Atlas Journal

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS Volume 3, Number 3, Jul-Sep 1999 Previous Issue / Next Issue Genes CBFb (subunit b of core binding factor) (16q22). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 286-290. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CBFbID45.html MYH11 (myosin heavy chain) (incomplete) (16p13). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 291-295. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MYH11ID43.html PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) (10q23.3). Michel Longy. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 296-300. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PTENID158.html CBLb (Cas-Br-M (murine) ecotropic retroviral transforming sequence b) (3q). Olivier Rosnet. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 301-3055. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CBLbID193.html CBLc (Cas-Br-M (murine) ecotropic retroviral transforming sequence c) (19q13.2). Olivier Rosnet. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 306-309. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/CBLcID194.html CBL (Cas-Br-M (murine) ecotropic retroviral transforming sequence) (11q23-q25). Olivier Rosnet. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 310-314. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 I URL : http://AtlasGeneticsOncology.org/Genes/CBLID171.html HLF (hepatic leukemia factor) (17q22). Franck Viguié. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 315-319. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/HLFID47.html RB1 (retinoblastoma) (13q14). Dietmar R Lohmann. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 320-325. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RB1ID90.html Leukaemias -7/del(7q) in childhood. François Desangles. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 326-330. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del7qChildID1152.html -7/del(7q) in adults. François Desangles. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 331-335. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del7qID1093.html dic(9;20)(p11-13;q11). Barbara Gibbons. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 336-337. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/dic920ID1143.html High hyperdiploid acute lymphoblastic leukaemia. Barbara Gibbons. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 338-340. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/hyperploidID1085.html Severe hypodiploid acute lymphoblastic leukaemia. Barbara Gibbons. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 341-342. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/hypoploidyID1087.html del(16)(q22); inv(16)(p13q22); t(16;16)(p13;q22) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 343-348. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/inv16.html Near haploid acute lymphoblastic leukaemia. Barbara Gibbons. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 349-350. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 II URL : http://AtlasGeneticsOncology.org/Anomalies/nearhaploidID1045.html 9p Rearrangements in ALL. Nyla A Heerema. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 351-353. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/9prearrALLID1156.html t(10;14)(q24;q11); t(7;10)(q34;q24) . Christine Pérot. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 354-357. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/1014ID1068.html t(1;18)(q25;q23). Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 358-359. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0118ID1162.html Solid Tumours Soft tissue tumors: Desmoplastic small round cell tumor. Christine Pérot. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 360-364. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/desmoplasticID5023.html Eye: Posterior uveal melanoma. Karen Sisley. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 365-368. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/UvealmelanomID5047.html Uterus: Carcinoma of the cervix. Niels B Atkin. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 369-373. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/CervixUteriID5046.html Cancer Prone Diseases Diamond-Blackfan anemia (DBA). Hope H. Punnett. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 374-375. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/DiamondBlackfanID10040.html Hyperparathyroidism-Jaw Tumor syndrome (HPT-JT). Maurine R Hobbs. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 376-379. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/Hyperpar-JawID10052.html Deep Insights

Atlas Genet Cytogenet Oncol Haematol 1999; 2 III Minimal residual disease in acute lymphoblastic leukemia. Hélène Cavé. Atlas Genet Cytogenet Oncol Haematol 1999; 3 (3): 380-388. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Deep/MinResidDisID20007.html Case Reports Educational Items

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Atlas Genet Cytogenet Oncol Haematol 1999; 2 IV Atlas of Genetics and Cytogenetics in Oncology and Haematology

NONO

Identity Hugo NONO Location Xq12 DNA/RNA Transcription alternative splicing; 2.4 mRNA complete cds; coding sequence: CDS 129 ... 1550 Protein

Description the protein encoded by NONO is called p54nrb (nuclear RNA binbing); 471 amino acids; 54 kDa; N-term glutamine/histidine rich region, tandem RNA binding domains (amino acids 75 to 228), helix-turn-helix implicated in DNA binding, and a proline rich region in C-term; N-term and C-term allow protein-protein interactions. Expression wide Function binds independantly to DNA and RNA; forms a heterodimer with PSF, a protein sharing vast homologies; both form complexes with DNA topoisomerase I, which renders this enzyme much more active; NONO also enhances the binding of several DNA-binding proteins (but not all). Homology with PSF and other proteins with a DBHS domain (Drosophila behaviour, human splicing) which includes the tandem RNA binding domains. Implicated in Entity inv(X)(p11.2q12) in renal cell carcinoma -->NonO/TFE3 Disease only one case of papillary renal cell carcinoma

Hybrid/Mutated 5' NONO- 3' TFE3 Gene Abnormal N-term NONO and most of it except the C-term proline rich sequence Protein fused to the DNA binding domains of TFE3 (excluding the acidic transcriptional activation domain, including the C-term helix-loop-

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -133- helix, and the leucine zipper); the reciprocal transcript is found

External links Nomenclature Hugo NONO GDB NONO Entrez_Gene NONO 4841 non-POU domain containing, octamer-binding Cards Atlas NONOID168 GeneCards NONO Ensembl NONO CancerGene NONO Genatlas NONO GeneLynx NONO eGenome NONO euGene 4841 Genomic and cartography NONO - Xq12 chrX:70286488-70304037 + Xq13.1 (hg17- GoldenPath May_2004) Ensembl NONO - Xq13.1 [CytoView]

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

Genbank Y11289 [ SRS ] Y11289 [ ENTREZ ]

Genbank AK055406 [ SRS ] AK055406 [ ENTREZ ]

Genbank AU119361 [ SRS ] AU119361 [ ENTREZ ]

Genbank BC002364 [ SRS ] BC002364 [ ENTREZ ]

Genbank BC003129 [ SRS ] BC003129 [ ENTREZ ]

RefSeq NM_007363 [ SRS ] NM_007363 [ ENTREZ ]

RefSeq NT_086956 [ SRS ] NT_086956 [ ENTREZ ] AceView NONO AceView - NCBI TRASER NONO Traser - Stanford

Unigene Hs.533282 [ SRS ] Hs.533282 [ NCBI ] HS533282 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q15233 [ SRS] Q15233 [ EXPASY ] Q15233 [ INTERPRO ]

Prosite PS50102 RRM [ SRS ] PS50102 RRM [ Expasy ]

Interpro IPR000504 RNA_rec_mot [ SRS ] IPR000504 RNA_rec_mot [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -134- CluSTr Q15233 Pfam PF00076 RRM_1 [ SRS ] PF00076 RRM_1 [ Sanger ] pfam00076 [ NCBI- CDD ] Blocks Q15233 Polymorphism : SNP, mutations, diseases OMIM 300084 [ map ] GENECLINICS 300084

SNP NONO [dbSNP-NCBI]

SNP NM_007363 [SNP-NCI]

SNP NONO [GeneSNPs - Utah] NONO [SNP - CSHL] NONO] [HGBASE - SRS] General knowledge Family NONO [UCSC Family Browser] Browser SOURCE NM_007363 SMD Hs.533282 SAGE Hs.533282 Amigo function|DNA binding Amigo function|RNA binding Amigo process|RNA splicing Amigo process|mRNA processing Amigo component|nucleus Amigo function|pre-mRNA splicing factor activity BIOCARTA RNA polymerase III transcription PubGene NONO Other databases Probes Probe NONO Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography Purification and cDNA cloning of HeLa cell p54nrb, a nuclear protein with two RNA recognition motifs and extensive homology to human splicing factor PSF and Drosophila NONA/BJ6. Dong B, Horowitz DS, Kobayashi R, Krainer AR Nucleic Acids Res 1993 Aug 25;21(17):4085-92 Medline 93382787

NonO, a non-POU-domain-containing, octamer-binding protein, is the mammalian homolog of Drosophila nonAdiss. Yang YS, Hanke JH, Carayannopoulos L, Craft CM, Capra JD, Tucker PW

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -135- Mol Cell Biol 1993 Sep;13(9):5593-603 Medline 93360993

Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma. Clark J, Lu YJ, Sidhar SK, Parker C, Gill S, Smedley D, Hamoudi R, Linehan WM, Shipley J, Cooper CS Oncogene 1997 Oct;15(18):2233-9 Medline 98054131

NonO enhances the association of many DNA-binding proteins to their targets. Yang YS, Yang MC, Tucker PW, Capra JD Nucleic Acids Res 1997 Jun 15;25(12):2284-92 Medline 97315317

The RNA-splicing factor PSF/p54 controls DNA-topoisomerase I activity by a direct interaction. Straub T, Grue P, Uhse A, Lisby M, Knudsen BR, Tange TO, Westergaard O, Boege F J Biol Chem 1998 Oct 9;273(41):26261-4 Medline 98434520

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Jean-Loup Huret 1999 Citation This paper should be referenced as such : Huret JL . NONO. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NONOID168.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -136- Atlas of Genetics and Cytogenetics in Oncology and Haematology

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PRCC (papillary renal cell carcinoma)

Identity Other RCCP1 (renal cell carcinoma, papillary, 1) names Hugo PRCC Location 1q21.2 DNA/RNA Description cDNA of 2039 bp Transcription 1989 bp RNA; coding sequence: CDS 191...1666 Protein

Description 491 amino acids; 52 kDa; proline/leucine/glycine rich domain of 150 amino acids in N-term Expression wide; in the fetus and in the adult Homology none is known Implicated in Entity t(X;1)(p11.2;q21.2) in renal cell carcinoma --> PRCC/TFE3 Disease t(X;1) is a very rare subtype of papillary renal cell carcinoma Prognosis overall 5-yr survival rate around 85%

Hybrid/Mutated 5' PRCC- 3' TFE3; variable breakpoint in PRCC; breakpoint in the Gene 1st intron of TFE3 Abnormal N-term PRCC with the proline rich sequence fused to most of TFE3, Protein including the ; the reciprocal TFE3-PRCC is expressed; it is to be noted that the normal TFE3 transcript is lost in female patients.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -137- External links Nomenclature Hugo PRCC GDB PRCC PRCC 5546 papillary renal cell carcinoma (translocation- Entrez_Gene associated) Cards Atlas PRCCID69 GeneCards PRCC Ensembl PRCC CancerGene PRCC Genatlas PRCC GeneLynx PRCC eGenome PRCC euGene 5546 Genomic and cartography PRCC - 1q21.2 chr1:153550347-153583681 + 1q23.1 (hg17- GoldenPath May_2004) Ensembl PRCC - 1q23.1 [CytoView]

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

Genbank AL590666 [ SRS ] AL590666 [ ENTREZ ]

Genbank X99720 [ SRS ] X99720 [ ENTREZ ]

Genbank AA846273 [ SRS ] AA846273 [ ENTREZ ]

Genbank AK126403 [ SRS ] AK126403 [ ENTREZ ]

Genbank BC004913 [ SRS ] BC004913 [ ENTREZ ]

RefSeq NM_005973 [ SRS ] NM_005973 [ ENTREZ ]

RefSeq NM_199416 [ SRS ] NM_199416 [ ENTREZ ]

RefSeq NT_086596 [ SRS ] NT_086596 [ ENTREZ ] AceView PRCC AceView - NCBI TRASER PRCC Traser - Stanford

Unigene Hs.516948 [ SRS ] Hs.516948 [ NCBI ] HS516948 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q92733 [ SRS] Q92733 [ EXPASY ] Q92733 [ INTERPRO ] CluSTr Q92733 Blocks Q92733

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -138- Polymorphism : SNP, mutations, diseases OMIM 179755 [ map ] GENECLINICS 179755

SNP PRCC [dbSNP-NCBI]

SNP NM_005973 [SNP-NCI]

SNP NM_199416 [SNP-NCI]

SNP PRCC [GeneSNPs - Utah] PRCC [SNP - CSHL] PRCC] [HGBASE - SRS] General knowledge Family PRCC [UCSC Family Browser] Browser SOURCE NM_005973 SOURCE NM_199416 SMD Hs.516948 SAGE Hs.516948 Amigo process|biological_process unknown Amigo component|cellular_component unknown Amigo function|molecular_function unknown PubGene PRCC Other databases Probes Probe PRCC Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwilliam R, Ross M, Linehan WM, Birdsall S, Shipley J, Cooper CS Hum Mol Genet 1996 Sep;5(9):1333-8 Medline 97026295

Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Weterman MA, Wilbrink M, Geurts van Kessel A Proc Natl Acad Sci U S A 1996 Dec 24;93(26):15294-8 Medline 97140324

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -139- Contributor(s) Written 01- Fran ois Desangles and Jean-Loup Huret 1999 Citation This paper should be referenced as such : Desangles F and Huret JL . PRCC (papillary renal cell carcinoma). Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PRCCID69.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -140- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PSF (PTB-associated splicing factor)

Identity Other SFPQ (splicing factor proline/glutamine rich) names Hugo SFPQ Location 1p34 DNA/RNA Transcription alternative splicing; 3 kb mRNA complete cds; coding sequence: CDS 86..2209 Protein

Description 707-712 amino acids; 76 kDa; N-term proline/glutamine rich domain, a prolin rich region, 2 tandem RNA binding domains, and C-term. Localisation nucleus Function splicing factor required early in spliceosome formation; form a complex with the polypyrimidine tract binding protein (PTB, herein the name); involved in pre-m RNA splicing step 2 (step 1: cut after exon n, intron n is still joined to exon n+1; step 2: cut between intron n and exon n+1, join exons n and n+1); forms a heterodimer with p54nrb (nuclear RNA binbing) a protein sharing vast homologies, encoded by NONO; both form complexes with DNA topoisomerase I, which renders this enzyme much more active. Homology with the above mentioned NONE product and with other proteins with a DBHS domain (Drosophila behaviour, human splicing) which includes the tandem RNA binding domains. Implicated in Entity t(X;1)(p11.2;p34) in renal cell carcinoma --> PSF/TFE3 Disease t(X;1)(p11.2;p34) has only been found in a handfull cases of papillary renal cell carcinoma

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -141- Hybrid/Mutated 5' PSF- 3' TFE3 Gene Abnormal N-term PSF and most of it fused to the DNA binding domains of Protein TFE3 (excluding the acidic transcriptional activation domain, including the C-term helix-loop-helix, and the leucine zipper); no TFE3-PSF reciprocal transcript, as the der(X) t(X;1) is missing; the normal TFE3 transcript is found.

