with downstream 6 bases (GAT CAG; 2 amino acids).

Description The human PSAP-precursor gene spans approximately 20 kb in length of the long arm of chromosome 10 and consists at least 15 exons. The size of exons range from 57 to 1200 bp and the size of the introns vary from 91 to more than 3800 bp in length. The PSAP gene can be cateogorized as a polycistronic gene. Further analysis of PSAP intronic positions has indicated that it may be evolved from an ancestral gene

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -370- subjected to two duplication and at least one gene rearrangement. Transcription Due to the presence of an alternative splice site in exon 8, PSAP gene could be transcribed into three mRNA isoforms: one with complete exon 8 (9 bases), one without exon 8, and one with downstream 6 bases of exon 8. While all three PSAP mRNAs could be detected in human, mice, and rat, differential expression of PSAP mRNA isoforms has been reported in human and mouse tissues or cell lines. However, in chicken, there are only two mRNA isoforms (+/- exon 8). The exact biological significances of different nucleotide sequences of saposin B domain in prosaposin precursor are not known. However, it has been shown that the stability of functionally mature saposin B is not significantly affected by the presence or absence of 6 or 9 base pairs (+3 or +2 amino acids) of exon 8. In addition, mutations in the PSAP gene leading to lack or disruption of saposin B protein in patients showed similar metabolic phenotypes. Taking into consideration that neurotrophic activity of PSAP has been attributed to saposin C domain of the molecule, alternative splicing is not expected to modulate this effect. Pseudogene No pseudogen is identified for PSAP. Protein

Structure of human PSAP, saposins, and sequence alignment of a known neurotrophic fragment of human saposin C. (A) Organization of human PSAP protein. Individual saposin domains and signal peptide are indicated; lightning bolts represent proteolytic cleavage sites in the intersaposin sequences; glycosylation sites and exon-intron boundaries are shown by 8-point stars and vertical lines, respectively. (B) Amino acid sequence of human saposin A-D. Potential N-Glycosylation type

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -371- carbohydrate side chain linked to asparagine are indicated with capital letter "N". As indicated, each saposin molecule also contains 6 cystein residues positioned at almost similar location. Neurotrophic sequence of saposin C is double-underlined. (C) Alignment and comparison of neurotrophic sequence of human saposin C with other vertebrates and known viruses. All sequences presented are linear. Each plus sign indicates the presence of a non-fit amino acid.

Description Prosaposin is a highly conserved glycoprotein (with approximate molecular weight of 65-72 kDa), and the precursor of 4 small lysosomal proteins (saposin A-D; of 8-13 kDa) which are required for intracellular degradation of certain sphingolipids. Proteolytic cleavage of PSAP precursor mediated by lysosomal cysteine protease-cathepsin D, leads to individual mature saposin proteins (acidic glycoproteins).PSAP is secreted as a full-length protein. However, individual saposin proteins also exist as extracellular mature proteins (e.g., in tissue culture supernatant, serum, prostatic secretions, malignant pleural effusion). Although the origin of mature saposin proteins in the extracellular fluids is not known, it is likely that circulating serum enzymes may participate in proteolytic cleavage of secreted PSAP. Each saposin domain presents with near identical localization of glycosylation sites and cysteine residues. The presence of high percentage homology in amino acid sequences between saposin A and C further indicates that they have originated from a single ancestroral gene at least via duplication and/or gene rearrangement.

Prosaposin is the saposin precursor protein with 524 amino acids including a 16 amino acids signal peptide. The full-length precursor molecule contains complex oligosaccharides chains which is probably the result of cotranslational glycosylation of the 53-kDa polypeptide and its later modification within the Golgi system that yield the 70-72 kDa precursor protein. After transport to the lysosome, cathepsin D participates in its proteolytic processing to intermediate molecular forms with 35 to 53 kDa and then to 13-kDa glycoprotein and finally to the mature 8-11 kDa less or partially glycosylated forms of individual saposin molecules. It is noteworthy that western analysis (using different anti-PSAP monoclonal and polyclonal antibodies) of human seminal fluid and whole cell lysates prepared from a number of malignant prostatic cells and other malignant cell types (e.g., breast, lung) show the presence of multiple bands with approximate molecular weight of 12-, 24-, and 36-kDa. These bands are most probably represent mono-, di-, and tri-saposins and are the result of sequential cleavage of the precursor molecule. Saposins are highly homologous molecules, each with approximately 80 amino acids containing six cysteine residues (forming 3 disulfide bonds and hair-pin structure) and N-glycosylated carbohydrate chains that are highly conserved. PSAP amino acid sequence among various species (e.g., human, rat, mouse, chicken, Zebrafish) reveals evolutionary conservation in terms of saposin domains and the homologus positioning of terminally-situated cysteine residues and an N-linked glycosylated site. Expression Prosaposin and individual saposin proteins are expressed by a wide

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -372- variety of cells types originating from ectodermal, mesodermal, and endodermal germ layers including but not limited to lung, skin, fibroblast, stromal cells, bone, smooth muscle, skeletal muscle, cardiac muscle, placenta, red and white blood cells, pancreas, placenta, lymphoreticular system (spleen, thymus, liver), micro and macrovascular system, genitourinary system (e.g., prostate, testes, seminal vesicle), central and peripheral nervous system, etc. Prosaposin and saposins also present as soluble proteins in extracellular space/fluid including pleural fluid, cerebrospinal fluid, seminal fluid, milk, and serum. PSAP and saposins are predominantly expressed in cells of hematopoietic origin (e.g., red- and white-blood cells) and neuroglial-derived tissues as compared to all other normal cell types in the mammalian system. In malignant cells, compared to their normal cellular counterparts, prosaposin is overexpressed in breast adenocarcinoma cell lines, non small-cell lung adenocarcinoma, neuroblastoma, and schwannoma cell lines. In addition, similar PSAP- overexpression is also detected in glioma cell lines, adult and pediatric brain tumors (e.g., medulloblastoma-, astrocytoma-, glioblastoma multiforme-cell lines), fibrosarcoma, osteosarcoma, and prostate cancer cell lines (koochekpour et al. published and unpublished observations). Most noticeably, PSAP is overexpressed and/or amplified in human prostate cancer tissues, xenografts, and cell lines. Quantitative SNP array hybridization in conjunction with southern hybridization and quantitative real-time PCR demonstrated a frequency of 20.6% for PSAP amplification (4 out of 25 prostate cancer xenografts and metastatic tissues and three out of nine prostate cancer cell lines). Expression of PSAP protein and mRNA in malignant prostate cancer cells is exclusively higher than normal prostate epithelial and stromal cells. Immunoblotting of conditioned media derived from prostate cancer cells shows the presence of PSAP-immunoreactive bands with approximate molecular size of 72-kDa, 140-kDa, and 220-kDa. It is not clear whether or not the 140- and 220-kDa bands represent the dimeric or trimeric form of PSAP. In addition, PSAP mRNA and protein expression is higher in several androgen-independent than the androgen-dependent prostate cancer cell lines. This finding suggests that PSAP expression might be under androgenic, steroid hormone regulation, or feedback control mediated by the hypothalamus-pituitary- gonadal neuroendocrine axis.

The involvement of pertussis toxin-sensitive GPCR-dependent mechanism for interaction between PSAP (or its active molecular derivatives such as saposin C, TX14A) has been demonstrated in a number of cell lines. In addition, using human and mouse fibroblasts and in vivo studies, it has been demonstrated that PSAP entry into the cells is also possible via at least three other independent receptor system including the mannose receptor, mannose-6-phosphate (M-6-P) receptor, and low density lipoprotein receptor-related protein (LRP). Cell type-specific distribution of any of the above receptor systems, their relative abundance, their involvement in various biological activities of soluble PSAP and/or saposin C (e.g., cell signaling, sphingolipid

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -373- transport), or post-receptor occupancy events require additional studies. Localisation Prosaposin and individual saposin molecules exist as intracellular (lysosomal) and extracellular proteins. In addition, prosaposin also exist as an integral membrane protein. The relative abundance of prosaposin is believed to be the highest as a secretory (soluble) protein and the lowest as an integral protein. However, it is not clear whether there is a tissue or cell type-specificity (e.g., benign versus malignant cells, epithelial versus stromal cells) for PSAP distribution. Function Prosaposin is a dual function molecule; as the precursor of intracellular lysosomal saposin proteins involved in sphingolipid hydrolysis activity and as a secreted soluble protein with neurotrophic activities, including growth, development, and maintenance of the peripheral and central nervous system, nerve regeneration and plasticity, stimulation of neurite outgrowth, stimulation of neuroblastoma cells proliferation, protection from cell-death or apoptosis, and activation of MAPK- and PI3K/Akt- signaling pathways. Column chromatography data indicated the formation of stable complexes between PSAP/saposins and several gangliosides. It has been suggested that PSAP functions as a sphingolipid binding protein and on the cell surface, complex formation between PSAP and gangliosides may suggests a role for this molecule in ganglioside function. Whether or not there is a link between the function of secreted soluble form as a trophic factor and its role as a ganglioside-binding or -career protein remain to be understood. Saposins function as coprotein for intracellular degradation of sphingolipids. Saposin A and C is involved in hydrlysis of glucosylceramide and galactosylceramide. saposin B stimulates galacto-cerebroside sulfate hydrolysis, GM1 ganglioside, and globotriaosylceramide. Saposin C is the activator of sphingomyelin phosphodiesterase. While several members of CD1 proteins are involved in lipid presentation to T cells, prosaposin-deficient mice exhibit certain defects in CD1d-mediated antigenic presentation suggesting that saposins are involved in mobilization of lipid monomers from the lysosomal membrane and their association with CD1d. In addition, prosaposin-deficient fibroblasts transfected with another member of CD1 family (CD1b) also failed to activate lipid-specific T lymphocytes. Upon reconstitution of fibroblasts with saposin C, T-cells response was restored. These findings might be suggestive of potential implications for saposin C or perhaps PSAP in recognition of tumor antigens.