External links Nomenclature Hugo SFPQ GDB SFPQ SFPQ 6421 splicing factor proline/glutamine rich (polypyrimidine Entrez_Gene tract binding protein associated) Cards Atlas PSFID167 GeneCards SFPQ Ensembl SFPQ CancerGene SFPQ Genatlas SFPQ GeneLynx SFPQ eGenome SFPQ euGene 6421 Genomic and cartography SFPQ - 1p34 chr1:35318296-35327828 - 1p34.3 (hg17- GoldenPath May_2004) Ensembl SFPQ - 1p34.3 [CytoView]

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

Genbank AL590434 [ SRS ] AL590434 [ ENTREZ ]

Genbank BC004534 [ SRS ] BC004534 [ ENTREZ ]

Genbank BC027708 [ SRS ] BC027708 [ ENTREZ ]

Genbank BC027717 [ SRS ] BC027717 [ ENTREZ ]

Genbank BC051192 [ SRS ] BC051192 [ ENTREZ ]

RefSeq NM_005066 [ SRS ] NM_005066 [ ENTREZ ]

RefSeq NT_086582 [ SRS ] NT_086582 [ ENTREZ ] AceView SFPQ AceView - NCBI

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -142- TRASER SFPQ Traser - Stanford

Unigene Hs.355934 [ SRS ] Hs.355934 [ NCBI ] HS355934 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P23246 [ SRS] P23246 [ EXPASY ] P23246 [ INTERPRO ]

Prosite PS50102 RRM [ SRS ] PS50102 RRM [ Expasy ]

Interpro IPR000504 RNA_rec_mot [ SRS ] IPR000504 RNA_rec_mot [ EBI ] CluSTr P23246 Pfam PF00076 RRM_1 [ SRS ] PF00076 RRM_1 [ Sanger ] pfam00076 [ NCBI- CDD ] Blocks P23246 Polymorphism : SNP, mutations, diseases OMIM 605199 [ map ] GENECLINICS 605199

SNP SFPQ [dbSNP-NCBI]

SNP NM_005066 [SNP-NCI]

SNP SFPQ [GeneSNPs - Utah] SFPQ [SNP - CSHL] SFPQ] [HGBASE - SRS] General knowledge Family SFPQ [UCSC Family Browser] Browser SOURCE NM_005066 SMD Hs.355934 SAGE Hs.355934 Amigo function|DNA binding Amigo function|RNA binding Amigo process|RNA splicing Amigo process|nuclear mRNA splicing, via spliceosome Amigo component|nucleus Amigo function|pre-mRNA splicing factor activity BIOCARTA RNA polymerase III transcription PubGene SFPQ Other databases Probes Probe SFPQ Related clones (RZPD - Berlin) PubMed PubMed 7 Pubmed reference(s) in LocusLink Bibliography A novel set of spliceosome-associated proteins and the essential splicing factor PSF bind stably to pre-mRNA prior to catalytic step II of the splicing reaction.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -143- Gozani O, Patton JG, Reed R EMBO J 1994 Jul 15;13(14):3356-67 Medline 94320600

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Jean-Loup Huret 1999 Citation This paper should be referenced as such : Huret JL . PSF (PTB-associated splicing factor). Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PSFID167.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -144- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PTCH1 (updated: old version not available)

Identity Other PTC, but this term was confusing with PTC/PKA names PTCH patched Hugo PTCH Location 9q22.3 (between FACC and XPAC PTCH1 is flanked by the microsatellite markers D9S196 and D9S287; a microsatellite marker, 1AJL, is located inside the gene DNA/RNA Description 24 exons, exon 24 is non-coding; 34 kb Transcription alternate splicing: 3 different 5' termini; 6.5 kb mRNA; coding sequence: CDS 1 ... 4344 Protein

Description glycoprotein; 12 transmembrane domains, 2 extra cellular loops, intracellular N-term and C-term and sterol-sensing domain (SSD) Expression widely expressed at low levels; increased levels in cells receiving a hedgehog signal Localisation transmembrane protein, cellular membrane, intracellular vesicles Function part of a signalling pathway; opposed by the gene products of hedgehog genes; transmembrane protein; is thought to have a repressive activity on cell proliferation; the recent demonstration of NBCCS syndrome (see below) as a chromosome instability syndrome suggests that this protein has a role in DNA maintenance, repair and/or replication Homology patched (drosophila segment polarity gene), PTCH2 (human gene with unknown function) Mutations Germinal germ-line mutations lead to protein truncation in naevoid basal cell carcinoma syndrome (NBCCS) patients (see below); mutations types are variable : nucleotide substitutions (missense/nonsense), small deletions, or small insertions mainly, leading to protein truncation; these mutations have been observed in most exons; there is, so far, no hot- spot.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -145- Somatic mutation and allele loss events in basal cell carcinoma, in NBCCS and in sporadic basal cell carcinoma are, so far, in accordance with the two- hit model for neoplasia, as is found in retinoblastoma; mutation and allele loss have also been found in sporadic primitive neuroectodermal tumours (PNETs), sporadic medulloblastomas and in a few cases of esophageal squamous cell carcinoma and invasive transitional cell carcinoma of the bladder; mutations have also been reported in a low frequency of sporadic trichoepitheliomas and in sporadic odontogenic keratocysts Implicated in Entity naevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome Disease autosomal dominant condition; cancer prone disease (multiple basal cell carcinomas, medulloblastomas); malformations; it is also a chromosome instability syndrome Cytogenetics spontaneous and induced chromosome instability

Entity skin cancers Disease sporadic basal cell carcinoma, but also in the benign trichoepithelioma, a tumor often associated with basal cell carcinomas sporadic basal cell carcinoma from xeroderma pigmentosum patients have a high frequency of typical UV-induced mutations in PTCH1

Entity brain diseases Disease in a subset of sporadic primitive neuroectodermal tumours (PNETs)of the central nervous system (cerebral PNETs, medulloblastomas, and desmoplastic medulloblastomas); note: NBCCS patients have a predisposition for the development of PNETs, while, herein mentioned are sporadic PNETs PTCH1 have also been found mutated in both familiar and sporadic cases of Holoprosencephaly (HPE)

Entity various cancers and benign tumors Disease invasive transitional cell carcinoma of the bladder: PTCH1 has been Entrez_Gene PTCH 5727 patched homolog (Drosophila) Cards Atlas PTCH100 GeneCards PTCH Ensembl PTCH CancerGene PTCH Genatlas PTCH GeneLynx PTCH eGenome PTCH euGene 5727 Genomic and cartography PTCH - 9q22.3 chr9:95285955-95350386 - 9q22.32 (hg17- GoldenPath May_2004) Ensembl PTCH - 9q22.32 [CytoView]

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

Genbank AY395758 [ SRS ] AY395758 [ ENTREZ ]

Genbank AY395768 [ SRS ] AY395768 [ ENTREZ ]

Genbank AY395772 [ SRS ] AY395772 [ ENTREZ ]

Genbank AB189436 [ SRS ] AB189436 [ ENTREZ ]

Genbank AB189437 [ SRS ] AB189437 [ ENTREZ ]

RefSeq NM_000264 [ SRS ] NM_000264 [ ENTREZ ]

RefSeq NT_086752 [ SRS ] NT_086752 [ ENTREZ ] AceView PTCH AceView - NCBI TRASER PTCH Traser - Stanford

Unigene Hs.494538 [ SRS ] Hs.494538 [ NCBI ] HS494538 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q13635 [ SRS] Q13635 [ EXPASY ] Q13635 [ INTERPRO ]

Prosite PS50156 SSD [ SRS ] PS50156 SSD [ Expasy ]

Interpro IPR003392 Patched [ SRS ] IPR003392 Patched [ EBI ] Interpro IPR004766 Patchedtm_recept [ SRS ] IPR004766 Patchedtm_recept [ EBI ]

Interpro IPR000731 SSD_5TM [ SRS ] IPR000731 SSD_5TM [ EBI ] CluSTr Q13635 Pfam PF02460 Patched [ SRS ] PF02460 Patched [ Sanger ] pfam02460 [ NCBI-CDD ] Blocks Q13635

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -147- Polymorphism : SNP, mutations, diseases OMIM 601309 [ map ] GENECLINICS 601309

SNP PTCH [dbSNP-NCBI]

SNP NM_000264 [SNP-NCI]

SNP PTCH [GeneSNPs - Utah] PTCH [SNP - CSHL] PTCH] [HGBASE - SRS] General knowledge Family PTCH [UCSC Family Browser] Browser SOURCE NM_000264 SMD Hs.494538 SAGE Hs.494538 Amigo process|cell proliferation Amigo function|hedgehog receptor activity Amigo component|integral to plasma membrane Amigo process|morphogenesis Amigo process|negative regulation of cell cycle Amigo function|receptor activity Amigo process|signal transduction BIOCARTA Sonic Hedgehog (SHH) Receptor Ptc1 Regulates cell cycle BIOCARTA Sonic Hedgehog (Shh) Pathway PubGene PTCH Other databases Other Locus specific database; PTCH Mutation Database database Probes Probe PTCH Related clones (RZPD - Berlin) PubMed PubMed 21 Pubmed reference(s) in LocusLink Bibliography The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Tabata T, Eaton S, Kornberg TB Genes Dev 1992 Dec;6(12B):2635-45 Medline 94040725

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

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -148- Medline 94195387

The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development. Capdevila J, Estrada MP, Sanchez-Herrero E, Guerrero I EMBO J 1994 Jan 1;13(1):71-82 Medline 94139676

The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R Nat Genet 1996 Sep;14(1):78-81 Medline 96376974

A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, Dean M, Wainwright B J Biol Chem 1996 May 24;271(21):12125-8 Medline 96218118

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE Cell 1996 Jun 14;85(6):841-51 Medline 96279829

Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP Science 1996 Jun 14;272(5268):1668-71 Medline 96247324

Characterisation of human patched germ line mutations in naevoid basal cell carcinoma syndrome. Lench NJ. Telford EA. High AS. Markham AF. Wicking C. Wainwright BJ. Hum Genet. 1997 Oct;100(5-6):497-502. Medline 98001068

Sporadic medulloblastomas contain PTCH mutations. Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -149- Cancer Res 1997 Mar 1;57(5):842-5 Medline 97193598

Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis. Vorechovsky I, Unden AB, Sandstedt B, Toftgard R, Stahle-Backdahl M Cancer Res 1997 Nov 1;57(21):4677-81 Medline 98014543

Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident. Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S, Suthers G, Haites N, Edwards M, Wainwright B, Chenevix-Trench G Am J Hum Genet 1997 Jan;60(1):21-6 Medline 97136566

Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G Cancer Res 1997 Jul 1;57(13):2581-5 Medline 97349054

Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Xie J. Johnson RL. Zhang X. Bare JW. Waldman FM. Cogen PH. Menon AG. Warren RS. Chen LC. Scott MP. Epstein EH Jr. Cancer Res 1997 Jun 15; 57(12):2369-72 Medline 97336016

Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, Zhang X, Scott MP, Epstein EH Jr J Invest Dermatol 1998 Jun;110(6):885-8 Medline 98281604

Patching together the genetics of Gorlin syndrome Bale SJ, Falk RT, Rogers GR J Cutan Med Surg 1998 Jul;3(1):31-4 Medline 99088403

Dinucleotide repeat polymorphism within the tumor suppressor gene PTCH at 9q22. Louhelainen J. Lindstrom E. Hemminki K. Toftgard R.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -150- Clin Genet 1998 Sep; 54(3):239-41 Medline 99002778

Mutations in the human homologue of the Drosophila patched gene in esophageal squamous cell carcinoma. Maesawa C. Tamura G. Iwaya T. Ogasawara S. Ishida K. Sato N. Nishizuka S. Suzuki Y. Ikeda K. Aoki K. Saito K. Satodate R. Genes Chromosom Cancer 1998; Mar;21(3):276-9

PTCH gene mutations in invasive transitional cell carcinoma of the bladder. McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ, Malkowicz SB Oncogene 1998 Sep 3;17(9):1167-72 Medline 98435856