Several reports have identified a number of linear 5-22 amino acid segments called prosaptides (e.g., D5, TX14A) that demonstrate in vitro and/or in vivo neurotrophic activities. These bioactive sequences are located at the downstream region of saposin C domain of PSAP. Prosaptides, saposin C, or PSAP exert their effect at least partially, by binding to a single high-affinity G protein-coupled receptor. This receptor has been partially characterized but not cloned. In malignant cells and tissues, several classic reports have indicated a pluripotent regulatory role for saposin C and PSAP in prostate cancer with potential involvement in prostate carcinogenesis or progression toward

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -374- metastatic or androgen-independent state.

Immunohistochemical staining on benign and malignant prostate tissues revealed an intense cytosolic and anti-prosaposin immunoreactivity in tumor cells, stromal, endothelial, and inflammatory mononuclear cells and the intensity of staining was proportional to the overall Gleason¹s score. PSAP-immunoreactivity was also noticeable as extracellular deposition in hypercellular regions in high-grade prostatic tumors. In addition, PSAP and/or its active molecular derivatives (saposin C or TX14A) stimulate prostate cancer cells growth, motility, and invasion, upregulates uPA/uPAR expression, activates the p42/44 MAPK (Raf- MEK-ERK-RSK-Elk-1 signaling cascade), p38 MAPK, and SAPK/JNK family members of the MAPK superfamily and PI3K/Akt signaling pathways, and protects cells from apoptotic cell-death induction by etoposide via modulation of caspase-3, -7, and -9 expression/activity and/or the PI3K/Akt signaling pathway activation. Homology The four saposin A-D proteins share a great deal of homology (~50% ) in their amino acids sequences. In addition to these, saposins also contain 6 highly conserved cysteines. Considering all these structural similarities, they differ from each other for their specificity of intracellular or potential extracellular functions. Among fopur saposins, cross- species analysis of saposin sequences, show evolutionary conservation for saposin A, B, and D. However, with the exception to the neurotrophic sequence, saposin C sequence appear to be more species-specific. For example, from the linear human saposin C-neurotrophic sequence (LIDNNKTEKEILD): (1) LID-NK and TEKEIL is shared with RNA polymerase subunit of sheep Pox virus; (2) LI‹NK and TEKEL is shared with Lumpy skin disease virus; (3) NNK and EKEIL is shared with the Hemagglutinin influenza A virus; (4) NNTEK-IL is shared with HIV-I envelop glycoprotein; (5) DN---EKEI is shared with Bacillus anthracis; or (6) LIDN-KT-KEI is shared with flagellar filament outer layer protein precursor (sheet protein) of Lyme disease spirochete. Although these linearly ordered sequence homologies appear to be remote and partial, but due to the observed profound biological activities of the neurotrophic sequence-derived peptides (in in vitro and in vivo studies) and their relative hydrophilic nature, their presence in pathogenic agents (e.g., HIV virus, anthrax) might have some potential clinical application or might be useful in understanding the mechanism underlying their pathogenicity (with respect to eukaryotic cells). Mutations Note Mutation in PSAP gene in human was reported for the first time in 1990 and so far there are 10 recorded mutations. Seven cases are identified with nucleotide substitutions in the form of missence or nonsense mutation. Among this three patients with non-sense mutations that led to prosaposin deficiency, 3 cases developed metachromatic leukodystrophy (MLD)phenotype, and one case showed the atypical

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -375- Gaucher disease. Two cases of PSAP mutation were in the form of nucleotide substitution (splicing type) and both showed clinical characteristics of MLD. In one patient, deletional mutation occurred in the saposin B domain (c.803delG) and led to premature stop codon and total prosaposin deficiency. Interestingly, mutant cDNA was detected in the heterozygous parents who were the careers for the same single base deletion (c.803delG)in exon 9. Implicated in Entity Metachromatic Leukodystrophy (MLD), Gaucher Disease, Combined SAP deficiency Disease The clinical features in patients with total PSAP deficiency (combined SAP deficiency) are reported to be similar to those in Gaucher disease type 2, which present with acute infantile neuronopathic symptoms, abnormally large size of visceral organs, deteriorating general physical condition, and death in the first two years of life. Saposin A deficiency as a disease entity has not been reported. However, mice with mutation in saposin A demonstrated a phenotype similar to late-onset Krabbe disease. Patients with saposin B deficiency show similar clinical finding to those with MLD. There are three main types of MLD; Late infantile MLD, Juvenile MLD, and adult MLD. Depending on the patient¹s age, their clinical signs and symptoms may vary. Saposin C deficient patients present with clinical findings similar to Gaucher disease type 3. Saposin D mutation in a mouse model has shown progressive polyuria and ataxia and accumulation of ceramide in the brain and kidney.

Accumulation of saposins (up to 80-fold) are detected in spleen, liver, and brain of individuals affected with lysosomal storage diseases (LSD) such as Gaucher disease, Niemann-Pick disease (type 1), fucosidosis, Tay-Sachs disease, and Sandhoff disease. Analysis of plasma levels of saposins in patients with LSD disorders has revealed an increase of 59%, 25%, 61%, and 57% above the 95 percentile of control population for saposin A, saposin B, saposin C, and saposin D, respectively.

Total prosaposin deficiency leads to a lethal phenotype in both man and mice. Mice with homozygous inactivation of prosaposin gene showed similar clinicopathologic pictures to the human patient with total PSAP deficiency. Among these features was intrauterine or early neonatal death in PSAP-/- mice. In other mice, severe developmental abnormalities in the nervous system and male reproductive system was detected. Neuroembryological developmental abnormalities presented as muscular weakness, trembling or shakiness of head, and ataxia of the limb and progressed to severe weakness and shaking of head and trunk and after 4 weeks they developed seizures and persistant tonic epilepsy and finally died at the age of 35 days. Evidence of lysosomal storage disease was detected by abnormal accumulation of ceramide in brain, liver, and kidney, and storage of gangliosides and ceramide and hypomyelination of the brain. Gross pathological features were also detected in the male reproductive

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -376- organ including atrophy of prostate gland, testes, epididymis, seminal vesicle, and reduced spermatogenesis. Microscopic examination of the involuted prostate, seminal vesicles, and epididymis revealed the presence of rudimentary undifferentiated epithelial cells. In spite of these abnormal findings, the testosterone level was normal or even elevated. Oncogenesis Overall the expression and biofunctional significances of prosaposin and saposins in cancer are largly unknown. Available in vitro data indicate its potential significance and involvement in prostate carcinogenesis and its progression toward metastatic and/or androgen- independent status. Probably the most important finding was the genomic amplification and/or overexpression of PSAP in androgen- independent prostate cancer cell lines and punch biopsy samples of xenografts and lymph node metastases obtained from patients with hormone-refractory androgen-dependent or independent prostate cancer. Immunohistochemical staining has demonstrated the relative abundance of immunoreactive-PSAP in high Gleason grade tumors as compared to the low-grade tumors or benign prostatic hyperplasia. Although PSAP appears to function as a protooncogene in prostate cancer cells, direct experimental evidence is not available at this time.

External links Nomenclature Hugo PSAP GDB PSAP PSAP 5660 prosaposin (variant Gaucher disease and variant Entrez_Gene metachromatic leukodystrophy) Cards Atlas PSAPID42980ch10q22 GeneCards PSAP Ensembl PSAP Genatlas PSAP GeneLynx PSAP eGenome PSAP euGene 5660 Genomic and cartography GoldenPath PSAP - 10q22.1 Ensembl PSAP - [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PSAP Gene and transcription

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -377- Genbank AB209776 [ ENTREZ ]

Genbank AK057878 [ ENTREZ ]

Genbank AK129790 [ ENTREZ ]

Genbank AK223290 [ ENTREZ ]

Genbank BC001503 [ ENTREZ ]

RefSeq NM_001042465 [ SRS ] NM_001042465 [ ENTREZ ]

RefSeq NM_001042466 [ SRS ] NM_001042466 [ ENTREZ ]

RefSeq NM_002778 [ SRS ] NM_002778 [ ENTREZ ] AceView PSAP AceView - NCBI TRASER PSAP Traser - Stanford

Unigene Hs.523004 [ SRS ] Hs.523004 [ NCBI ] HS523004 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O75905 [ SRS] O75905 [ EXPASY ] O75905 [ INTERPRO ] CluSTr O75905 Blocks O75905 HPRD O75905 Protein Interaction databases DIP O75905 IntAct O75905 Polymorphism : SNP, mutations, diseases OMIM 176801 [ map ] GENECLINICS 176801

SNP PSAP [dbSNP-NCBI]

SNP NM_001042465 [SNP-NCI]

SNP NM_001042466 [SNP-NCI]

SNP NM_002778 [SNP-NCI]

SNP PSAP [GeneSNPs - Utah] PSAP] [HGBASE - SRS]

HAPMAP PSAP [HAPMAP] General knowledge Family PSAP [UCSC Family Browser] Browser SOURCE NM_001042465 SOURCE NM_001042466 SOURCE NM_002778 SMD Hs.523004 SAGE Hs.523004 Amigo cerebroside-sulfatase activity Amigo galactosylceramidase activity

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -378- Amigo glucosylceramidase activity Amigo alpha-galactosidase activity Amigo beta-galactosidase activity Amigo sphingomyelin phosphodiesterase activity Amigo extracellular space Amigo lysosome Amigo lipid metabolism Amigo sphingolipid metabolism Amigo glycosphingolipid metabolism Amigo lipid transport Amigo lysosome organization and biogenesis Amigo enzyme activator activity Amigo lipid binding Amigo integral to membrane PubGene PSAP Other databases Probes Probe PSAP Related clones (RZPD - Berlin) PubMed PubMed 50 Pubmed reference(s) in LocusLink Bibliography Concentrations of an activator protein for sphingolipid hydrolysis in liver and brain samples from patients with lysosomal storage diseases. Inui K, Wenger DA. J Clin Invest 1983 Nov; 72(5):1622-1628. Medline 6415115

Saposin A: second cerebrosidase activator protein. Morimoto S, Martin BM, Yamamoto Y, Kretz KA, O'Brien JS, Kishimoto Y. Proc Natl Acad Sci U S A. 1989 May; 86(9): 3389-3393. Medline 2717620

Determination of saposin proteins (sphingolipid activator proteins) in human tissues. Morimoto S, Yamamoto Y, O'Brien JS, Kishimoto Y. Anal Biochem 1990 Nov 1; 190(2): 154-157. Medline 2127157

Saposins: structure, function, distribution, and molecular genetics. Kishimoto Y, Hiraiwa M, O'Brien JS. J Lipid Res 1992 Sep; 33(9): 1255-1267. Review.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -379- Medline 1402395

Structure and evolution of the human prosaposin chromosomal gene. Rorman EG, Scheinker V, Grabowski GA. Genomics 1992 Jun; 13(2): 312-318. Medline 1612590

Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene. Schnabel D, Schroder M, Furst W, Klein A, Hurwitz R, Zenk T, Weber J, Harzer K, Paton BC, Poulos A, et al. J Biol Chem 1992 Feb 15; 267(5): 3312-3315. Medline 1371116

Identification of prosaposin as a neurotrophic factor. O'Brien JS, Carson GS, Seo HC, Hiraiwa M, Kishimoto Y. Proc Natl Acad Sci U S A. 1994 Sep 27; 91(20): 9593-9596. Medline 7937812

Identification of the neurotrophic factor sequence of prosaposin. O'Brien JS, Carson GS, Seo HC, Hiraiwa M, Weiler S, Tomich JM, Barranger JA, Kahn M, Azuma N, Kishimoto Y. FASEB J 1995 May; 9(8): 681-685. Medline 7768361

Induction of MAPK phosphorylation by prosaposin and prosaptide in PC12 cells. Campana WM, Hiraiwa M, Addison KC, O'Brien JS. Biochem Biophys Res Commun 1996 Dec 24; 229(3): 706-712. Medline 8954961

Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids. Fujita N, Suzuki K, Vanier MT, Popko B, Maeda N, Klein A, Henseler M, Sandhoff K, Nakayasu H, Suzuki K. Hum Mol Genet 1996 Jun; 5(6): 711-725. Medline 8776585

Expression of the three alternative forms of the sphingolipid activator protein precursor in baby hamster kidney cells and functional assays in a cell culture system. Henseler M, Klein A, Glombitza GJ, Suziki K, Sandhoff K. J Biol Chem 1996 Apr 5; 271(14): 8416-8423. Medline 8626540

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -380- A hydrophilic peptide comprising 18 amino acid residues of the prosaposin sequence has neurotrophic activity in vitro and in vivo. Kotani Y, Matsuda S, Wen TC, Sakanaka M, Tanaka J, Maeda N, Kondoh K, Ueno S, Sano A. J Neurochem 1996 May; 66(5): 2197-2200. Medline 8780053

Expression and tissue distribution of rat sulfated glycoprotein-1 (prosaposin). Morales CR, El-Alfy M, Zhao Q, Igdoura SA. J Histochem Cytochem 1996 Apr; 44(4): 327-337. Medline 8601692

Biosynthesis, processing, and targeting of sphingolipid activator protein (SAP )precursor in cultured human fibroblasts. Mannose 6-phosphate receptor- independent endocytosis of SAP precursor. Vielhaber G, Hurwitz R, Sandhoff K. J Biol Chem 1996 Dec 13; 271(50): 32438-32446. Medline 8943309

Prosaposin receptor: evidence for a G-protein-associated receptor. Hiraiwa M, Campana WM, Martin BM, O'Brien JS. Biochem Biophys Res Commun 1997 Nov 17; 240(2): 415-418. Medline 9388493

Cell death prevention, mitogen-activated protein kinase stimulation, and increased sulfatide concentrations in Schwann cells and oligodendrocytes by prosaposin and prosaptides. Hiraiwa M, Taylor EM, Campana WM, Darin SJ, O'Brien JS. Proc Natl Acad Sci U S A 1997 Apr 29; 94(9): 4778-4781. Medline 9114068

Prosaptide activates the MAPK pathway by a G-protein-dependent mechanism essential for enhanced sulfatide synthesis by Schwann cells. Campana WM, Hiraiwa M, O'Brien JS. FASEB J 1998 Mar; 12(3): 307-314. Medline 9506474

Cellular uptake of saposin (SAP) precursor and lysosomal delivery by the low density lipoprotein receptor-related protein (LRP). Hiesberger T, Huttler S, Rohlmann A, Schneider W, Sandhoff K, Herz J. EMBO J 1998 Aug 17; 17(16): 4617-4625. Medline 9707421

Isolation and characterization of the human prosaposin promoter. Sun Y, Jin P, Witte DP, Grabowski GA. Gene 1998 Sep 18; 218(1-2): 37-47.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -381- Medline 9751800

Secretion of prosaposin, a multifunctional protein, by breast cancer cells. Campana WM, O'Brien JS, Hiraiwa M, Patton S. Biochim Biophys Acta 1999 May 24; 1427(3): 392-400. Medline 10350655

Phosphatidylinositol 3-kinase and Akt protein kinase mediate IGF-I- and prosaptide-induced survival in Schwann cells. Campana WM, Darin SJ, O'Brien JS. J Neurosci Res 1999 Aug 1; 57(3): 332-341. Medline 10412024

Saposins A, B, C, and D in plasma of patients with lysosomal storage disorders. Chang MH, Bindloss CA, Grabowski GA, Qi X, Winchester B, Hopwood JJ, Meikle PJ. Clin Chem 2000 Feb; 46(2): 167-174. Medline 10657372

Physiology and pathophysiology of sphingolipid metabolism and signaling. Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K. Biochim Biophys Acta 2000 May 31; 1485(2-3): 63-99. Review. Medline 10832090

Targeted disruption of the mouse prosaposin gene affects the development of the prostate gland and other male reproductive organs. Morales CR, Zhao Q, El-Alfy M, Suzuki K. J Androl 2000 Nov-Dec; 21(6): 765-775. Medline 11105903

A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hulkova H, Cervenkova M, Ledvinova J, Tochackova M, Hrebicek M, Poupetova H, Befekadu A, Berna L, Paton BC, Harzer K, Boor A, Smid F, Elleder M. Hum Mol Genet 2001 Apr 15; 10(9): 927-940. Medline 11309366

Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase. Misasi R, Sorice M, Di Marzio L, Campana WM, Molinari S, Cifone MG, Pavan A, Pontieri GM, O'Brien JS. FASEB J 2001 Feb; 15(2): 467-474. Medline 11156962

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -382- Differential membrane interactions of saposins A and C: implications for the functional specificity. Qi X, Grabowski GA. J Biol Chem 2001 Jul 20; 276(29): 27010-27017. Epub 2001 May 16. Medline 11356836

Molecular and cell biology of acid beta-glucosidase and prosaposin. Qi X, Grabowski GA. Prog Nucleic Acid Res Mol Biol 2001; 66: 203-239. Review Medline 11051765

Large-scale genotyping of complex DNA. Kennedy GC, Matsuzaki H, Dong S, Liu WM, Huang J, Liu G, Su X, Cao M, Chen W, Zhang J, Liu W, Yang G, Di X, Ryder T, He Z, Surti U, Phillips MS, Boyce-Jacino MT, Fodor SP, Jones KW. Nat Biotechnol 2003 Oct; 21(10): 1233-1237. Epub 2003 Sep 7. Medline 12960966

Prosaposin ablation inactivates the MAPK and Akt signaling pathways and interferes with the development of the prostate gland. Morales CR, Badran H. Asian J Androl 2003 Mar; 5(1): 57-63. Review. Medline 12647005

Biosynthesis and degradation of mammalian glycosphingolipids. Sandhoff K, Kolter T. Philos Trans R Soc Lond B Biol Sci 2003 May 29; 358(1433): 847-861. Review. Medline 12803917

Analyses of temporal regulatory elements of the prosaposin gene in transgenic mice. Sun Y, Witte DP, Jin P, Grabowski GA. Biochem J 2003 Mar 1; 370(Pt 2): 557-566. Medline 12467496

Conservation of expression and alternative splicing in the prosaposin gene. Cohen T, Ravid L, Altman N, Madar-Shapiro L, Fein A, Weil M, Horowitz M. Res Mol Brain Res 2004 Oct 22; 129(1-2): 8-19. Medline 15469878

Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells. Kang SJ, Cresswell P. Nat Immunol 2004 Feb; 5(2): 175-181. Epub 2004 Jan 11. Medline 14716312

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -383- Prosaptide TX14A stimulates growth, migration, and invasion and activates the Raf-MEK-ERK-RSK-Elk-1 signaling pathway in prostate cancer cells. Koochekpour S, Sartor O, Lee TJ, Zieske A, Patten DY, Hiraiwa M, Sandhoff K, Remmel N, Minokadeh A. Prostate 2004 Oct 1; 61(2): 114-123. Medline 15305334

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Shahriar Koochekpour 2006 Citation This paper should be referenced as such : Koochekpour S . PSAP (Prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)). Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PSAPID42980ch10q22.html

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Atlas Genet Cytogenet Oncol Haematol 2006; 3 -384- Atlas of Genetics and Cytogenetics in Oncology and Haematology

RCHY1 (ring finger and CHY zinc finger domain containing 1)

Identity Other PIRH2 names ARNIP CHIMP RNF199 ZNF363 PRO1996 DKFZp586C1620 Hugo RCHY1 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

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

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -385- 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 (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 RCHY1to 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 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) protein 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 Entity 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -386- 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.