Mutations of PATCHED in holoprosencephaly. Ming JE, Kaupas ME, Roessler E, Brunner HG, Nance WE, Stratton RF, Sujansky E, Bale Sj, Muenke M Am J Hum Genet 1998; 63 Suppl 140

The naevoid basal-cell carcinoma syndrome (Gorlin syndrome) is a chromosomal instability syndrome. Shafei-Benaissa E, Savage JR, Babin P, Larregue M, Papworth D, Tanzer J, Bonnetblanc JM, Huret JL Mutat Res 1998 Feb 2;397(2):287-92 Medline 98202735

High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum. Bodak N. Queille S. Avril MF. Bouadjar B. Drougard C. Sarasin A. Daya-Grosjean L. Proc Natl Acad Sci USA 1999 Apr 27; 96(9):5117-22. Medline 99238492

The hedgehog signalling pathway and its role in basal cell carcinoma. [Review] Booth DR. Cancer & Metastasis Reviews 1999;18(2):261-84 Medline 20191332

PTCH gene mutations in odontogenic keratocysts. Barreto DC. Gomez RS. Bale AE. Boson WL. De Marco L. J Dent Res 2000 Jun; 79(6):1418-22 Medline 20346776

UV-specific mutations of the human patched gene in basal cell carcinomas from normal individuals and xeroderma pigmentosum patients. [Review] Daya-Grosjean L. Sarasin A Mut Res 2000 May 30;450(1-2):193-9

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -151- Medline 20299177

UV mutation signature in tumor suppressor genes involved in skin carcinogenesis in xeroderma pigmentosum patients. D'Errico M. Calcagnile A. Canzona F. Didona B. Posteraro P. Cavalieri R. Corona R. Vorechovsky I. Nardo T. Stefanini M. Dogliotti E. Oncogene 2000 Jan 20;19(3):463-7 Medline 20120488

Identification of PATCHED mutations in medulloblastomas by direct sequencing. Dong J. Gailani MR. Pomeroy SL. Reardon D. Bale AE. Hum Mut 2000 Jul;16(1):89-90 Medline 20334946

The spectrum of patched mutations in a collection of Australian basal cell carcinomas. Evans T. Boonchai W. Shanley S. Smyth I. Gillies S. Georgas K. Wainwright B. Chenevix-Trench G. Wicking C. Hum Mut 2000;16(1):43-8 Medline 20334495

Hedgehog signaling in animal development and human disease. [Review] Bailey EC. Scott MP. Johnson RL Ernst Schering Research Foundation Workshop. 2000;(29):211-35 Medline 20399009

Hedgehog signalling in cancer. (Review) Toftgård R. Cell Mol Life Sci 2000;(57):1720-1731

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

BiblioGene - INIST

Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -152- Written 05- Jean-Loup Huret 1997 Updated 01- Jean-Loup Huret 1999 Updated 12- Erika Lindström, Rune Toftgård 2000

Citation This paper should be referenced as such : Huret JL . PTCH1. Atlas Genet Cytogenet Oncol Haematol. May 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PTCH100.html Huret JL . PTCH1. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PTCH100.html Lindstrom E, Toftgård R . PTCH1. Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PTCH100.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -153- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TFE3 (transcription factor E3) (updated: old version not available)

Identity Hugo TFE3 Location Xp11.2 DNA/RNA

Description 8 exons Transcription differential splicing removing exon 3 (with dominant negative activity of the resulting protein) Protein

Description 743 amino acids; 80 kDa; N-term acidic transcriptional activation domain (domain 260-271, exon 3), helix-loop-helix (344 -400), leucine zipper (409-430), and a proline/arginine rich sequence (575-743) C-term Expression wide; in fetal and adult tissues Localisation nucleus Function transcription factor; member of the basic helix-loop-helix family (b-HLH) of transcription factors primarily found to bind to the immunoglobulin enchancer muE3 motif, Ig K enhancers and Ig H variable regions promotors; the helix-loop-helix - leucine zipper region is implicated in DNA binding and dimerization (homo and heterodimerizations); mice which lack TFE3 in their B and T lymphocytes reconstitute the B- and T- cell compartments, but IgM levels are reduced Homology to other members of the myc family of helix-loop-helix transcription factors Implicated in Entity t(X;1)(p11.2;q21.2) in renal cell carcinoma --> PRCC/TFE3

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -154- Prognosis overall 5-yr survival rate around 85% Hybrid/Mutated Gene Protein fused to the DNA binding domains of TFE3 (excluding the acidic transcriptional activation domain, including the C-term helix-loop- helix, and the leucine zipper); the reciprocal transcript is found

Entity Alveolar soft part sarcoma with ASPSCR1 -TFE3 fusion Cytogenetics der(X)t(X;17)(p11;q25) is consistently involved; it implicates: 1- the formation of a hybrid gene at the breakpoint, and also, 2- gain in Xp11-pter sequences, and loss of heterozygocity in 11q25-qter, with possible implications Hybrid/Mutated 5' ASPSCR1-3' TFE3; the reciprocal 5' TFE3 - 3' ASPSCR1 is most Gene often absent. ASPSCR1 is fused in frame to TFE3 exon 3 or 4 Abnormal NH2 term ASPSCR1, fused to the C term of TFE3 Protein Oncogenesis might combine the effect of a fusion protein to that of gene(s) dosage

Entity primary renal ASPSCR1-TFE3 tumour Disease a subset of renal cell carcinoma, which presents with a combination of alveolar soft part sarcoma-like features and epithelial features is found to carry this anomaly Cytogenetics balanced t(X;17)(p11.2;q25), in contrast with what is found in the alveolar soft part sarcoma (see above) Hybrid/Mutated 5' ASPSCR1-3' TFE3 Gene Abnormal NH2 term ASPSCR1, fused to the C term of TFE3 Protein

Entity other Xp11 involvements in renal cell carcinoma (t(X;10)(p11;q23), etc ...) are likely to implicate TFE3

Breakpoints

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -156- External links Nomenclature Hugo TFE3 GDB TFE3 Entrez_Gene TFE3 7030 transcription factor binding to IGHM enhancer 3 Cards Atlas TFE3ID86 GeneCards TFE3 Ensembl TFE3 CancerGene TFE3 Genatlas TFE3 GeneLynx TFE3 eGenome TFE3 euGene 7030 Genomic and cartography TFE3 - Xp11.2 chrX:48642490-48657239 - Xp11.23 (hg17- GoldenPath May_2004) Ensembl TFE3 - Xp11.23 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TFE3 Gene and transcription

Genbank X97160 [ SRS ] X97160 [ ENTREZ ]

Genbank X99721 [ SRS ] X99721 [ ENTREZ ]

Genbank AL161985 [ SRS ] AL161985 [ ENTREZ ]

Genbank BC001532 [ SRS ] BC001532 [ ENTREZ ]

Genbank BC026027 [ SRS ] BC026027 [ ENTREZ ]

RefSeq NM_006521 [ SRS ] NM_006521 [ ENTREZ ]

RefSeq NT_086942 [ SRS ] NT_086942 [ ENTREZ ] AceView TFE3 AceView - NCBI TRASER TFE3 Traser - Stanford

Unigene Hs.274184 [ SRS ] Hs.274184 [ NCBI ] HS274184 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P19532 [ SRS] P19532 [ EXPASY ] P19532 [ INTERPRO ]

Prosite PS50888 HLH [ SRS ] PS50888 HLH [ Expasy ]

Interpro IPR001092 HLH_basic [ SRS ] IPR001092 HLH_basic [ EBI ] CluSTr P19532

Pfam PF00010 HLH [ SRS ] PF00010 HLH [ Sanger ] pfam00010 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -157- Blocks P19532 Polymorphism : SNP, mutations, diseases OMIM 314310 [ map ] GENECLINICS 314310

SNP TFE3 [dbSNP-NCBI]

SNP NM_006521 [SNP-NCI]

SNP TFE3 [GeneSNPs - Utah] TFE3 [SNP - CSHL] TFE3] [HGBASE - SRS] General knowledge Family TFE3 [UCSC Family Browser] Browser SOURCE NM_006521 SMD Hs.274184 SAGE Hs.274184 Amigo function|ATP binding Amigo function|catalytic activity Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo process|tRNA aminoacylation for protein translation Amigo function|tRNA ligase activity Amigo function|transcription factor activity Amigo process|transcription from Pol II promoter PubGene TFE3 Other databases Probes Probe TFE3 Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Beckmann H, Su LK, Kadesch T Genes Dev 1990 Feb;4(2):167-79 Medline 90249724

The leucine zipper of TFE3 dictates helix-loop-helix dimerization specificity Beckmann H, Kadesch T Genes Dev 1991 Jun;5(6):1057-66 Medline 91257572

A dominant negative form of transcription activator mTFE3 created by

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -158- differential splicing. Roman C, Cohn L, Calame K Science 1991 Oct 4;254(5028):94-7 Medline 92022552

Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Weterman MA, Wilbrink M, Geurts van Kessel A. Proc Natl Acad Sci USA 1996; 93: 15294-15298. Medline 8986805

The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Sidhar SK, Clark J, Gill S, Hamoudi R, Crew AJ, Gwilliam R, Ross M, Linehan WM, Birdsall S, Shipley J, Cooper CS Hum Mol Genet 1996 Sep;5(9):1333-8 Medline 97026295

The absence of the transcription activator TFE3 impairs activation of B cells in vivo. Merrell K, Wells S, Henderson A, Gorman J, Alt F, Stall A, Calame K Mol Cell Biol 1997 Jun;17(6):3335-44 Medline 97299683

Nuclear localization and transactivating capacities of the papillary renal cell carcinoma-associated TFE3 and PRCC (fusion) proteins. Weterman MJ, van Groningen JJ, Jansen A, van Kessel AG. Oncogene 2000; 19: 69-74. Medline 10644981

The der(17)t(X.17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PHB, Mertens F, Mandahl N, van den Berghe H, Sciot R, dal Cin P, Bridge J. Oncogene 2001; 20: 48-57. Medline 21140288

Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -159- sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M. Am J Pathol 2001; 159: 179-192. Medline 21331068

Transformation capacities of the papillary renal cell carcinoma-associated PRCCTFE3 and TFE3PRCC fusion genes. Weterman MA, van Groningen JJ, den Hartog A, Geurts van Kessel A. Oncogene 2001; 20: 1414-1424. Medline 11313885

Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)- bearing papillary renal cell carcinomas. Heimann P, El Housni H, Ogur G, Weterman MA, Petty EM, Vassart G. Cancer Res 2001; 61: 4130-4135. Medline 11358836

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 01- Jean-Loup Huret and François Desangles 1999 Updated 08- Jean-Loup Huret 2001 Updated 05- Roland P Kuiper 2004 Citation This paper should be referenced as such : Huret JL and Desangles F . TFE3 (transcription factor E3). Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFE3ID86.html Kuiper RP . TFE3 (transcription factor E3). Atlas Genet Cytogenet Oncol Haematol. August 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFE3ID86.html

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -160-

HRAS (Harvey rat sarcoma viral oncogene homolog)

Identity Note more on the RAS family is available as a deep insight. Other c-Ha-ras 1 names Hugo HRAS Location 11p15.5 DNA/RNA Note to be quoted is the existence of a pseudogene, c-Ha-ras 2, inactivated, processed pseudogene which is located on Chromosome X.