External links Nomenclature Hugo RCHY1 GDB RCHY1 Entrez_Gene RCHY1 25898 ring finger and CHY zinc finger domain containing 1 Cards Atlas -RCHY1ID43012ch04q21 GeneCards RCHY1 Ensembl RCHY1 Genatlas RCHY1 GeneLynx RCHY1 eGenome RCHY1 euGene 25898 Genomic and cartography RCHY1 - 4q21.1 chr4:76623381-76658652 - 4q21.1 (hg18- GoldenPath Mar_2006) Ensembl RCHY1 - 4q21.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RCHY1 Gene and transcription

Genbank AB209072 [ ENTREZ ]

Genbank AF247041 [ ENTREZ ]

Genbank AF255666 [ ENTREZ ]

Genbank AF305424 [ ENTREZ ]

Genbank AK091501 [ ENTREZ ]

RefSeq NM_001008925 [ SRS ] NM_001008925 [ ENTREZ ]

RefSeq NM_001009922 [ SRS ] NM_001009922 [ ENTREZ ]

RefSeq NM_015436 [ SRS ] NM_015436 [ ENTREZ ] AceView RCHY1 AceView - NCBI TRASER RCHY1 Traser - Stanford

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -387- Unigene Hs.48297 [ SRS ] Hs.48297 [ NCBI ] HS48297 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q59GN7 [ SRS] Q59GN7 [ EXPASY ] Q59GN7 [ INTERPRO ]

Prosite PS50089 ZF_RING_2 [ SRS ] PS50089 ZF_RING_2 [ Expasy ]

Interpro IPR008913 Znf_CHY [ SRS ] IPR008913 Znf_CHY [ EBI ]

Interpro IPR001841 Znf_RING [ SRS ] IPR001841 Znf_RING [ EBI ] CluSTr Q59GN7 Pfam PF00097 zf-C3HC4 [ SRS ] PF00097 zf-C3HC4 [ Sanger ] pfam00097 [ NCBI-CDD ] Pfam PF05495 zf-CHY [ SRS ] PF05495 zf-CHY [ Sanger ] pfam05495 [ NCBI- CDD ]

Smart SM00184 RING [EMBL] Blocks Q59GN7 HPRD Q59GN7 Protein Interaction databases DIP Q59GN7 IntAct Q59GN7 Polymorphism : SNP, mutations, diseases OMIM 607680 [ map ] GENECLINICS 607680

SNP RCHY1 [dbSNP-NCBI]

SNP NM_001008925 [SNP-NCI]

SNP NM_001009922 [SNP-NCI]

SNP NM_015436 [SNP-NCI]

SNP RCHY1 [GeneSNPs - Utah] RCHY1] [HGBASE - SRS]

HAPMAP RCHY1 [HAPMAP] General knowledge Family RCHY1 [UCSC Family Browser] Browser SOURCE NM_001008925 SOURCE NM_001009922 SOURCE NM_015436 SMD Hs.48297 SAGE Hs.48297 Amigo protein binding Amigo protein binding Amigo cytoplasm Amigo zinc ion binding Amigo metal ion binding

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -388- PubGene RCHY1 Other databases Probes Probe RCHY1 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography Cloning and characterization of an androgen receptor N-terminal-interacting protein with ubiquitin-protein ligase activity. Beitel LK, Elhaji YA, Lumbroso R, Wing SS, Panet-Raymond V, Gottlieb B, Pinsky L, Trifiro MA. J Mol Endocrinol 2002; 29: 41-60. Medline 12200228

Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S. Cell. 2003; 112: 779-791. Medline 12654245

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

Control of human PIRH2 protein stability: involvement of TIP60 and the proteosome. Logan IR, Sapountzi V, Gaughan L, Neal DE, Robson CN. J Biol Chem 2004; 279: 11696-11704. Medline 14701804

A new human gene hNTKL-BP1 interacts with hPirh2. Zhang L, Li J, Wang C, Ma Y, Huo K. Biochem Biophys Res Commun 2005; 330: 293-297. Medline 15781263

Inhibition of ubiquitination and stabilization of human ubiquitin E3 ligase PIRH2 by measles virus phosphoprotein. Chen M, Cortay JC, Logan IR, Sapountzi V, Robson CN, Gerlier D. J Virol 2005; 79: 11824-11836. Medline 16140759

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -389- BiblioGene - INIST Contributor(s) Written 03- Wenrui Duan, Miguel A. Villalona-Calero 2006 Citation This paper 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. March 2006 . URL : http://AtlasGeneticsOncology.org/Genes/RCHY1ID43012ch04q21.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -390- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Follicular lymphoma (FL)

Clinics and Pathology Phenotype / Pan-B antigens test positive. The immunophenotypic profile is CD10+, cell stem CD5-, sIg+ and the cell of origin is a germinal centre B-cell that has origin 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 Seventy-80% of the cases carry the t(14;18)(q32;q21) as the primary Morphological chromosome anomaly. Rare variant translocation t(2;18)(p11;q21) and t(18;22)(q21;q11) were described. Approximately 15% of the cases

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -391- 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 The incidence of 6q21 deletion and 17p13/p53 deletion (see below) by Molecular interphase FISH analysis may be around 60% and 20%, respectively Additional Secondary chromosome changes are both numerical and anomalies structural. Trisomy 7, +8; +12, +3, +18, +X each 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 Result of the chromosomal anomaly Fusion No fusion protein. The t(14;18) brings about the juxtaposition of BCL-2 Protein with the Ig heavy chain joining segment, with consequent marked Description 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 5¹ 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. Bibliography LAZ3 rearrangements in Non-Hodgkin's lymphoma: correlation with histoogy, immunophenotype, karyotype and clinical outcome in 217 patients. Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F, Fruchart C, Duval C, Monconduit M, Tilly H. Blood 1994; 83: 2423-2427.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -392- Medline 8167331

A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. 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. Blood 1994; 84: 1361. Medline 8068936

Prognostic value of chromosomal abnormalities in follicular lymphoma. Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, Monconduit M, Bastard C. Blood 1994; 84: 1043-1049. Medline 8049424

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

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

Frequent deletions of 6q23-24 in B-cell non-Hodgkin's lymphomas detected by fluorescence in situ hybridization. Zhang Y, Weber-Matthiesen K, Siebert R, Matthiesen P, Schlegelberger B. Genes Chromosomes Cancer 1997; 18: 310-313. Medline 9087572

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. Bernell P, Jacobsson B, Liliemark J, Hjalmar V, Arvidsson I, Hast R. Br J Haematol 1998; 101: 487-491. Medline 9633892

Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma. Elenitoba-Johnson KS, Gascoyne RD, Lim MS, Chhanabai M, Jaffe ES, Raffeld M. Blood 1998; 91: 4677-4685. Medline 9616165

Analysis of PTEN mutations and deletions in B-cell non-Hodgkin's lymphomas. Butler MP, Wang SI, Chaganti RS, Parsons R, Dalla-Favera R.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -393- Genes Chromosomes Cancer 1999; 24: 322-327. Medline 10092130

Rearrangements of chromosome band 1p36 in non-Hodgkin's lymphoma. Dave BJ, Hess MM, Pickering DL, Zaleski DH, Pfeifer AL, Weisenburger DD, Armitage JO, Sanger WG. Clin Cancer Res 1999; 5:1401-1409. Medline 10389925

World Health Organization classification of neoplastic diseases of hematopoietic and lymphoid tissues: Report of the clinical advisory committee - Airlie House, Virginia, Novembre 1997. Harris NNL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. J Clin Oncol 1999; 17: 3835-3849. Medline 10577857

BCL6 alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B. Bosga-Bouwer AG, Haralambieva E, Booman M, Boonstra R, van den Berg A, Schuuring E, van den Berg E, Kluin P, Poppema S. Genes Chromosomes Cancer 2005; 44: 301-304. Medline 16075463

Follicular lymphoma with a burkitt translocation--predictor of an aggressive clinical course: a case report and review of the literature. Voorhees PM, Carder KA, Smith SV, Ayscue LH, Rao KW, Dunphy CH. Arch Pathol Lab Med. 2004; 128: 210-213 Medline 14736281 Contributor(s) Written 03- Antonio Cuneo and Gianluigi Castoldi 2001 Updated 12- Antonio Cuneo, Antonella Russo Rossi and Gianluigi Castoldi 2005 Citation This paper should be referenced as such : Cuneo A, Castoldi GL . Follicular lymphoma (FL). Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://AtlasGeneticsOncology.org/Anomalies/FollLymphomID2075.html Cuneo A, Russo Rossi A and Castoldi GL . Follicular lymphoma (FL). Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Anomalies/FollLymphomID2075.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -394- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Mucosa-associated lymphoid tissue (MALT) lymphoma (updated: old version not available)

Identity

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

Clinics and Pathology Disease MALT lymphoma is the extra-nodal presentation of marginal zone B- cell lymphomas (MZBCL) Phenotype / The morphologic and phenotypic characteristics of malignant cells cell stem correspond to those of lymphocytes belonging to the marginal zone, origin 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -395- 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 The most common anomalies in extra-nodal MZBCL of MALT type Molecular 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 >CC: TXT: BCL10 ID: 222> 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -396- Probes BCL6 rearrangements and the API2-MLT fusion, encoded on the derivative 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. Result of the chromosomal anomaly Fusion MALT1 overexpression and API2-MALT fusion confer constitutional Protein NFkB activity. This, in turn, leads to enhanced proliferation and Oncogenesis 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.