H-ras splicing variants : alternative splicing of H-ras precursor mRNA leads to the two transcripts p19 and p21 which differ by the ex- or inclusion of the Intron D Exon (IDX); Exons that encode protein are shown as black boxes, untranslated exons as white boxes; the upstream untranslated exon is indicated as Exon -1

Description consists of six exons, spread over 6.6kb of genomic DNA Transcription alternative RNA splicing reveals two different transcripts (see Fig); if the Intron D Exon (IDX) is skipped exon 4 is directly joined to exon 3 Protein

Description 170 amino acids; 19kDa; shares a common effector region with regular RAS proteins; absence of residues 152-165, abrogating the GDP/GTP binding, and lack of a cysteine residue in the carboxy-terminus preventing the posttranslational modifications essential for the attachment of RAS proteins to the cytoplasmic membrane regular RAS protein - characterized in the RAS family page

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -161- Expression p19H-ras is expected to be produced at a much higher level than p21H- ras; the surprising low abundance of p19H-ras could be explained by instability of mRNA or unproductive splicing ubiquitously expressed Localisation cytoplasmic anchored to the inner surface of the plasma membrane Function no oncogenic ability; it has been assumed, that p19H-ras might act as a antagonist to p21H-ras; due to the intact effector region it would interact constitutively with candidate effector molecules or regulators such as GAP, thereby suppressing the biological function of p21H-ras; additionally the expression of p19H-ras was found to limit the production of p21H-ras analogously to other GTP-binding proteins (such as Translation Elongation Factor EFTu or signal transducing G-Proteins) RAS proteins are involved in signal transduction pathways Homology RAS, RAL, RAC, RHO, RAP, and RAB ras gene family is part of the ras superfamily including the mammalian RAS, RAL, RAC, RHO, RAP, and RAB gene families and the yeast homologs like SEC4 and YPT1 genes; genes encode small monomeric proteins of low molecular mass (20-30 kDa) which share at least 30% homology with RAS proteins. Implicated in Entity tumor (frequency of H-RAS mutations); references in Full Bibliography

Entity stomach (0-40%)

Entity urinary bladder (0-65%)

Entity prostate (0-10%)

Entity skin (0-45%)

Entity thyroid (0-60%)

Entity breast (0-10%)

Entity head and neck (0-30%)

Entity endometrium (5%)

External links Nomenclature Hugo HRAS GDB HRAS

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -162- Entrez_Gene HRAS 3265 v-Ha-ras Harvey rat sarcoma viral oncogene homolog Cards Atlas HRASID108 GeneCards HRAS Ensembl HRAS CancerGene HRAS Genatlas HRAS GeneLynx HRAS eGenome HRAS euGene 3265 Genomic and cartography HRAS - 11p15.5 chr11:522243-525550 - 11p15.5 (hg17- GoldenPath May_2004) Ensembl HRAS - 11p15.5 [CytoView]

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

Genbank AF375987 [ SRS ] AF375987 [ ENTREZ ]

Genbank J00277 [ SRS ] J00277 [ ENTREZ ]

Genbank K00654 [ SRS ] K00654 [ ENTREZ ]

Genbank M17232 [ SRS ] M17232 [ ENTREZ ]

Genbank M19990 [ SRS ] M19990 [ ENTREZ ]

RefSeq NM_005343 [ SRS ] NM_005343 [ ENTREZ ]

RefSeq NM_176795 [ SRS ] NM_176795 [ ENTREZ ]

RefSeq NT_086778 [ SRS ] NT_086778 [ ENTREZ ] AceView HRAS AceView - NCBI TRASER HRAS Traser - Stanford

Unigene Hs.505033 [ SRS ] Hs.505033 [ NCBI ] HS505033 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P01112 [ SRS] P01112 [ EXPASY ] P01112 [ INTERPRO ]

Interpro IPR001806 Ras_trnsfrmng [ SRS ] IPR001806 Ras_trnsfrmng [ EBI ]

Interpro IPR005225 Small_GTP [ SRS ] IPR005225 Small_GTP [ EBI ] CluSTr P01112

Pfam PF00071 Ras [ SRS ] PF00071 Ras [ Sanger ] pfam00071 [ NCBI-CDD ] Blocks P01112

PDB 121P [ SRS ] 121P [ PdbSum ], 121P [ IMB ]

PDB 1AA9 [ SRS ] 1AA9 [ PdbSum ], 1AA9 [ IMB ]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -163- PDB 1AGP [ SRS ] 1AGP [ PdbSum ], 1AGP [ IMB ]

PDB 1BKD [ SRS ] 1BKD [ PdbSum ], 1BKD [ IMB ]

PDB 1CLU [ SRS ] 1CLU [ PdbSum ], 1CLU [ IMB ]

PDB 1CRP [ SRS ] 1CRP [ PdbSum ], 1CRP [ IMB ]

PDB 1CRQ [ SRS ] 1CRQ [ PdbSum ], 1CRQ [ IMB ]

PDB 1CRR [ SRS ] 1CRR [ PdbSum ], 1CRR [ IMB ]

PDB 1CTQ [ SRS ] 1CTQ [ PdbSum ], 1CTQ [ IMB ]

PDB 1GNP [ SRS ] 1GNP [ PdbSum ], 1GNP [ IMB ]

PDB 1GNQ [ SRS ] 1GNQ [ PdbSum ], 1GNQ [ IMB ]

PDB 1GNR [ SRS ] 1GNR [ PdbSum ], 1GNR [ IMB ]

PDB 1HE8 [ SRS ] 1HE8 [ PdbSum ], 1HE8 [ IMB ]

PDB 1IAQ [ SRS ] 1IAQ [ PdbSum ], 1IAQ [ IMB ]

PDB 1IOZ [ SRS ] 1IOZ [ PdbSum ], 1IOZ [ IMB ]

PDB 1JAH [ SRS ] 1JAH [ PdbSum ], 1JAH [ IMB ]

PDB 1JAI [ SRS ] 1JAI [ PdbSum ], 1JAI [ IMB ]

PDB 1K8R [ SRS ] 1K8R [ PdbSum ], 1K8R [ IMB ]

PDB 1LF0 [ SRS ] 1LF0 [ PdbSum ], 1LF0 [ IMB ]

PDB 1LF5 [ SRS ] 1LF5 [ PdbSum ], 1LF5 [ IMB ]

PDB 1LFD [ SRS ] 1LFD [ PdbSum ], 1LFD [ IMB ]

PDB 1NVU [ SRS ] 1NVU [ PdbSum ], 1NVU [ IMB ]

PDB 1NVV [ SRS ] 1NVV [ PdbSum ], 1NVV [ IMB ]

PDB 1NVW [ SRS ] 1NVW [ PdbSum ], 1NVW [ IMB ]

PDB 1NVX [ SRS ] 1NVX [ PdbSum ], 1NVX [ IMB ]

PDB 1P2S [ SRS ] 1P2S [ PdbSum ], 1P2S [ IMB ]

PDB 1P2T [ SRS ] 1P2T [ PdbSum ], 1P2T [ IMB ]

PDB 1P2U [ SRS ] 1P2U [ PdbSum ], 1P2U [ IMB ]

PDB 1P2V [ SRS ] 1P2V [ PdbSum ], 1P2V [ IMB ]

PDB 1PLJ [ SRS ] 1PLJ [ PdbSum ], 1PLJ [ IMB ]

PDB 1PLK [ SRS ] 1PLK [ PdbSum ], 1PLK [ IMB ]

PDB 1PLL [ SRS ] 1PLL [ PdbSum ], 1PLL [ IMB ]

PDB 1Q21 [ SRS ] 1Q21 [ PdbSum ], 1Q21 [ IMB ]

PDB 1QRA [ SRS ] 1QRA [ PdbSum ], 1QRA [ IMB ]

PDB 1RVD [ SRS ] 1RVD [ PdbSum ], 1RVD [ IMB ]

PDB 1WQ1 [ SRS ] 1WQ1 [ PdbSum ], 1WQ1 [ IMB ]

PDB 221P [ SRS ] 221P [ PdbSum ], 221P [ IMB ]

PDB 2Q21 [ SRS ] 2Q21 [ PdbSum ], 2Q21 [ IMB ]

PDB 421P [ SRS ] 421P [ PdbSum ], 421P [ IMB ]

PDB 4Q21 [ SRS ] 4Q21 [ PdbSum ], 4Q21 [ IMB ]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -164- PDB 521P [ SRS ] 521P [ PdbSum ], 521P [ IMB ]

PDB 5P21 [ SRS ] 5P21 [ PdbSum ], 5P21 [ IMB ]

PDB 621P [ SRS ] 621P [ PdbSum ], 621P [ IMB ]

PDB 6Q21 [ SRS ] 6Q21 [ PdbSum ], 6Q21 [ IMB ]

PDB 721P [ SRS ] 721P [ PdbSum ], 721P [ IMB ]

PDB 821P [ SRS ] 821P [ PdbSum ], 821P [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 190020 [ map ] GENECLINICS 190020

SNP HRAS [dbSNP-NCBI]

SNP NM_005343 [SNP-NCI]

SNP NM_176795 [SNP-NCI]

SNP HRAS [GeneSNPs - Utah] HRAS [SNP - CSHL] HRAS] [HGBASE - SRS] General knowledge Family HRAS [UCSC Family Browser] Browser SOURCE NM_005343 SOURCE NM_176795 SMD Hs.505033 SAGE Hs.505033 Amigo function|GTP binding Amigo function|GTPase activity Amigo process|cell motility Amigo process|cell surface receptor linked signal transduction Amigo process|chemotaxis Amigo component|cytoplasm Amigo process|organogenesis Amigo component|plasma membrane Amigo process|regulation of cell cycle Amigo process|small GTPase mediated signal transduction Angiotensin II mediated activation of JNK Pathway via Pyk2 BIOCARTA dependent signaling BIOCARTA CCR3 signaling in Eosinophils BIOCARTA Calcium Signaling by HBx of Hepatitis B virus BIOCARTA Influence of Ras and Rho proteins on G1 to S Transition BIOCARTA TPO Signaling Pathway Roles of ß-arrestin-dependent Recruitment of Src Kinases in GPCR BIOCARTA Signaling BIOCARTA BCR Signaling Pathway

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -165- BIOCARTA Bioactive Peptide Induced Signaling Pathway Role of EGF Receptor Transactivation by GPCRs in Cardiac BIOCARTA Hypertrophy BIOCARTA Cadmium induces DNA synthesis and proliferation in macrophages Phosphorylation of MEK1 by cdk5/p35 down regulates the MAP BIOCARTA kinase pathway BIOCARTA Transcription factor CREB and its extracellular signals BIOCARTA CXCR4 Signaling Pathway Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal BIOCARTA Epithelia BIOCARTA EGF Signaling Pathway BIOCARTA EPO Signaling Pathway BIOCARTA Role of Erk5 in Neuronal Survival BIOCARTA Erk1/Erk2 Mapk Signaling pathway BIOCARTA METS affect on Macrophage Differentiation BIOCARTA fMLP induced chemokine gene expression in HMC-1 cells BIOCARTA Fc Epsilon Receptor I Signaling in Mast Cells BIOCARTA Growth Hormone Signaling Pathway BIOCARTA Inhibition of Cellular Proliferation by Gleevec BIOCARTA Signaling Pathway from G-Protein Families BIOCARTA Role of ERBB2 in Signal Transduction and Oncology BIOCARTA IGF-1 Signaling Pathway Multiple antiapoptotic pathways from IGF-1R signaling lead to BAD BIOCARTA phosphorylation BIOCARTA IL 2 signaling pathway BIOCARTA IL-2 Receptor Beta Chain in T cell Activation BIOCARTA IL 3 signaling pathway BIOCARTA IL 6 signaling pathway BIOCARTA Insulin Signaling Pathway BIOCARTA Integrin Signaling Pathway BIOCARTA Keratinocyte Differentiation BIOCARTA The IGF-1 Receptor and Longevity BIOCARTA mCalpain and friends in Cell motility BIOCARTA How Progesterone Initiates the Oocyte Maturation BIOCARTA Role of MAL in Rho-Mediated Activation of SRF BIOCARTA MAPKinase Signaling Pathway BIOCARTA Signaling of Hepatocyte Growth Factor Receptor NFAT and Hypertrophy of the heart (Transcription in the broken BIOCARTA heart)

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -166- BIOCARTA Nerve growth factor pathway (NGF) BIOCARTA p38 MAPK Signaling Pathway BIOCARTA PDGF Signaling Pathway BIOCARTA Regulation of transcriptional activity by PML BIOCARTA Links between Pyk2 and Map Kinases BIOCARTA Ras Signaling Pathway BIOCARTA Inhibition of Matrix Metalloproteinases BIOCARTA Regulation of Splicing through Sam68 BIOCARTA Aspirin Blocks Signaling Pathway Involved in Platelet Activation BIOCARTA Sprouty regulation of tyrosine kinase signals BIOCARTA T Cell Receptor Signaling Pathway BIOCARTA Trefoil Factors Initiate Mucosal Healing BIOCARTA Trka Receptor Signaling Pathway BIOCARTA VEGF, Hypoxia, and Angiogenesis KEGG PubGene HRAS Other databases Other Somatic mutation (COSMIC-CGP-Sanger) database Probes Probe Cancer Cytogenetics (Bari) Probe HRAS Related clones (RZPD - Berlin) PubMed PubMed 38 Pubmed reference(s) in LocusLink Bibliography A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Kraus MH, Yuasa Y, Aaronson SA Proc Natl Acad Sci U S A 1984 Sep;81(17):5384-8 Medline 84298143

Oncogenes and bladder cancer. Malone PR, Visvanathan KV, Ponder BA, Shearer RJ, Summerhayes IC Br J Urol 1985 Dec;57(6):664-7 Medline 86104868

A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Fusco A, Grieco M, Santoro M, Berlingieri MT, Pilotti S, Pierotti MA, Della Porta G, Vecchio G Nature 1987 Jul 9-15;328(6126):170-2

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -167- Medline 87258234

Human cancer and cellular oncogenes. Nishimura S, Sekiya T Biochem J 1987 Apr 15;243(2):313-27 Medline 87326252

Oncogene activation in malignant transformation: a study of H-ras in human breast cancer. Spandidos DA Anticancer Res 1987 Sep-Oct;7(5B):991-6 Medline 88132560

Activated ras oncogenes in human thyroid cancers. Lemoine NR, Mayall ES, Wyllie FS, Farr CJ, Hughes D, Padua RA, Thurston V, Williams ED, Wynford-Thomas D Cancer Res 1988 Aug 15;48(16):4459-63 Medline 88282371

Detection of activated ras oncogenes in human thyroid carcinomas. Suarez HG, Du Villard JA, Caillou B, Schlumberger M, Tubiana M, Parmentier C, Monier R Oncogene 1988 Apr;2(4):403-6 Medline 88202933

Preferential and novel activation of H-ras in human bladder carcinomas. Visvanathan KV, Pocock RD, Summerhayes IC Oncogene Res 1988;3(1):77-86 Medline 89083213 ras oncogenes in human cancer: a review. Bos JL Cancer Res 1989 Sep 1;49(17):4682-9 Published erratum appears in Cancer Res 1990 Feb 15;50(4):1352 Medline 89336671

Expression of the H-ras proto-oncogene is controlled by alternative splicing. Cohen JB, Broz SD, Levinson AD Cell 1989 Aug 11;58(3):461-72 Medline 89336778

High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Lemoine NR, Mayall ES, Wyllie FS, Williams ED, Goyns M, Stringer B, Wynford- Thomas D Oncogene 1989 Feb;4(2):159-64

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -168- Medline 89183149 ras oncogenes: their role in neoplasia. Barbacid M Eur J Clin Invest 1990 Jun;20(3):225-35 Medline 90316140 ras gene mutations in human prostate cancer. Carter BS, Epstein JI, Isaacs WB Cancer Res 1990 Nov 1;50(21):6830-2 Medline 91004047

Infrequent point mutations of ras oncogenes in gastric cancers. Nanus DM, Kelsen DP, Mentle IR, Altorki N, Albino AP Gastroenterology 1990 Apr;98(4):955-60 Medline 90185017

Low incidence of ras oncogene activation in human squamous cell carcinomas. Rumsby G, Carter RL, Gusterson BA Br J Cancer 1990 Mar;61(3):365-8 Medline 90226976

No evidence for point mutations in codons 12, 13, and 61 of the ras gene in a high-incidence area for esophageal and gastric cancers. Victor T, Du Toit R, Jordaan AM, Bester AJ, van Helden PD Cancer Res 1990 Aug 15;50(16):4911-4 Medline 90335785

Correlation of mutations of oncogene C-Ha-ras at codon 12 with metastasis and survival of gastric cancer patients. Deng GR, Liu XH, Wang JR Oncogene Res 1991;6(1):33-8 Medline 91149077

Activated ras alleles in human carcinoma of the prostate are rare. Gumerlock PH, Poonamallee UR, Meyers FJ, deVere White RW Cancer Res 1991 Mar 15;51(6):1632-7 Medline 91152721

K-ras activation in gastric epithelial tumors in Japanese. Miki H, Ohmori M, Perantoni AO, Enomoto T Cancer Lett 1991 Jun 14;58(1-2):107-13 Medline 91266255

High frequency mutation in codons 12 and 61 of H-ras oncogene in chewing

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -169- tobacco-related human oral carcinoma in India. Saranath D, Chang SE, Bhoite LT, Panchal RG, Kerr IB, Mehta AR, Johnson NW, Deo MG Br J Cancer 1991 Apr;63(4):573-8 Medline 91214820 ras activation in experimental carcinogenesis. Mangues R, Pellicer A Semin Cancer Biol 1992 Aug;3(4):229-39 Medline 93043055

Mapping of UV photoproducts within ras proto-oncogenes in UV-irradiated cells: correlation with mutations in human skin cancer. Tormanen VT, Pfeifer GP Oncogene 1992 Sep;7(9):1729-36 Medline 92366157

Codon 12 Harvey-ras mutations are rare events in non-melanoma human skin cancer. Campbell C, Quinn AG, Rees JL Br J Dermatol 1993 Feb;128(2):111-4 Medline 93207972

The absence of Harvey ras mutations during development and progression of squamous cell carcinomas of the head and neck. Clark LJ, Edington K, Swan IR, McLay KA, Newlands WJ, Wills LC, Young HA, Johnston PW, Mitchell R, Robertson G, et al Br J Cancer 1993 Sep;68(3):617-20 Medline 93357163

Mutations, expression and genomic instability of the H-ras proto-oncogene in squamous cell carcinomas of the head and neck. Kiaris H, Spandidos DA, Jones AS, Vaughan ED, Field JK Br J Cancer 1995 Jul;72(1):123-8 Medline 95322291

Ras oncogene mutations in thyroid tumors: polymerase chain reaction- restriction-fragment-length polymorphism analysis from paraffin-embedded tissues. Capella G, Matias-Guiu X, Ampudia X, de Leiva A, Perucho M, Prat J Diagn Mol Pathol 1996 Mar;5(1):45-52 Medline 97078621

A PCR-RFLP method for the detection of activated H-ras oncogene with a point mutation at codon 12 and 61. Hong SJ, Lee T, Park YS, Lee KO, Chung BH, Lee SH

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -170- Yonsei Med J 1996 Dec;37(6):371-9 Medline 97200567 ras gene mutations in human endometrial carcinoma. Varras MN, Koffa M, Koumantakis E, Ergazaki M, Protopapa E, Michalas S, Spandidos DA Oncology 1996 Nov-Dec;53(6):505-10 Medline 97119324

A splicing enhancer in the 3'-terminal c-H-ras exon influences mRNA abundance and transforming activity. Hwang DY, Cohen JB J Virol 1997 Sep;71(9):6416-26 Medline 97404647

Mutation of ras oncogene in gastric adenocarcinoma: association with histological phenotype. Kim TY, Bang YJ, Kim WS, Kang SH, Lee KU, Choe KJ, Kim NK Anticancer Res 1997 Mar-Apr;17(2B):1335-9 Medline 97283361

Comparison of ras activation in prostate carcinoma in Japanese and American men. Konishi N, Hiasa Y, Tsuzuki T, Tao M, Enomoto T, Miller GJ Prostate 1997 Jan 1;30(1):53-7 Medline 97171063

Screening of H-ras gene point mutations in 50 cases of bladder carcinoma. Saito S, Hata M, Fukuyama R, Sakai K, Kudoh J, Tazaki H, Shimizu N Int J Urol 1997 Mar;4(2):178-85 Medline 97323203

Variability of Ha-ras (codon 12) proto-oncogene mutations in diverse thyroid cancers. Bouras M, Bertholon J, Dutrieux-Berger N, Parvaz P, Paulin C, Revol A Eur J Endocrinol 1998 Aug;139(2):209-16 Medline 98389472

Low-frequency mutation of Ha-ras and Ki-ras oncogenes in transitional cell carcinoma of the bladder. Olderoy G, Daehlin L, Ogreid D Anticancer Res 1998 Jul-Aug;18(4A):2675-8 Medline 98369550

Mutations of ras genes are relatively frequent in Japanese prostate cancers: pointing to genetic differences between populations.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -171- Shiraishi T, Muneyuki T, Fukutome K, Ito H, Kotake T, Watanabe M, Yatani R Anticancer Res 1998 Jul-Aug;18(4B):2789-92 Medline 98379084

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Franz Watzinger and Thomas Lion 1999 Citation This paper should be referenced as such : Watzinger F and Lion T . HRAS (Harvey rat sarcoma viral oncogene homolog). Atlas Genet Cytogenet Oncol Haematol. February 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/HRASID108.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -172- Atlas of Genetics and Cytogenetics in Oncology and Haematology

K-RAS (Kirsten rat sarcoma 2 viral oncogene homolog)

Identity Note more on the RAS family is available as a deep insight Other c-Ki-ras 2 names Hugo KRAS Location 12p12 DNA/RNA

K-ras splicing variants alternative splicing of K-ras precursor mRNA leads to the two transcripts which differ by the ex- or inclusion of Exon 4a; Exons that encode protein are shown as black boxes, untranslated exons as white boxes; the upstream untranslated exon is indicated as Exon -1

Description consists of six exons, spread over 35kb of genomic DNA. Transcription alternative RNA splicing reveals two different transcripts of 5.5 and 3.8kb (see Fig); if Exon 4a is skipped exon 4b is directly joined to exon 3; in 98% of the transcripts exon 4a is spliced out and only exon 4b is available for translation into protein. Pseudogene c-Ki-ras 1, inactivated, processed pseudogene which is located on Chromosome 6 Protein

Description regular RAS protein - characterized in the RAS family page.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -173- Expression ubiquitously expressed Localisation anchored to the inner surface of the plasma membrane Function analogously to other GTP-binding proteins (such as Translation Elongation Factor EFTu or signal transducing G-Proteins) RAS proteins are involved in signal transduction pathways Homology ras gene family is part of the ras superfamily including the mammalian RAS, RAL, RAC, RHO, RAP, and RAB gene families and the yeast homologs like SEC4 and YPT1 genes; genes encode small monomeric proteins of low molecular mass (20-30 kDa) which share at least 30% homology to RAS proteins. Implicated in Entity tumor (frequency of K-RAS mutations); references in Full Bibliography

Entity pancreas (80-90%)

Entity colon and rectum (25-60%)

Entity lung (25-60%)

Entity prostate (0-25%)

Entity skin (0-25%)

Entity thyroid (0-60%)

Entity liver (10-25%)

Entity ovary (0-50%)

Entity endometrium (10-40%)

Entity kidney (0-50%)

Entity brain (0-15%)

Entity testis (seminoma) (10-45%)

Entity acute non lymphocytic leukemia and myelodysplasia (5-15%)

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -174- Entity urinary bladder (5%)

Entity head and neck (10%)

Entity breast (10%)

External links Nomenclature Hugo KRAS GDB KRAS Entrez_Gene KRAS 3845 v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog Cards Atlas KRASID91 GeneCards KRAS Ensembl KRAS CancerGene KRAS2 Genatlas KRAS GeneLynx KRAS eGenome KRAS euGene 3845

Genomic and cartography KRAS - 12p12 chr12:25249447-25295121 - 12p12.1 (hg17- GoldenPath May_2004) Ensembl KRAS - 12p12.1 [CytoView]

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

Genbank K03210 [ SRS ] K03210 [ ENTREZ ]

Genbank L00044 [ SRS ] L00044 [ ENTREZ ]

Genbank L00045 [ SRS ] L00045 [ ENTREZ ]

Genbank L00048 [ SRS ] L00048 [ ENTREZ ]

Genbank L00049 [ SRS ] L00049 [ ENTREZ ]

RefSeq NM_004985 [ SRS ] NM_004985 [ ENTREZ ]

RefSeq NM_033360 [ SRS ] NM_033360 [ ENTREZ ]

RefSeq NT_086793 [ SRS ] NT_086793 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -175- AceView KRAS AceView - NCBI TRASER KRAS Traser - Stanford

Unigene Hs.505033 [ SRS ] Hs.505033 [ NCBI ] HS505033 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P01116 [ SRS] P01116 [ EXPASY ] P01116 [ INTERPRO ]

Interpro IPR003577 GTPase_Ras [ SRS ] IPR003577 GTPase_Ras [ EBI ]

Interpro IPR001806 Ras_trnsfrmng [ SRS ] IPR001806 Ras_trnsfrmng [ EBI ]

Interpro IPR005225 Small_GTP [ SRS ] IPR005225 Small_GTP [ EBI ] CluSTr P01116

Pfam PF00071 Ras [ SRS ] PF00071 Ras [ Sanger ] pfam00071 [ NCBI-CDD ]

Smart SM00173 RAS [EMBL] Blocks P01116

PDB 1D8D [ SRS ] 1D8D [ PdbSum ], 1D8D [ IMB ]

PDB 1D8E [ SRS ] 1D8E [ PdbSum ], 1D8E [ IMB ]

PDB 1KZO [ SRS ] 1KZO [ PdbSum ], 1KZO [ IMB ]

PDB 1KZP [ SRS ] 1KZP [ PdbSum ], 1KZP [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 190070 [ map ] GENECLINICS 190070

SNP KRAS [dbSNP-NCBI]

SNP NM_004985 [SNP-NCI]

SNP NM_033360 [SNP-NCI]

SNP KRAS [GeneSNPs - Utah] KRAS [SNP - CSHL] KRAS] [HGBASE - SRS] General knowledge Family KRAS [UCSC Family Browser] Browser SOURCE NM_004985 SOURCE NM_033360 SMD Hs.505033 SAGE Hs.505033 Amigo function|GTP binding Amigo function|GTPase activity Amigo process|regulation of cell cycle Amigo process|small GTPase mediated signal transduction BIOCARTA Telomeres, Telomerase, Cellular Aging, and Immortality PubGene KRAS Other databases Other Somatic mutation (COSMIC-CGP-Sanger)

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -176- database Probes Probe KRAS Related clones (RZPD - Berlin) PubMed PubMed 67 Pubmed reference(s) in LocusLink Bibliography Human cancer and cellular oncogenes. Nishimura S, Sekiya T Biochem J 1987 Apr 15;243(2):313-27 Medline 87326252 ras oncogenes in human cancer: a review. Bos JL Cancer Res 1989 Sep 1;49(17):4682-9 Published erratum appears in Cancer Res 1990 Feb 15;50(4):1352 Medline 89336671 ras oncogenes: their role in neoplasia. Barbacid M Eur J Clin Invest 1990 Jun;20(3):225-35 Medline 90316140 ras activation in experimental carcinogenesis. Mangues R, Pellicer A Semin Cancer Biol 1992 Aug;3(4):229-39 Medline 93043055

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

BiblioGene - INIST

Contributor(s)

Written 02- Franz Watzinger and Thomas Lion 1999

Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -177- Watzinger F and Lion T . K-RAS (Kirsten rat sarcoma 2 viral oncogene homolog). Atlas Genet Cytogenet Oncol Haematol. February 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/KRASID91.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -178- Atlas of Genetics and Cytogenetics in Oncology and Haematology