To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf- Peeters C, Falini B, Gatter KC. Blood 1994; 84: 1361-1392. Medline 8068936

BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma. 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. Br J Haematol 1997; 98: 719-725. Medline 933233

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. Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, Ott MM, Muller-

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -397- Hermelink HK. Cancer Res 1997; 57: 3944-3948. Medline 9307277

A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. The Non Hodgkin¹s Lymphoma Classification Project. Blood 1997; 89: 3909-3918. Medline 9166827

B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours. Zucca E, Roggero E, Pileri S. Br J Haematol 1998; 100: 3-14. Medline 9450784

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. 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. Blood 1999; 93: 3601-3609. Medline 10339464

Frequent mutation of bcl-6 proto-oncogene in high grade, but not low grade, MALT lymphomas of the gastrointestinal tract. Gaidano G, Capello D, Gloghini A, Fassone L, Vivenza D, Ariatti C, Migliazza A, Saglio G, Carbone A. Haematologica 1999; 84: 582-588. Medline 10406897

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. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. J Clin Oncol 1999; 17: 3835-3849. Medline 10577857

Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy. Hoeve MA, Gisbertz IA, Schouten HC, Schuuring E, Bot FJ, Hermans J, Hopman A, Kluin PM, Arends JW, van Krieken JH. Leukemia 1999; 13: 799-807. Medline 10374886

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -398- Translocation t(11;18) absent in early gastric marginal zone B-cell lymphoma of MALT type responding to eradication of Helicobacter pylori infection. Alpen B, Neubauer A, Dierlamm J, Marynen P, Thiede C, Bayerdorfer E, Stolte M. Blood 2000; 95: 4014-4015. Medline 10939796

Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes. 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. Blood 2000; 96: 2215-2218. Medline 10979968

BCL10 gene mutation in lymphoma. Du MQ, Peng H, Liu H, Hamoudi RA, Diss TC, Willis TG, Ye H, Dogan A, Wotherspoon AC, Dyer MJ, Isaacson PG. Blood 2000; 95: 3885-3890. Medline 10845924

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. Maes B, Baens M, Marynen P, De Wolf-Peeters C. Ann Oncol 2000; 11: 521-526. Medline 10907943

Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases. 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. Haematologica 2001; 86: 64-70. Medline 11146573

Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. 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. Lancet 2001; 357: 39-40. Medline 11197361

T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A. Blood 2003; 101: 2335-2339. Medline 12406890

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -399- Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1. Remstein ED, Kurtin PJ, Einerson RR, Paternoster SF, Dewald GW. Leukemia 2004; 18: 156-160. Medline 14574335

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. Ho L, Davis RE, Conne B, Chappuis R, Berczy M, Mhawech P, Staudt LM, Schwaller J. Blood 2005; 105: 2891-2899. Medline 15598810

Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E. J Clin Oncol 2005; 23: 1979-1983. Medline 15668468

T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. Leukemia 2005; 19: 652-658. Medline 15703784

Bcl10 can promote survival of antigen-stimulated B lymphocytes. Tian MT, Gonzalez G, Scheer B, DeFranco AL. Blood 2005; 106: 2105-2112. Medline 15878976

Long-Term Follow-Up of Gastric MALT Lymphoma After Helicobacter Pylori Eradication. Wundisch T, Thiede C, Morgner A, Dempfle A, Gunther A, Liu H, Ye H, Du MQ, Kim TD, Bayerdorffer E, Stolte M, Neubauer A. J Clin Oncol 2005; 23(31): 8018-8024. Medline 16204012

Contributor(s) Written 12- Antonio Cuneo, Gianluigi Castoldi 2005 Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -400- Cuneo A, Castoldi G . Mucosa-associated lymphoid tissue (MALT) lymphoma. Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Anomalies/MALTlymphID2095.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -401- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Marginal Zone B-cell lymphoma

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 / The morphologic and phenotypic characteristics of malignant cells cell stem correspond to those of lymphocytes belonging to the marginal zone, origin 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -402- 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 Prognosis The patients usually have prolonged survival, as in other indolent lymphomas, but some cases may feature an aggressive disease. Cytogenetics Cytogenetics The most common anomalies in extra-nodal MZBCL of MALT type Morphological 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -403- 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 Note 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),

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -404- 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. Bibliography Cytogenetic studies in splenic lymphoma with villous lymphocytes. Oscier DG, Matutes E, Gardiner A, Glide S, Mould S, Brito-Babapulle V, Ellis J, Catovsky D. Br J Haematol 1993; 85: 487-491. Medline 8136270 p53 in hematologic malignancies. Imamura J, Miyoshi I, Koeffler HP. Blood 1994; 84: 2412-2421. Medline 7919360

A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf- Peeters C, Falini B, Gatter KC. Blood 1994; 84: 1361-1392. Medline 8068936

Characteristic pattern of chromosomal gains and losses in marginal zone B cell lymphoma detected by comparative genomic hybridization. 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. Leukemia 1997; 11: 747-758. Medline 9180302

BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma. 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. Br J Haematol 1997; 98: 719-725. Medline 9332330

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. Ott G, Katzenberger T, Greiner A, Kalla J, Rosenwald A, Heinrich U, Ott MM, Muller-

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -405- Hermelink HK. Cancer Res 1997; 57: 3944-3948. Medline 9307277

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

B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours. Zucca E, Roggero E, Pileri S. Br J Haematol 1998; 100: 3-14. Medline 9450784

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. 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. Blood 1999; 93: 3601-3609. Medline 10339464

Frequent mutation of bcl-6 proto-oncogene in high grade, but not low grade, MALT lymphomas of the gastrointestinal tract. Gaidano G, Capello D, Gloghini A, Fassone L, Vivenza D, Ariatti C, Migliazza A, Saglio G, Carbone A. Haematologica 1999; 84: 582-588. Medline 10406897

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. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. J Clin Oncol 1999; 17: 3835-3849. Medline 10577857

Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy. Hoeve MA, Gisbertz IA, Schouten HC, Schuuring E, Bot FJ, Hermans J, Hopman A, Kluin PM, Arends JW, van Krieken JH. Leukemia 1999; 13: 799-807. Medline 10374886

7q31-32 allelic loss is a frequent finding in splenic marginal zone lymphoma.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -406- Mateo M, Mollejo M, Villuendas R, Algara P, Sanchez-Beato M, Martinez P, Piris MA. Am J Pathol 1999; 154: 1583-1589. Medline 10329610

Marginal zone B-cell lymphoma: A clinical comparison of nodal and mucosa- associated lymphoid tissue types. Non-Hodgkin's Lymphoma Classification Project. Nathwani BN, Anderson JR, Armitage JO, Cavalli F, Diebold J, Drachenberg MR, Harris NL, MacLennan KA, Muller-Hermelink HK, Ullrich FA, Weisenburger DD. J Clin Oncol 1999; 17: 2486-2492. Medline 10561313

Translocation t(11;18) absent in early gastric marginal zone B-cell lymphoma of MALT type responding to eradication of Helicobacter pylori infection. Alpen B, Neubauer A, Dierlamm J, Marynen P, Thiede C, Bayerdorfer E, Stolte M. Blood 2000; 95: 4014-4015. Medline 10939796

Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes. 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. Blood 2000; 96: 2215-2218. Medline 10979968

BCL10 gene mutation in lymphoma. Du MQ, Peng H, Liu H, Hamoudi RA, Diss TC, Willis TG, Ye H, Dogan A, Wotherspoon AC, Dyer MJ, Isaacson PG. Blood 2000; 95: 3885-3890. Medline 10845924

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. Maes B, Baens M, Marynen P, De Wolf-Peeters C. Ann Oncol 2000; 11: 521-526 Medline 10907943

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

Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases. Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P, Cavazzini F, Minotto C, De

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -407- Angeli C, Bardi A, Tammiso E, Negrini M, Cavazzini P, Castoldi GL. Haematologica 2001; 86: 64-70. Medline 11146573

A novel recurrent translocation t(11;14)(p11;q32) in splenic marginal zone B- cell lymphoma. 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. Leukemia in press, 2001 Medline 11146573 p53 abnormalities in splenic lymphoma with villous lymphocytes. Gruszka-Westwood AM, Hamoudi RA, Matutes E, Tuset E, Catovsky D. Blood 2001; 97: 3552-3558. Medline 11369650

Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics. Hernandez JM, Garcia JL, Gutierrez NC, Mollejo M, Martinez-Climent JA, Flores T, Gonzalez MB, Piris MA, San Miguel JF. Am J Pathol 2001; 158: 1843-1850. Medline 11337382

Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. 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. Lancet 2001; 357: 39-40. Medline 11197361

Splenic marginal zone B-cell lymphomas: two cytogenetic subtypes, one with gain of 3q and the other with loss of 7q. Sole F, Salido M, Espinet B, Garcia JL, Martinez Climent JA, Granada I, Hernandez JM, Benet I, Piris MA, Mollejo M, Martinez P, Vallespi T, Domingo A, Serrano S, Woessner S, Florensa L. Haematologica 2001; 86: 71-77. Medline 11146574

T(14;18)(q32;q21) involving IGH and MALT1 is a frequent chromosomal aberration in MALT lymphoma. Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott G, Raderer M, Chott A. Blood 2003; 101: 2335-2339. Medline 12406890

Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -408- API2 and MALT1 and IGH and MALT1. Remstein ED, Kurtin PJ, Einerson RR, Paternoster SF, Dewald GW. Leukemia 2004; 18: 156-160. Medline 14574335

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. Ho L, Davis RE, Conne B, Chappuis R, Berczy M, Mhawech P, Staudt LM, Schwaller J. Blood 2005; 105: 2891-2899. Medline 15598810

Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E. J Clin Oncol 2005; 23: 1979-1983. Medline 15668468

T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. Leukemia 2005; 19: 652-658. Medline 15703784

Bcl10 can promote survival of antigen-stimulated B lymphocytes. Tian MT, Gonzalez G, Scheer B, DeFranco AL. Blood 2005; 106: 2105-2112. Medline 15878976 Contributor(s) Written 07- Antonio Cuneo and Gianluigi Castoldi 2001 Updated 12- Antonio Cuneo and Gianluigi Castoldi 2005 Citation This paper should be referenced as such : Cuneo A, Castoldi GL . Marginal Zone B-cell lymphoma. Atlas Genet Cytogenet Oncol Haematol. July 2001 . URL : http://AtlasGeneticsOncology.org/Anomalies/MarginalZoneBID2078.html Cuneo A, Castoldi GL . Marginal Zone B-cell lymphoma. Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Anomalies/MarginalZoneBID2078.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -409- Atlas of Genetics and Cytogenetics in Oncology and Haematology

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

Identity Note 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -410- 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 ATRA treatment not reached yet, adverse prognosis factors: high WBC, FLT3- internal tandem duplication (ITD), bleeding episodes. Cytogenetics Cytogenetics t(15;17)(q22;q12) leading to a PML-RARA-rearrangement on the Morphological 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 are observed in 35-45% of cases, most frequent: +8, del(9q), anomalies ider(17)(q10)t(15;17) Variants 3 variant translocation 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. Bibliography Proposals for the Classification of the acute leukemias. Bennett JM, Catovsky D, Daniel M-T, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Br J Haematol 1976; 33: 451-458. Medline 188440

15/17 translocation, a consistent chromosomal change in acute promyelocytic leukemia. Rowley JD, Golomb HM, Dougherty C.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -411- Lancet 1977; 1: 549-550. Medline 65649

A variant form of hypergranular promyelocytic leukemia (M3). Bennett JM, Catovsky D, Daniel M-T, Flandrin G, Galton DAG, Gralnick HR, Sultan C. Br J Haematol 1980; 44: 169-170. Medline 7352737

All-trans-retinoic acid in acute promyelocytic leukemia. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A et al. N Engl J Med 1997; 337: 1021-1028. Medline 9321529

Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. Lengfelder E, Reichert A, Schoch C, Haase D, Haferlach T, Löffler H et al. Leukemia 2000; 14: 1362-1370. Medline 10942230

Rapid diagnostic approach to PML-RARalpha-positive acute promyelocytic leukemia. Schoch C, Schnittger S, Kern W, Lengfelder E, Löffler H, Hiddemann W, Haferlach T Hematol J 2002; 3: 259-263. Medline 12391544

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. Schoch C, Schnittger S, Kern W, Dugas M, Hiddemann W, Haferlach T. Haematologica 2003; 88: 351-352 Medline 12651278

Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S. Br J Haematol 2005; 130: 196-202. Medline 16029447

WHO histological classification of acute myeloid leukaemias. Brunning RD, Matutes E, Harris NL, Flandrin G, Vardiman J, Bennett JM, Head DR. World Health Organozation 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -412-

Contributor(s) Written 01- Claudia Schoch 2006 Citation This paper 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. January 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/M3ANLLID1240.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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t(10;11)(p11.2;q23)

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 M4/M5 origin Epidemiology Only three cases reported to date: all infants (2M/1F). Clinics Two boys aged 2 and 8 months respectively, achieved complete remission (1 yrs+, 5 yrs+), 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -414- 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.

Genes involved and Proteins Gene ABI-1 Name Location 10p11.2 Dna / Rna different splicings Protein possesses a SH3 domain; cell growth inhibitor Gene MLL Name 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 Result of the chromosomal anomaly Hybrid 5' MLL-3' ABI1; fusion at MLL exon 6-7. gene The breakpoint of ABI1 gene is the same in the two cases studied Description (nucleotide 433), while the breakpoint of MLL can be located either in exon 6 or 7.

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

External links Other t(10;11)(p11.2;q23) Mitelman database (CGAP - NCBI) database Other t(10;11)(p11.2;q23) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -415- Bibliography 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). Taki T, Shibuya N, Taniwaki M, Hanada R, Morishita K, Bessho F, Yanagisawa M, Hayashi Y. Blood 1998; 92: 1125-1130. 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. Shibuya N, Taki T, Mugishima H, Chin M, Tsuchida M, Sako M, Kawa K, Ishii E, Miura I, Yanagisawa M, Hayashi Y. Genes Chromosomes Cancer 2001; 32: 1-10. Medline 11477655

Is t(10;11)(p11.2;q23) involving MLL and ABI-1 genes associated with congenital acute monocytic leukemia? Morerio C, Rosanda C, Rapella A, Micalizzi C, Panarello C. Cancer Genet Cytogenet 2002; 139: 57-59. Medline 12547160

Contributor(s) Written 04- Jean-Loup Huret 2000 Updated 01- Cristina Morerio, Claudio Panarello 2006 Citation This paper should be referenced as such : Huret JL . t(10;11)(p11.2;q23). Atlas Genet Cytogenet Oncol Haematol. April 2000 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1011ID1178.html Morerio C, Panarello C . t(10;11)(p11.2;q23). Atlas Genet Cytogenet Oncol Haematol. January 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1011ID1178.html

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t(5;14)(q33;q32) PDGFRB/KIAA1509

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 yr 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 mths before death, 27 mths after diagnosis). Clinics The sole case of t(5;14)(q33;q32) with certain PDGFRB/KIAA1509 involvement was a 42 yr old male patient, BCR-ABL negative, treatad with imatinib, and maintained in complete remission 18 mths after diagnosis. Genes involved and Proteins Gene PDGFRB Name Location 5q33 Protein PDGFRB is the receptor for PDGFB (platelet-derived growth factor-b); Ig like, transmembrane and domains; membrane tyrosine kinase; can homodimerize Gene KIAA1509 Name Location 14q32 Protein poorly known; 1935 amino acids; possess a coiled coil domain. Result of the chromosomal anomaly Hybrid 5' KIAA1509-3' PDGFRB; breakpoint in PDGFRB intron 10, identical to gene most PDGFRB breakpoints Description

Fusion 934 amino acids composed of the 355 amino acids from KIAA1506 in Protein N-term and 579 amino acids from PDGFRB C-term Description Oncogenesis the coiled coil domain may mediate PDGFRB homodimerization and constitutive activation

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External links Other t(5;14)(q33;q32) Mitelman database (CGAP - database PDGFRB/KIAA1509 NCBI) Other t(5;14)(q33;q32) CancerChromosomes (NCBI) database PDGFRB/KIAA1509 To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Acute myeloblastic leukemia (M2) with translocation (7;11) followed by marked eosinophilia and additional abnormalities of chromosome 5. Abe A, Tanimoto M, Towatari M, Matsuoka A, Kitaori K, Kato H, Toyozumi H, Takeo T, Adachi K, Emi N, Kawashima K, Saito H.. Cancer Genet Cytogenet 1995; 83: 37-41. Medline 7656202

KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). Levine RL, Wadleigh M, Sternberg DW, Wlodarska I, Galinsky I, Stone RM, DeAngelo DJ, Gilliland DG, Cools J. Leukemia 2005;19: 27-30. Medline 15496975

Contributor(s) Written 02- Jean-Loup Huret 2006 Citation This paper should be referenced as such : Huret JL . t(5;14)(q33;q32) PDGFRB/KIAA1509. Atlas Genet Cytogenet Oncol Haematol. February 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0514q33q32ID1379.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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t(5;15)(q33;q22)

Clinics and Pathology Disease Atypical chronic myelogenous leukemia (a-CML) (BCR-ABL negative chronic myeloproliferative disease) Epidemiology Only one case to date, a 79 yr old male patient Prognosis The disease was sensitive to imatinib, but the patient developped resistance to imatinib and died 14 mths after diagnosis Genes involved and Proteins Gene PDGFRB Name 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 Gene TP53BP1 Name Location 15q22 Protein Component of the cellular response to DNA damage Result of the chromosomal anomaly Hybrid 5' TP53BP1-3' PDGFRB; breakpoint in PDGFRB intron 10, identical to gene most PDGFRB breakpoints; exon 23 of TP53BP1 fused in frame to Description PDGFRB exon 11; reciprocal product not detectable

Fusion 247 kDa; composed of the N-term TP53BP1 including the coiled coil Protein domains and the kinetochore binding domain from TP53BP1 fused to Description 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.

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External links Other t(5;15)(q33;q22) Mitelman database (CGAP - NCBI) database Other t(5;15)(q33;q22) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Tumor suppressor p53 binding protein 1 (53BP1) is involved in DNA damage- signaling pathways. Rappold I, Iwabuchi K, Date T, Chen J. J Cell Biol. 2001; 153: 613-620. Medline 11331310

The Tudor tandem of 53BP1: a new structural motif involved in DNA and RG- rich peptide binding. Charier G, Couprie J, Alpha-Bazin B, Meyer V, Quemeneur E, Guerois R, Callebaut I, Gilquin B, Zinn-Justin S. Structure. 2004; 12: 1551-1562. Medline 15341721 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. Grand FH, Burgstaller S, Kuhr T, Baxter EJ, Webersinke G, Thaler J, Chase AJ, Cross NC. Cancer Res. 2004; 64: 7216-7219. Medline 15492236

53BP1 cooperates with p53 and functions as a haploinsufficient tumor suppressor in mice. Ward IM, Difilippantonio S, Minn K, Mueller MD, Molina JR, Yu X, Frisk CS, Ried T, Nussenzweig A, Chen J. Mol Cell Biol. 2005; 25: 10079-10086. Medline 16260621

ATM signaling and 53BP1. Zgheib O, Huyen Y, DiTullio RA Jr, Snyder A, Venere M, Stavridi ES, Halazonetis TD Radiother Oncol. 2005; 76: 119-122. Medline 16024119

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Contributor(s) Written 02- JeanLoup Huret 2006

Citation This paper should be referenced as such : Huret JL . t(5;15)(q33;q22). Atlas Genet Cytogenet Oncol Haematol. February 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0515q33q22ID1326.html

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t(1;21)(p36;q22)

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). Bottom partial karyotype reprinted from Leukemia, June 2006, with permission from Nautre Publishing Group

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 , 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.