N-RAS (neuroblastoma RAS viral oncogene homolog)

Identity Note more on the RAS family is available as a deep insight Hugo NRAS Location 1p13 DNA/RNA

evolution of two N-ras mRNA transcripts the slightly differing consensus sequence of the poly A addition site (AATATA instead of AATAAA) leads to inefficient processing and to two different RNA transcripts; exons that encode protein are shown as black boxes, untranslated exons as white boxes; the upstream untranslated exon is indicated as Exon -1

Description consists of seven exons, spread over 8kb of genomic DNA Transcription inefficient processing of pre-mRNA reveals two different transcripts of 4.3kb and 2kb (see Fig), differing in the extension of the 3« end of the smaller message; the longer transcript is probably a result of an RNA- extension through the termination site Protein

Description p21N-ras; regular RAS protein - characterized in the page Expression ubiquitously expressed Localisation anchored to the inner surface of the plasma membrane Function analogously to other GTP-binding proteins (such as Translation

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -179- Elongation Factor EFTu or signal transducing G-Proteins) RAS proteins are involved in signal transduction pathways Homology ras gene family is part of the ras superfamily including the mammalian RAS, RAL, RAC, RHO, RAP, and RAB gene families and the yeast homologs like SEC4 and YPT1 genes; genes encode small monomeric proteins of low molecular mass (20-30 kDa) which share at least 30% homology to RAS proteins Implicated in Entity tumor (frequency of N-RAS mutations); references in Full Bibliography

Entity acute non lymphocytic leukemia and myelodysplasia (20-40%)

Entity chronic myelogenous leukemia, acute lymphocytic leukemia (0-10%)

Entity brain (0-15%)

Entity skin (0-20%)

Entity thyroid (0-60%)

Entity testis (0-40%)

Entity stomach (gastric tumors) (5%)

Entity testis liver (0-15%)

External links Nomenclature Hugo NRAS GDB NRAS Entrez_Gene NRAS 4893 neuroblastoma RAS viral (v-ras) oncogene homolog Cards Atlas NRASID92 GeneCards NRAS Ensembl NRAS CancerGene NRAS Genatlas NRAS GeneLynx NRAS

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -180- eGenome NRAS euGene 4893 Genomic and cartography NRAS - 1p13 chr1:114961627-114971557 - 1p13.1 (hg17- GoldenPath May_2004) Ensembl NRAS - 1p13.1 [CytoView]

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

Genbank AL096773 [ SRS ] AL096773 [ ENTREZ ]

Genbank AY428630 [ SRS ] AY428630 [ ENTREZ ]

Genbank K03211 [ SRS ] K03211 [ ENTREZ ]

Genbank L00043 [ SRS ] L00043 [ ENTREZ ]

Genbank M25898 [ SRS ] M25898 [ ENTREZ ]

RefSeq NM_002524 [ SRS ] NM_002524 [ ENTREZ ]

RefSeq NT_086588 [ SRS ] NT_086588 [ ENTREZ ] AceView NRAS AceView - NCBI TRASER NRAS Traser - Stanford

Unigene Hs.486502 [ SRS ] Hs.486502 [ NCBI ] HS486502 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P01111 [ SRS] P01111 [ EXPASY ] P01111 [ INTERPRO ]

Interpro IPR001806 Ras_trnsfrmng [ SRS ] IPR001806 Ras_trnsfrmng [ EBI ]

Interpro IPR005225 Small_GTP [ SRS ] IPR005225 Small_GTP [ EBI ] CluSTr P01111

Pfam PF00071 Ras [ SRS ] PF00071 Ras [ Sanger ] pfam00071 [ NCBI-CDD ] Blocks P01111 Polymorphism : SNP, mutations, diseases OMIM 164790 [ map ] GENECLINICS 164790

SNP NRAS [dbSNP-NCBI]

SNP NM_002524 [SNP-NCI]

SNP NRAS [GeneSNPs - Utah] NRAS [SNP - CSHL] NRAS] [HGBASE - SRS] General knowledge Family NRAS [UCSC Family Browser] Browser SOURCE NM_002524 SMD Hs.486502

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -181- SAGE Hs.486502 Amigo function|GTP binding Amigo function|GTPase activity Amigo process|regulation of cell cycle Amigo process|small GTPase mediated signal transduction PubGene NRAS Other databases Other Somatic mutation (COSMIC-CGP-Sanger) database Probes Probe NRAS Related clones (RZPD - Berlin) PubMed PubMed 25 Pubmed reference(s) in LocusLink Bibliography Transforming ras genes from human melanoma: amanifestation of tumour heterogeneity? Albino AP, Le Strange R, Oliff AI, Furth ME, Old LJ Nature 1984 Mar 1-7;308(5954):69-72 Medline 84142253

Human cancer and cellular oncogenes. Nishimura S, Sekiya T Biochem J 1987 Apr 15;243(2):313-27 Medline 87326252

Incidence of ras gene mutations in neuroblastoma. Ballas K, Lyons J, Janssen JW, Bartram CR Eur J Pediatr 1988 Apr;147(3):313-4 Medline 88271474

The ras gene family and human carcinogenesis. Bos JL Mutat Res 1988 May;195(3):255-71 Medline 88201992

Activated ras oncogenes in human thyroid cancers.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -182- Lemoine NR, Mayall ES, Wyllie FS, Farr CJ, Hughes D, Padua RA, Thurston V, Williams ED, Wynford-Thomas D Cancer Res 1988 Aug 15;48(16):4459-63 Medline 88282371

Detection of activated ras oncogenes in human thyroid carcinomas. Suarez HG, Du Villard JA, Caillou B, Schlumberger M, Tubiana M, Parmentier C, Monier R Oncogene 1988 Apr;2(4):403-6 Medline 88202933 ras oncogenes in human cancer: a review. Bos JL Cancer Res 1989 Sep 1;49(17):4682-9 Published erratum appears in Cancer Res 1990 Feb 15;50(4):1352 Medline 89336671

Activated ras genes in human seminoma: evidence for tumor heterogeneity. Mulder MP, Keijzer W, Verkerk A, Boot AJ, Prins ME, Splinter TA, Bos JL Oncogene 1989 Nov;4(11):1345-51 Medline 90045478

N-ras mutations in human cutaneous melanoma from sun-exposed body sites. van 't Veer LJ, Burgering BM, Versteeg R, Boot AJ, Ruiter DJ, Osanto S, Schrier PI, Bos JL Mol Cell Biol 1989 Jul;9(7):3114-6 Medline 89384576 ras oncogenes: their role in neoplasia. Barbacid M Eur J Clin Invest 1990 Jun;20(3):225-35 Medline 90316140

Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Tada M, Omata M, Ohto M Cancer Res 1990 Feb 15;50(4):1121-4 Medline 90124317

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -183- No N-ras mutations in human uveal melanoma: therole of ultraviolet light revisited. Mooy CM, Van der Helm MJ, Van der Kwast TH, De Jong PT, Ruiter DJ, Zwarthoff EC Br J Cancer 1991 Aug;64(2):411-3 Medline 91369845

Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. Challen C, Guo K, Collier JD, Cavanagh D, Bassendine MF J Hepatol 1992 Mar;14(2-3):342-6 Medline 92364281 ras activation in experimental carcinogenesis. Mangues R, Pellicer A Semin Cancer Biol 1992 Aug;3(4):229-39 Medline 93043055

Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization. Moul JW, Theune SM, Chang EH Genes Chromosomes Cancer 1992 Sep;5(2):109-18 Medline 92399340

Multiple point mutation of N-ras and K-ras oncogenes in myelodysplastic syndrome and acute myelogenous leukemia. Nakagawa T, Saitoh S, Imoto S, Itoh M, Tsutsumi M, Hikiji K, Nakamura H, Matozaki S, Ogawa R, Nakao Y, et al Oncology 1992;49(2):114-22 Medline 92244551

High incidence of ras gene mutation in intrahepatic cholangiocarcinoma. Tada M, Omata M, Ohto M Cancer 1992 Mar 1;69(5):1115-8 Medline 92154554

N-ras gene mutations in acute myeloid leukemia: accurate detection by solid- phase minisequencing. Syvanen AC, Soderlund H, Laaksonen E, Bengtstrom M, Turunen M, Palotie A Int J Cancer 1992 Mar 12;50(5):713-8 Medline 92184378

K-ras oncogene codon 12 point mutations in testicular cancer. Ridanpaa M, Lothe RA, Onfelt A, Fossa S, Borresen AL, Husgafvel-Pursiainen K Environ Health Perspect 1993 Oct;101 Suppl 3:185-7 Medline 94192547

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -184-

Investigation of the role of the ras protooncogene point mutation in human uveal melanomas. Soparker CN, O'Brien JM, Albert DM Invest Ophthalmol Vis Sci 1993 Jun;34(7):2203-9 Medline 93279936

Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Neubauer A, Dodge RK, George SL, Davey FR, Silver RT, Schiffer CA, Mayer RJ, Ball ED, Wurster-Hill D, Bloomfield CD, et al Blood 1994 Mar 15;83(6):1603-11 Medline 94169375

Absence of N-ras mutations in myeloid and lymphoid blast crisis of chronic myeloid leukemia. Watzinger F, Gaiger A, Karlic H, Becher R, Pillwein K, Lion T Cancer Res 1994 Jul 15;54(14):3934-8 Medline 94306408

N-ras gene point mutations in Brazilian acute myelogenous leukemia patients correlate with a poor prognosis. De Melo MB, Lorand-Metze I, Lima CS, Saad ST, Costa FF Leuk Lymphoma 1997 Jan;24(3-4):309-17 Medline 97206099

Ras oncogene mutations in childhood brain tumors. Maltzman TH, Mueller BA, Schroeder J, Rutledge JC, Patterson K, Preston-Martin S, Faustman EM Cancer Epidemiol Biomarkers Prev 1997 Apr;6(4):239-43 Medline 97261501

RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -185- 10-year follow-up. Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, Ridge S, Carter G, White D, Oscier D, Chevret S, West R Leukemia 1998 Jun;12(6):887-92 Medline 98301287

Correlation of N-ras point mutations with specific chromosomal abnormalities in primary myelodysplastic syndrome. de Souza Fernandez T, Menezes de Souza J, Macedo Silva ML, Tabak D, Abdelhay E Leuk Res 1998 Feb;22(2):125-34 Medline 98254301

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Franz Watzinger and Thomas Lion 1999 Citation This paper should be referenced as such : Watzinger F and Lion T . N-RAS (neuroblastoma RAS viral oncogene homolog). Atlas Genet Cytogenet Oncol Haematol. February 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NRASID92.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -186- Atlas of Genetics and Cytogenetics in Oncology and Haematology

SMARCB1 (SW1/SNF related, matrix associated, actin dependent regulator of chromatin B1)

Identity Other hSNF5 names SNF5L1 INI1 (integrase interactor 1) BAF47 (BRG1-associated factor) Hugo SMARCB1 Location 22q11.2 distal to BCR DNA/RNA Description spans over 50 kb; 9 exons Transcription alternative splicing including/excluding exon 2 Protein

Description 385 amino acids; 47 kDa ; a DNA binding domain and 2 repeat motifs Localisation nucleus; associated with the chromatin and with the nuclear matrix Function binds and activates human immunodeficiency virus integrase; member of the SWI/SNF complex, thought to facilitate the transcriptional activation of inducible genes through the remodelling of the chromatin; could be involved in the chromatin organization associated with the nuclear matrix attachment; could also have a role in the cell cycle control, through binding to P105-Rb Homology with SNF5 (yeast transcription factor) Mutations Germinal found in the rhabdoid tumor predisposition syndrome Somatic mutation and allele loss events in sporadic rhabdoid tumors are consistent with the two-hit model of Knutson; deletion of the entire gene on one allele (sometimes due to translocations involving 22q11), and mutation (frameshift mutations, widely dispersed through the entire gene and leading to stop codons) on the other allele Implicated in Entity rhabdoid tumor

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -187- Disease tumor of uncertain origin, occuring in early childhood Prognosis highly aggressive; 80% mortality rate Cytogenetics normal karyotype or t(Var; 22)(-;q11.2) Hybrid/Mutated no hybrid gene but inactivation of both alleles Gene

Entity rhabdoid tumor predisposition syndrome Hybrid/Mutated germline mutation on one allele, predisposing to a rabdoid tumor Gene (and perhaps to tumors of the central nervous system) when the other allele is also inactivated

External links Nomenclature Hugo SMARCB1 GDB SMARCB1 SMARCB1 6598 SWI/SNF related, matrix associated, actin Entrez_Gene dependent regulator of chromatin, subfamily b, member 1 Cards Atlas SMARCB1ID169 GeneCards SMARCB1 Ensembl SMARCB1 CancerGene SMARCB1 Genatlas SMARCB1 GeneLynx SMARCB1 eGenome SMARCB1 euGene 6598 Genomic and cartography SMARCB1 - 22q11.2 chr22:22453704-22501258 + 22q11.23 GoldenPath (hg17-May_2004) Ensembl SMARCB1 - 22q11.23 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene SMARCB1 Gene and transcription