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Prognosis poor; median survival 6 months Cytogenetics

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. Reprinted from Leukemia, June 2006, with permission from Nautre Publishing Group

Probes AML1/ETO dual-color, dual-fusion probe Additional -7, del(7q) anomalies Genes involved and Proteins Note The gene involved in 1p36 is unknown

Gene PRDM16 Name Location 1p36 Note This gene is also involved in the t(1;3)(p36;q21) (AML/MDS)

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -423- 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. Gene RUNX1/AML1 Name 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 Result of the chromosomal anomaly Hybrid Two different chimeric transcripts have been identified. One contains the gene Note 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 below).

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. Reprinted from Leukemia, June 2006, with permission from Nautre Publishing Group

Description 5'RUNX1- 3'PRDM16

External links Other t(1;21)(p36;q22) Mitelman database (CGAP - NCBI) database Other t(1;21)(p36;q22) CancerChromosomes (NCBI) database To be noted

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -424- Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD. Blood 1998; 92: 2879-2885. Medline 9763573

Results of treatment of children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt) in Great Britain 1990-99 Webb DKH, Passmore SJ, Hann IM, Harrison G, Wheatley K, Chessells JM. Br. J. Haematol 2002; 117: 33-39 Medline 11918530

A novel syndrome of radiation-associated acute myeloid leukemia involving AML1 gene translocations. Hromas R, Shopnick R, Jumean HG, Bowers C, Varella-Garcia M, Richkind K. Blood 2000; 95: 4011-4013. Medline 10845943

Novel RUNX1-PRDM16 fusion transcripts in a patient with acute myeloid leukemia showing t(1;21)(p36;q22) Sakai I, Tamura T, Narumi H, Uchida N, Yakushijin Y, Hato T, Fujita S, Yasukawa M. Genes Chromosomes Cancer 2005; 44: 265-270. Medline 16015645

Identification of truncated RUNX1 and RUNX1-PRDM16 fusion transcripts in a case of t(1;21)(p36;q22)-positive therapy-related AML Stevens-Kroef MJPL, Schoenmakers EFPM, van Kraaij M, Huys E, Vermeulen S, van der Reijden B, Geurts van Kessel A. Leukemia 2006; 20: 1187-1189. Medline 16598304

Contributor(s) Written 02- Jean-Loup Huret 2000 Updated 03- Marian Stevens-Kroef 2006

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Citation This paper should be referenced as such : Huret JL . t(1;21)(p36;q22). Atlas Genet Cytogenet Oncol Haematol. February 2000 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0121ID1186.html Stevens-Kroef M . t(1;21)(p36;q22). Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0121ID1186.html

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t(3;16)(q27;p13)

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 yrs ago, when aged 47 yr. This patient died 6 mths later of progressive disease. Cytogenetics Additional 2 out of 2 cases had a t(14;18)(q32;q21) and both patients presented anomalies with MAKA (major karyotypic anomalies) Genes involved and Proteins Gene BCL6 Name Location 3q27 Dna / Rna spans on 25 kb;. 11 exons Protein Sequence-specific DNA binding transcriptional repressor Gene MHC2TA Name Location 16p13 Protein Non-DNA-binding transcriptional coactivator; transactivator of the major histocompatibility complex (MHC) class II genes Result of the chromosomal anomaly Hybrid 5'-MHC2TA/BCL6-3' fusion transcripts but also the 5'-BCL6/MHC2TA-3' gene fusion transcripts, Description

External links Other t(3;16)(q27;p13) Mitelman database (CGAP - NCBI) database

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -427- Other t(3;16)(q27;p13) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Concurrent chromosomal alterations at 3q27, 8q24 and 18q21 in B-cell lymphomas. Au WY, Gascoyne RD, Viswanatha DS, Skinnider BF, Connors JM, Klasa RJ, Horsman DE. Br J Haematol. 1999; 105: 437-440. Medline 10233417

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. Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M. Oncogene. 1999; 18: 7994-7999. Medline 10637510

Detection of translocations affecting the BCL6 locus in B cell non-Hodgkin's lymphoma by interphase fluorescence in situ hybridization. Sanchez-Izquierdo D, Siebert R, Harder L, Marugan I, Gozzetti A, Price HP, Gesk S, Hernandez-Rivas JM, Benet I, Sole F, Sonoki T, Le Beau MM, Schlegelberger B, Dyer MJ, Garcia-Conde J, Martinez-Climent JA. Leukemia. 2001;15: 1475-1484. Medline 11516111

Detection of reciprocal fusion 5'-BCL6/partner-3' transcripts in lymphomas exhibiting reciprocal BCL6 translocations. Kaneita Y, Yoshida S, Ishiguro N, Sawada U, Horie T, Mori S, Moriyama M. Br J Haematol. 2001; 113: 803-806. Medline 11380473 Contributor(s) Written 03- Jean Loup Huret 2006 Citation This paper should be referenced as such : Huret JL . t(3;16)(q27;p13). Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0316q27p13ID2089.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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t(4;16)(q26;p13)

Clinics and Pathology Disease T-cell lymphoma of the small intestine of low grade malignancy Phenotype / cell stem CD3, CD4, TCR A-B phenotype origin Epidemiology only 1 case to date, a 28 yr old male patient Cytogenetics Cytogenetics sole anomaly Morphological Genes involved and Proteins Gene IL2 Name 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 Gene TNFRSF17 Name 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 Result of the chromosomal anomaly Hybrid gene 5' IL2-3'TNFRSF17; breakpoint in intron 3 of IL2 Description

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -429- External links Other t(4;16)(q26;p13) Mitelman database (CGAP - NCBI) database Other t(4;16)(q26;p13) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography 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. Laabi Y, Gras MP, Carbonnel F, Brouet JC, Berger R, Larsen CJ, Tsapis A. EMBO J. 1992; 11: 3897-3904. Medline 1396583

Extensive small intestinal T-cell lymphoma of low-grade malignancy associated with a new chromosomal translocation. Carbonnel F, Lavergne A, Messing B, Tsapis A, Berger R, Galian A, Nemeth J, Brouet JC, Rambaud JC. Cancer 1994; 73: 1286-1291. Medline 8313332

Contributor(s) Written 03- Jean Loup Huret 2006 Citation This paper should be referenced as such : Huret JL . t(4;16)(q26;p13). Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0416q26p13ID1358.html

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t(11;20)(q23;q11)

Clinics and Pathology Disease pro-B acute lymphoblastic leukemia (L2) Epidemiology One case described (42 yrs); 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 109/L with 97% blasts, and platelet 37.0 x 109/L. 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 Cytogenetic analysis was not performed. Morphological Genes involved and Proteins Gene MLL Name 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 Gene MAPRE1 Name 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,

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -431- and chromosomal stability Result of the chromosomal anomaly Hybrid gene

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

Description 5' MLL-3' MAPRE1, with fusion of MLL exon 6 to MAPRE1 exon 5; the reciprocal in-frame MAPRE1-MLL is also transcribed Detection cDNA panhandle PCR

Fusion Protein

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.

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

External links Other t(11;20)(q23;q11) Mitelman database (CGAP - NCBI) database Other t(11;20)(q23;q11) CancerChromosomes (NCBI)

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -432- database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography MLL is fused to EB1 (MAPRE1), which encodes a microtubule-associated protein, in a patient with acute lymphoblastic leukemia. Fu JF, Hsu HC, Shih LY. Genes Chromosomes Cancer 2005; 43: 206-210. Medline 15751040

Contributor(s) Written 03- JF Fu, LY Shih 2006 Citation This paper should be referenced as such : Fu JF, Shih LY . t(11;20)(q23;q11). Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1120q23q11ID1415.html

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Liver adenoma

Identity Other Hepatocellular adenoma names 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -434- 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. Gene TCF1 Name 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.

Gene CTNNB1 Name 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.

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Bibliography Liver-cell adenomas associated with use of oral contraceptives. Edmondson HA, Henderson B, Benton B. N Engl J Med 1976; 294: 470-472. Medline 173996

Familial liver-cell adenomas and diabetes mellitus. Foster JH, Donohue TA, Berman MM. N Engl J Med 1978; 299: 239-241. Medline 207987

Liver adenomatosis. An entity distinct from liver adenoma? Flejou JF, Barge J, Menu Y, Degott C, Bismuth H, Potet F, et al. Gastroenterology 1985; 89: 1132-1138. Medline 2412930

Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). 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. Nature 1996 Dec 5; 384(6608): 455-458. Medline 8945470

Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature. Chiche L, Dao T, Salame E, Galais MP, Bouvard N, Schmutz G, Rousselot P, Bioulac-Sage P, Segol P, Gignoux M. Ann Surg 2000; 231: 74-81. Medline 10636105

Bi-allelic inactivation of TCF1 in hepatic adenomas. Bluteau O, Jeannot E, Bioulac-Sage P, Marques JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J. Nat Genet 2002; 32: 312-315. Medline 12355088

P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Chen YW, Jeng YM, Yeh SH, Chen PJ. Hepatology 2002; 36: 927-935. Medline 12297840

Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -436- inactivation. 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. Gastroenterology 2003; 125: 1470-1475. Medline 14598263

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. 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. J Clin Endocrinol Metab 2004; 89: 1476-1480. Medline 15001650

Genotype-phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC. 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. Hepatology 2006; 43: 515-524. Medline 16496320

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 03- Jessica Zucman-Rossi 2006 Citation This paper should be referenced as such : Zucman-Rossi J . Liver adenoma. Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Tumors/LiverAdenomID5420.html

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Birt-Hogg-Dubé Syndrome (BHD) 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 BHDS is a genodermatosis characterized by the triad of benign tumors of and clinics 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.

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Multiple trichodiscomas of the neck

Neoplastic Approximately 27% of BHDS patients develop renal tumors of different risk 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 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

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Gene FLCN Name Location 17p11.2 DNA/RNA Description Total gene size: 24971 bp. Protein Note 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 Note 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.

External links Association Hogg Dube Family Alliance http://www.birthoggdube.org/

Bibliography Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Birt AR, Hogg GR, Dubé WJ. Arch Derm 1977; 113: 1674-1677. Medline 596896

Multiple fibrofolliculomas (Birt-Hogg-Dubé) associated with a large connective tissue nevus. Weintraub R, Pinkus H. J Cutan Pathol 1977; 4: 289-299. Medline 753849

Multiple fibrofolliculomas with trichodiscomas and acrochordons. Fujita WH, Barr RJ, Headley JL. Arch Derm 1981; 117: 32-35. Medline 7458379

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -440- Medline 4015134

Fibrofolliculomas, trichodiscomas, and acrochordons: the Birt-Hogg-Dubé syndrome. Ubogy-Rainey Z, James WD, Lupton GP, Rodman OG. J Am Acad Derm 1987; 16: 452-457. Medline 3819093

Fibrofolliculomas, tricodiscomas and acrochordons (Birt-Hogg-Dubé) associated with intestinal polyposis. Rongioletti F, Hazini R, Gianotti G, Rebora A. Clin Exp Derm 1989; 14: 72-74. Medline 2805394

Familial multiple desmoplastic trichoepitheliomas. Shapiro PE, Kopf, AW. Arch Derm 1991; 127: 83-87. Medline 1986711

Bilateral renal cell carcinoma in the Birt-Hogg-Dubé syndrome. Roth JS, Rabinowitz AD, Benson M, Grossman ME. J Am Acad Derm 1993; 29: 1055-1056. Medline 8245249

Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dubé syndrome. Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F. Int J Dermatol 1996; 35: 365-367. Medline 8734663

The Heidelberg classification of renal cell tumors. 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, Storkel S, Van Den Berg E, Zbar B. J Path 1997; 183: 131-133. Medline 9390023

Multiple trichodiscomas associated with intestinal polyposis. Le Guyadec T, Dufau J.-P, Poulain J.-F, Vaylet F, Grossin M, Lanternier G. Ann Derm Venereol 1998; 125: 717-719. Medline 9835964

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -441- Medline 9679872

Parotid oncocytoma in the Birt-Hogg-Dubé syndrome. Liu V, Kwan T, Page EH. J Am Acad Dermatol 2000; 43: 1120-1122. Medline 11100034

Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Oncogene 2001; 20: 5239-5242. Medline 11526515

Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. 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. Am J Hum Genet 2001; 69: 876-882. Medline 11533913

Clinical and genetic studies of Birt-Hogg-Dubé syndrome. Khoo SK, Giraud S, Kahnoski K, Chen J, Motorna O, Nickolov R, Binet O, Lambert D, Friedel J, Levy R, Ferlicot S, Wolkenstein P, Hammel P. Bergerheim U, Hedblad MA, Bradley M, Teh BT, Nordenskjold M, Richard S. J Med Genet 2002; 39: 906-912. Medline 12471204

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. 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. Cancer Cell 2002; 2: 157-164. Medline 12204536

Renal tumors in the Birt-Hogg-Dubé syndrome. Pavlovich CP, Walther MW, Eyler RA, Hewitt SM, Zbar B, Linehan WM, Merino MJ. Am J Surg Path 2002; 26: 1542-1552. Medline 12459621

Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -442- Cancer Epidemiol. Biomarkers Prev. 2002; 11: 393-400. Medline 11927500

Expression of Birt-Hogg-Dubé gene mRNA in normal and neoplastic human tissues. Warren MB, Torres-Cabala CA, Turner ML, Merino MJ, Matrosova VY, Nickerson ML, Ma W, Linehan WM, Zbar B, Schmidt LS. Mod Pathol 2004; 17: 998-1011. Medline 15143337

Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. 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. J Urol 2005; 173: 1482-1486. Erratum in: J Urol 2005; 174: 796. Medline 15821464

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. 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. Am J Hum Genet 2005; 76: 1023-1033. Medline 15852235

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 02- Benedetta Toschi, Maurizio Genuardi 2006 Citation This paper should be referenced as such : Toschi B, Genuardi M . Birt-Hogg-Dubé Syndrome (BHD). Atlas Genet Cytogenet Oncol Haematol. February 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/BirtHoggDubeID10091.html

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Neurofibromatosis type 1 (NF1) Identity Other Von Recklinghausen neurofibromatosis names 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 Note 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 Diagnosis is made on the ground of at least 2 of the following: and clinics 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 5% of NF1 patients experience a malignant neoplasm risk 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 %

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -444- 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 yrs; no increased risk of leukaemia in the adult. pheochromocytomas various other neoplasias, of which are rhabdomyosarcomas Treatment early diagnosis, lifetime monitoring and surgery are essential Cytogenetics Inborn no special feature conditions Cytogenetics according to the cancer type in most cases of cancer JMML : monosomy 7 Genes involved and Proteins

Gene NF1 Name 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

External links GeneCards NF1 GDB NF1 OMIM 162200 Orphanet Neurofibromatosis type 1 HGMD 120231 Other Neurofibromatosis Type 1 - GeneClinics database

Association Neurofibromatosis

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Bibliography A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. Huson SM, Compston DA, Clark P, Harper PS. J Med Genet 1989 Nov; 26(11): 704-711. Medline 90064452

Chromosome pattern in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis. Kaneko Y, Maseki N, Sakurai M, Shibuya A, Shinohara T, Fujimoto T, Kanno H, Nishikawa A. Leukemia 1989 Jan; 3(1): 36-41. Medline 89082060

Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I. Metheny LJ, Cappione AJ, Skuse GR. J Neuropathol Exp Neurol 1995 Nov; 54(6): 753-760. Medline 96067328

The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D. JAMA 1997 Jul 2; 278(1): 51-57. Medline 97350963

Elevated risk for MPNST in NF1 microdeletion patients. De Raedt T, Brems H, Wolkenstein P, Vidaud D, Pilotti S, Perrone F, Mautner V, Frahm S, Sciot R, Legius E. Am J Hum Genet 2003 May; 72(5): 1288-1292. Medline 12660952

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Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -446- Written 09- Jean-Loup Huret 1997 Updated 02- Katharina Wimmer 2006

Citation This paper should be referenced as such : Huret JL . Neurofibromatosis type 1 (NF1). Atlas Genet Cytogenet Oncol Haematol. September 1997 . URL : http://AtlasGeneticsOncology.org/Kprones/NF1ID10006.html Wimmer K . Neurofibromatosis type 1 (NF1). Atlas Genet Cytogenet Oncol Haematol. February 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/NF1ID10006.html

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Familial liver adenomatosis Identity 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. Other Familial hepatic adenomas names Inheritance autosomal dominant disorder with low penetrance Clinics Phenotype To date, all familial liver adenomatosis cases described are related to and clinics TCF1/HFN1a constitutional mutation. Genotype-phenotype correlation analysis showed that TCF1/HNF1a benign lesions were steatotic. Neoplastic Among MODY3 patients only a very small minority will develop liver risk 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.

Gene TCF1 Name Location 12q24.31 DNA/RNA Description 10 coding exons Protein

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -448- 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.

Bibliography Familial liver-cell adenomas and diabetes mellitus. Foster JH, Donohue TA, Berman MM. N Engl J Med 1978; 299: 239-241. Medline 207987

Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). 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. Nature 1996 Dec 5; 384(6608): 455-458. Medline 8945470

Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature. Chiche L, Dao T, Salame E, Galais MP, Bouvard N, Schmutz G, Rousselot P, Bioulac-Sage P, Segol P, Gignoux M. Ann Surg 2000; 231: 74-81. Medline 10636105

Bi-allelic inactivation of TCF1 in hepatic adenomas. Bluteau O, Jeannot E, Bioulac-Sage P, Marques JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J. Nat Genet 2002; 32: 312-315. Medline 12355088

Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation. 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. Gastroenterology 2003; 125: 1470-1475. Medline 14598263

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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. 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. J Clin Endocrinol Metab 2004; 89: 1476-1480. Medline 15001650

Genotype-phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC. 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. Hepatology 2006 Feb 22; 43(3): 515-524 Medline 16496320

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 03- Jessica Zucman-Rossi 2006 Citation This paper should be referenced as such : Zucman-Rossi J . Familial liver adenomatosis. Atlas Genet Cytogenet Oncol Haematol. March 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/FamLiverAdenomID10130.html

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Ethical issues in cancer genetics

Robert Roger Lebel, MD, FACMG*

Greenwood Genetic Center, Greenwood, SC (Senior Medical Geneticist, and Director of the Program in Medical Ethics) and Genetic Risk Assessment Service, Adventist Hinsdale Hospital, Hinsdale, IL (Medical Director)

December 2005

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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -451- 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. 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -452- 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -453- 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -454- 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.

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -455- 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -456- 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -457- 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

Atlas Genet Cytogenet Oncol Haematol 2006; 3 -458- 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.

Contributor(s) Written 12- Robert Roger Lebel 2005 Citation This paper should be referenced as such : Lebel RR . Ethical issues in cancer genetics. Atlas Genet Cytogenet Oncol Haematol. December 2005 . URL : http://AtlasGeneticsOncology.org/Deep/EthicCancerGenetID20054.html

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