Genbank Y17118 [ SRS ] Y17118 [ ENTREZ ]

Genbank AB017523 [ SRS ] AB017523 [ ENTREZ ]

Genbank AJ011737 [ SRS ] AJ011737 [ ENTREZ ]

Genbank AJ011738 [ SRS ] AJ011738 [ ENTREZ ]

Genbank AK021419 [ SRS ] AK021419 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -188- RefSeq NM_001007468 [ SRS ] NM_001007468 [ ENTREZ ]

RefSeq NM_003073 [ SRS ] NM_003073 [ ENTREZ ]

RefSeq NT_086921 [ SRS ] NT_086921 [ ENTREZ ] AceView SMARCB1 AceView - NCBI TRASER SMARCB1 Traser - Stanford

Unigene Hs.534350 [ SRS ] Hs.534350 [ NCBI ] HS534350 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q12824 [ SRS] Q12824 [ EXPASY ] Q12824 [ INTERPRO ]

Interpro IPR006939 SNF5 [ SRS ] IPR006939 SNF5 [ EBI ] CluSTr Q12824

Pfam PF04855 SNF5 [ SRS ] PF04855 SNF5 [ Sanger ] pfam04855 [ NCBI-CDD ] Blocks Q12824 Polymorphism : SNP, mutations, diseases OMIM 601607 [ map ] GENECLINICS 601607

SNP SMARCB1 [dbSNP-NCBI]

SNP NM_001007468 [SNP-NCI]

SNP NM_003073 [SNP-NCI]

SMARCB1 [GeneSNPs - Utah] SMARCB1 [SNP - CSHL] SMARCB1] [HGBASE - SNP SRS] General knowledge Family SMARCB1 [UCSC Family Browser] Browser SOURCE NM_001007468 SOURCE NM_003073 SMD Hs.534350 SAGE Hs.534350 Amigo process|DNA integration Amigo process|chromatin remodeling Amigo process|negative regulation of cell cycle Amigo component|nuclear chromosome Amigo component|nucleoplasm Amigo process|regulation of transcription from Pol II promoter BIOCARTA Chromatin Remodeling by hSWI/SNF ATP-dependent Complexes PubGene SMARCB1 Other databases Other Somatic mutation (COSMIC-CGP-Sanger) database Probes

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -189- Probe SMARCB1 Related clones (RZPD - Berlin) PubMed PubMed 27 Pubmed reference(s) in LocusLink Bibliography Paravertebral malignant rhabdoid tumor in infancy. In vitro studies of a familial tumor. Lynch HT, Shurin SB, Dahms BB, Izant RJ Jr, Lynch J, Danes BS Cancer 1983 Jul 15;52(2):290-6 Medline 83232583

Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms' Tumor Study Pathology Center. Weeks DA, Beckwith JB, Mierau GW, Luckey DW Am J Surg Pathol 1989 Jun;13(6):439-58 Medline 89270848

Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Wick MR, Ritter JH, Dehner LP Semin Diagn Pathol 1995 Aug;12(3):233-48 Medline 96050185

Components of the human SWI/SNF complex are enriched in active chromatin and are associated with the nuclear matrix. Reyes JC, Muchardt C, Yaniv M J Cell Biol 1997 Apr 21;137(2):263-74 Medline 97274093

Structure-function analysis of integrase interactor 1/hSNF5L1 reveals differential properties of two repeat motifs present in the highly conserved region. Morozov A, Yung E, KaProc Natl Acad Sci U S A 1998 Feb 3;95(3):1120-5 lpana GV Proc Natl Acad Sci U S A 1998 Feb 3;95(3):1120-5 Medline 98115884

Cytogenetic and molecular analysis of a t(1;22)(p36;q11.2) in a rhabdoid tumor with a putative homozygous deletion of chromosome 22. Rosty C, Peter M, Zucman J, Validire P, Delattre O, Aurias A Genes Chromosomes Cancer 1998 Feb;21(2):82-9 Medline 98152018

Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O Nature 1998 Jul 9;394(6689):203-6

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -190- Medline 98334382

Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B Cancer Res 1999 Jan 1;59(1):74-9 Medline 99107207

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Jean-Loup Huret 1999 Citation This paper should be referenced as such : Huret JL . SMARCB1 (SW1/SNF related, matrix associated, actin dependent regulator of chromatin B1). Atlas Genet Cytogenet Oncol Haematol. March 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SMARCB1ID169.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -191- Atlas of Genetics and Cytogenetics in Oncology and Haematology

FLT3 (FMS-like tyrosine kinase 3)

Identity Other CD135 names FLK2 (Fetal liver kinase 2) STK1 (Stem cell kinase 1) Hugo FLT3 Location 13q12.2 DNA/RNA Description the FLT3 gene contains 24 exons and spans 96,982 bases (start:27,475,753 bp to end 27,572,735 from 13pter) oriented at the minus strand. Transcription 3.7 kb; 2979 bp open reading frame Protein

Description Size: 993 amino acids; 112804 Da; FLT3 is a class III receptor tyrosine kinase (RTK) structurally related to the receptors for platelet derived growth factor (PDGF), colony stimulating factor 1 (CSF1), and KIT ligand (KL).; these RTK contain five immunoglobulin-like domains in the extracellular region and an intracelular tyrosine kinase domain splitted in two by a specific hydrophilic insertion (kinase insert); immunoprecipitation of the human FLT3 protein results in the appearance of a minor band of Mr 130 000 and a major band of Mr 155 000/160 000; the high-molecular-weight band corresponds to the mature, N-glycosylated form, and the low- molecular-weight band to the immature, high mannose-containing form; N-linked glycosylations account for 50 000 daltons. Expression FLT3 expression was described on bone marrow CD34-positive cells, corresponding to multipotential, myeloid and B-lymphoid progenitor cells, and on monocytic cells; FLT3 expression is restricted to cells of the fetal liver expressing high levels of CD34; in addition, the FLT3 protein is expressed on blast cells from most ANLL and B-ALL. Localisation Subcellular location: Type I membrane protein. 3D structure: PDB id 1RJB (3D). Function FLT3 receptor function can be defined by the activity of its ligand (FL); FL is an early acting factor and supports the survival, proliferation and differentiation of primitive hemopoietic progenitor cells. Ligand binding to FLT3 promotes receptor dimerization and subsequent signalling

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -192- through posphorylation of multiple cytoplasmatic proteins, including SHC, SHP-2, SHIP, Cbl, Cbl-b, Gab1 and Gab2, as well as the activation of several downstream signalling pathways, such as the Ras/Raf/MAPK and PI3 kinase cascades. Function: Receptor for the FL cytokine. Has a tyrosine-protein kinase activity. Catalytic activity: ATP + a protein tyrosine = ADP + protein tyrosine phosphate. Similarity: Belongs to the Tyr protein kinase family. CSF-1/PDGF receptor subfamily. Contains 1 immunoglobulin-like C2-type domain. Homology Other tyrosine kinases: KIT, PDGFRA, PDGFRB, VEGFR Mutations Somatic Mutations in the FLT3 gene are the most frequent genetic aberration that have been described in acute myeloid leukemia. With 20-25% length mutations in the juxtamembrane domain are the most frequent, followed by 7-8% mutations in the second tyrosine kinase kinase domain, mostly point mutations in codon 835 or deletions of codon 836. Also point mutations in the juxta membrane domain have been described and the number of new mutations all over the total gene is still growing. Implicated in Entity FLT3-length mutation (FLT3-LM) Disease Internal tandem duplications and/or insertions and, rarely, deletions in the FLT3-gene are implicated in 20-25% of all acute myeloid leukemias (AML). It was also described to be involved in 5-10 % myelodysplastic syndromes (MDS) refractory anaemia with excess of blasts (RAEB 1 and RAEB 2) and rare cases with acute lymphoblastic leukemia (ALL) The duplicated sequence belongs to exon 11 but sometimes involves intron 11 and exon 12. The most frequently used nomenclature is FLT3-ITD (internal tandem duplication). Because of the very heterogenous molecular structure the term FLT3-LM (length mutation) seems to be more adequate. Prognosis An unfavourable impact on prognosis especially a high relapse rate of the FLT3-LM has been shown by many study groups. Patients with loss of the wildtype allele have an even worse prognosis than the mutated with retention of the wildtype allele. Perspective : It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients. Cytogenetics FLT3-LM are highly correlated with a) normal karyotype, b) t(15;17)(q25;q21) c) CYTOGENETICS Perspective: It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients. Oncogenesis This mutation leads to constitutive ligand independent autophosphorylation of the receptor. The FLT3-LM vary in size and position in a nearly patient specific manner. Overall the aberrant

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -193- structure of the juxtamembrane domain disrupts a negative regulatory domain, which leads to the constitutive receptor activation. Several Groups have reported qualitative differences in the intracellular signals provided by wild type and mutated receptors.Mutated receptor weakly works through MAP kinase and Akt but instead through strong and constitutively activated STAT5.

Entity FLT3 Tyrosine Kinase Domain Mutation (FLT3-TKD) Disease In the second tyrosine kinase domain point mutations and small deletions mostly of codons 835 and 836, respectively, can be found in 7-8% of all AML. Prognosis No independent impact on prognosis shown yet. Cytogenetics In contrast to the FLT3-LM they do not seem to be specifically correlated to a certain AML type. Oncogenesis These mutations also lead to constitutive autoactivation of the receptor. It has been suggested that TKD mutation may both trigger the activation loop and stabilize it in the active state.

External links Nomenclature Hugo FLT3 GDB FLT3 Entrez_Gene FLT3 2322 fms-related tyrosine kinase 3 Cards Atlas FLT3ID144 GeneCards FLT3 Ensembl FLT3 CancerGene FLT3 Genatlas FLT3 GeneLynx FLT3 eGenome FLT3 euGene 2322 Genomic and cartography FLT3 - 13q12.2 chr13:27475753-27572703 - 13q12.2 (hg17- GoldenPath May_2004) Ensembl FLT3 - 13q12.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene FLT3 Gene and transcription

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -194- Genbank AL445262 [ SRS ] AL445262 [ ENTREZ ]

Genbank AL591024 [ SRS ] AL591024 [ ENTREZ ]

Genbank L36162 [ SRS ] L36162 [ ENTREZ ]

Genbank U02687 [ SRS ] U02687 [ ENTREZ ]

Genbank Z26652 [ SRS ] Z26652 [ ENTREZ ]

RefSeq NM_004119 [ SRS ] NM_004119 [ ENTREZ ]

RefSeq NT_086801 [ SRS ] NT_086801 [ ENTREZ ] AceView FLT3 AceView - NCBI TRASER FLT3 Traser - Stanford

Unigene Hs.507590 [ SRS ] Hs.507590 [ NCBI ] HS507590 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P36888 [ SRS] P36888 [ EXPASY ] P36888 [ INTERPRO ]

Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ]

PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 Prosite PROTEIN_KINASE_ATP [ Expasy ]

PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 Prosite PROTEIN_KINASE_DOM [ Expasy ]

PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 Prosite PROTEIN_KINASE_TYR [ Expasy ]

PS00240 RECEPTOR_TYR_KIN_III [ SRS ] PS00240 Prosite RECEPTOR_TYR_KIN_III [ Expasy ]

Interpro IPR003599 Ig [ SRS ] IPR003599 Ig [ EBI ]

Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ]

Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ]

Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ]

Interpro IPR001824 RecepttyrkinsIII [ SRS ] IPR001824 RecepttyrkinsIII [ EBI ]

Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ]

Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ] CluSTr P36888

Pfam PF00047 ig [ SRS ] PF00047 ig [ Sanger ] pfam00047 [ NCBI-CDD ] Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI- CDD ]

Smart SM00409 IG [EMBL]

Smart SM00219 TyrKc [EMBL]

Prodom PD000001 Prot_kinase[INRA-Toulouse] Prodom P36888 FLT3_HUMAN [ Domain structure ] P36888 FLT3_HUMAN [ sequences sharing at least 1 domain ] Blocks P36888

PDB 1RJB [ SRS ] 1RJB [ PdbSum ], 1RJB [ IMB ] Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -195- OMIM 136351 [ map ] GENECLINICS 136351

SNP FLT3 [dbSNP-NCBI]

SNP NM_004119 [SNP-NCI]

SNP FLT3 [GeneSNPs - Utah] FLT3 [SNP - CSHL] FLT3] [HGBASE - SRS] General knowledge Family FLT3 [UCSC Family Browser] Browser SOURCE NM_004119 SMD Hs.507590 SAGE Hs.507590

2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG Enzyme ] 2.7.1.112 [ WIT ] Amigo function|ATP binding Amigo component|integral to plasma membrane Amigo process|positive regulation of cell proliferation Amigo process|protein amino acid phosphorylation Amigo function|receptor activity Amigo function|transferase activity process|transmembrane receptor protein tyrosine kinase signaling Amigo pathway Amigo function|vascular endothelial growth factor receptor activity BIOCARTA Erythrocyte Differentiation Pathway PubGene FLT3 Other databases Other Somatic mutation (COSMIC-CGP-Sanger) database Probes Probe FLT3 Related clones (RZPD - Berlin) PubMed PubMed 42 Pubmed reference(s) in LocusLink Bibliography A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell- enriched populations. Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR Cell 1991 Jun 28;65(7):1143-52 Medline 91292518

Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -196- Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D Oncogene 1991 Sep;6(9):1641-50 Medline 92019834

Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Birg F, Courcoul M, Rosnet O, Bardin F, Pebusque MJ, Marchetto S, Tabilio A, Mannoni P, Birnbaum D Blood 1992 Nov 15;80(10):2584-93 Medline 93043306

Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Lyman SD, James L, Vanden Bos T, de Vries P, Brasel K, Gliniak B, Hollingsworth LT, Picha KS, McKenna HJ, Splett RR, et al Cell 1993 Dec 17;75(6):1157-67 Medline 94084791

Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Rosnet O, Schiff C, Pebusque MJ, Marchetto S, Tonnelle C, Toiron Y, Birg F, Birnbaum D Blood 1993 Aug 15;82(4):1110-9 Medline 93357464

Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J, et al Nature 1994 Apr 14;368(6472):643-8 Medline 94195428

Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells. Zeigler FC, Bennett BD, Jordan CT, Spencer SD, Baumhueter S, Carroll KJ, Hooley J, Bauer K, Matthews W Blood 1994 Oct 15;84(8):2422-30 Medline 95002959

Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR Immunity 1995 Jul;3(1):147-61 Medline 95346505

Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -197- Rosnet O, Buhring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, Arnoulet C, Chabannon C, Kanz L, Hannum C, Birnbaum D Leukemia 1996 Feb;10(2):238-48 Medline 96200134

Flt3 ligand induces tumor regression and antitumor immune responses in vivo. Lynch DH, Andreasen A, Maraskovsky E, Whitmore J, Miller RE, Schuh JC Nat Med 1997 Jun;3(6):625-31 Medline 97319585

Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase. Rappold I, Ziegler BL, Kohler I, Marchetto S, Rosnet O, Birnbaum D, Simmons PJ, Zannettino AC, Hill B, Neu S, Knapp W, Alitalo R, Alitalo K, Ullrich A, Kanz L, Buhring HJ Blood 1997 Jul 1;90(1):111-25 Medline 97351069 c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Lyman SD, Jacobsen SE Blood 1998 Feb 15;91(4):1101-34 Medline 98122762

Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R Blood 1999 May 1;93(9):3074-80 Medline 99233671

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Olivier Rosnet 1999 Updated 06- Susanne Schnittger 2005 Citation This paper should be referenced as such : Rosnet O . FLT3 (FMS-like tyrosine kinase 3). Atlas Genet Cytogenet Oncol Haematol. May 1999 .

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -198- URL : http://www.infobiogen.fr/services/chromcancer/Genes/FLT3ID144.html Schnittger S . FLT3 (FMS-like tyrosine kinase 3). Atlas Genet Cytogenet Oncol Haematol. June 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FLT3ID144.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -199- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MEN1

Identity Note Mutiple Endocrine neoplasia type 1: MEN1 (or Wermer syndrome) is an inherited predisposition to parathyroid, endocrine pancreas, pituitary, adrenal and neuroendocrine tumors and segregates as an autosomal dominant disease with high penetrance Hugo MEN1 Location 11q13 DNA/RNA

structure of the MEN1 gene (The European Consortium on MEN1, 1997)

Description the MEN1 gene spans 9 Kb of the genome and is characterized by 10 exons; exon 1 and the 3' 832 bp of exon 10 are untranslated. The figure shows the general structure of the gene and some of germline mutations in patients affected by inherited MEN1 disease Transcription a major 2,8 Kb transcript is detected in all tissues tested; a large 4,0 Kb mRNA has been characterized in the pancreas and in the thymus but the 5' structure of the MEN1 gene and the promoter region remain to date unknown; the 2,8 Kb major mRNA could be initiated inside exon 1 Protein

Description the MEN1 protein, menin, contains 610 amino-acids (67 Kda); contains two nuclear localization signals (NLS-1 and NLS-2) at the C-terminal end of the protein (exon 10), between amino-acids 479-497 for NLS-1 and 588-608 for NLS-2; this has been shown in vitro by deletion mutants construction with GFP-coexpressing vectors Expression menin is widely expressed and mainly in testis and central nervous

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -200- system; murine equivalent to MEN1 has been cloned and most of the expression data have been confirmed in murine tissues, either in adults and during embryogenesis by RNA in situ experiments Localisation primarily localized in the nucleus and could translate in the cytoplasm during specific steps of the cell cycle Function the MEN1 gene is a growth-suppressor gene, as shown by allelic deletion (LOH) in tumoral DNA from MEN1 patients; menin has been showed to interact with the AP1 transcrition factor through his JunD component; this interaction involves mainly the first 40 amino-acids at the N-terminal end of menin and some specifics amino-acids in the central domain of the protein; Menin interacts specifically with JunD but with none of the other AP1 proteins, such as JunB, c-Jun, c-Fos and Fra1/2; among 11 missense mutations described in MEN1 patients, the authors reported that four of them decreased or abolished binding to JunD suggesting a separate domain between amino-acids residues 139 and 142 could have a critical role in menin-JunD interaction; using mammalian two-hybrid assays, menin has been shown to repress JunD- mediated transcriptionnal activation but most of menin mutatnts with impaired JunD-binding properties lossed this inhibitory activity; strikingly, overexpression of normal or mutant menin in similar experimental assays led to the absence of repressional activity suggesting that unknown factors could be involved in the menin-JunD interaction; new partners binding menin will be probably characterized in a near future and help us to understand the MEN1-related pathways Homology no homology has been found to date either by comparison of primary sequence and secondary/tertiary structure of this protein with all known proteins involved in cellular physiology Mutations Germinal germline mutations in the MEN1 gene cause familial and sporadic multiple endocrine neoplasia type 1 (MEN1) and the majority of mutations described predict premature protein truncation either by nonsenses and frameshifts in coding sequences; missense mutations have been identified in » 30% of cases and when characterized in sporadic cases, most of them need analysis of a large (> 50) number of control individuals in order to exclude frequent polymorphisms; interestingly, all truncating mutations affect one or both NLS's and no missense mutations were observed inside NLS-1 and NLS-2; mutations are spread over the gene and most of them occur once in a single family; some mutations were observed in more than one family and when a common ancestor was excluded by haplotyping, these recurrent mutations might be accounted for 'hot-spots' in the MEN1 sequence; most recurrent mutations are nonsenses and frameshifts in exons 2 and 10; for example, single base deletion occurs frequently at nucleotide 1650 in exon 10 and has been related to the presence of an highly repetitive motif (CCCCCCCG) in this region inducing replication errors by slipped-strand mispairing; between 10 and 15% of sporadic MEN1 could be explained by de novo mutations, but this must be confirmed by an exhautive analysis of affected individuals and both parents

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -201- Implicated in Entity Multiple Endocrine Neoplasia type 1 or Wermer Syndrome Disease an inherited autosomal dominant predisposition to endocrine tumors, including parathyroids, endocrine pancreas, pituitary, adrenal glands, and the diffuse neuroendocrine tissues deriving from foregut; non- endocrine tumors have been observed in some MEN1 patients, including ependymoma, meningioma, cutaneous angiofibroma and lipoma, melanoma and rare visceral lesions such as rhabdomyosarcoma and leiomyoma; MEN1 is highly penetrant and more than 90% of gene-carriers will present biological and/or clinical signs of the disease affter the fifth decade; around 5-10% of patients have an agressive disease before age 20 no genotype-phenotype correlation were found to date in MEN1; nevertheless, most families with agressive NET have truncating mutations either in exons 2, 3, 9 or 10 but no studies have been able to find statistical evidence of this putative correlation; recent investigations suggested that some MEN1 families could express only primary hyperparathyroidism, so called familial primary hyperparathyroidism (FIHPT), an allelic variant of MEN1; MEN1related FIHPT appears as a benign disease but hyperplasia and/or adenoma occur in all parathyroid glands; recent data suggest that this variant could be associated to missense mutations in exons 4 to 7 of the MEN1 sequence; nevertheless, such correlations remain uncertain an do not have clinical implications in medical practice; the identification of germline missense mutations in exons 4 to 7 must lead to an extensive biological and clinical screening of patients in order to exclude the occurrence of pancreatic and pituitary disease, as recently shown in a typical MEN1 family carrying a Leu264Pro in exon 5; approximately 10-15% of MEN1 families do not show any mutation in the known part of MEN1 sequence; clinical profile in these families do not differ from that of families with identified mutations and it is therefore possible that MEN1 mutations occur outside the coding sequence; deletion of part or full MEN1 sequence has been also suggested as a rare mechanism of germline mutation Prognosis it is mainly related to metabolic and organic complications of hormonal hypersecretion by tumoral cells (Zollinger-Ellison syndrome induced by gastrinoma, hyperinsulinism, hyperparathyroidism, hyeperaldoseronism, Cushing syndrome, hyperprolactinemia, acromegaly; more than 30-50% of digestive neuroendocrine tumors and those localized in thymus and bronchi have a metastatic potential

External links Nomenclature Hugo MEN1 GDB MEN1 Entrez_Gene MEN1 4221 multiple endocrine neoplasia I Cards

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -202- Atlas MEN1ID148 GeneCards MEN1 Ensembl MEN1 CancerGene MEN1 Genatlas MEN1 GeneLynx MEN1 eGenome MEN1 euGene 4221 Genomic and cartography MEN1 - 11q13 chr11:64327572-64334764 - 11q13.1 (hg17- GoldenPath May_2004) Ensembl MEN1 - 11q13.1 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MEN1 Gene and transcription

Genbank AJ132593 [ SRS ] AJ132593 [ ENTREZ ]

Genbank AJ132594 [ SRS ] AJ132594 [ ENTREZ ]

Genbank AJ132596 [ SRS ] AJ132596 [ ENTREZ ]

Genbank AY306001 [ SRS ] AY306001 [ ENTREZ ]

Genbank U93237 [ SRS ] U93237 [ ENTREZ ]

RefSeq NM_000244 [ SRS ] NM_000244 [ ENTREZ ]

RefSeq NM_130799 [ SRS ] NM_130799 [ ENTREZ ]

RefSeq NM_130800 [ SRS ] NM_130800 [ ENTREZ ]

RefSeq NM_130801 [ SRS ] NM_130801 [ ENTREZ ]

RefSeq NM_130802 [ SRS ] NM_130802 [ ENTREZ ]

RefSeq NM_130803 [ SRS ] NM_130803 [ ENTREZ ]

RefSeq NM_130804 [ SRS ] NM_130804 [ ENTREZ ]

RefSeq NT_086784 [ SRS ] NT_086784 [ ENTREZ ] AceView MEN1 AceView - NCBI TRASER MEN1 Traser - Stanford

Unigene Hs.423348 [ SRS ] Hs.423348 [ NCBI ] HS423348 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt O00255 [ SRS] O00255 [ EXPASY ] O00255 [ INTERPRO ]

Interpro IPR007747 Menin [ SRS ] IPR007747 Menin [ EBI ] CluSTr O00255

Pfam PF05053 Menin [ SRS ] PF05053 Menin [ Sanger ] pfam05053 [ NCBI-CDD ] Blocks O00255

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -203- Polymorphism : SNP, mutations, diseases OMIM 131100 [ map ] GENECLINICS 131100

SNP MEN1 [dbSNP-NCBI]

SNP NM_000244 [SNP-NCI]

SNP NM_130799 [SNP-NCI]

SNP NM_130800 [SNP-NCI]

SNP NM_130801 [SNP-NCI]

SNP NM_130802 [SNP-NCI]

SNP NM_130803 [SNP-NCI]

SNP NM_130804 [SNP-NCI]

SNP MEN1 [GeneSNPs - Utah] MEN1 [SNP - CSHL] MEN1] [HGBASE - SRS] General knowledge Family MEN1 [UCSC Family Browser] Browser SOURCE NM_000244 SOURCE NM_130799 SOURCE NM_130800 SOURCE NM_130801 SOURCE NM_130802 SOURCE NM_130803 SOURCE NM_130804 SMD Hs.423348 SAGE Hs.423348 Amigo process|negative regulation of transcription from Pol II promoter Amigo component|nucleus Amigo function|protein binding Amigo process|regulation of transcription, DNA-dependent PubGene MEN1 Other databases Other MEN1 mutation database database Bibliography Genetic aspects of adenomatosis of endocrine glands. Wermer P. Am J Med 1954; 16: 363-375.

Multiple Endocrine Neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M. Nature 1988; 332: 85-87. Medline 88156919

Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. Bystrom C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, Oberg K, Werner S, Nordenskjöld M. Proc Natl Acad Sci USA 1990; 87: 1968-1972. Medline 90175418

Multiple Endocrine Neoplasia type 1 : clinical features and management. Metz DC, Jensen RT, Bale AE, Skarulis MC, Eastman RC, Niemann L, Norton JA, Friedman E, Larsson C, Amorosi A, Bernadi ML, Marx SJ. In : The Parathyroids, JP Bilezikian, R. Marcus, MA Levine. Ed. Raven Press, New York 1994; pp 591-646.

Germline mutations of the MEN1 gene in familial MEN1 and related states. Agarwal S, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis M, Doppman J, Kim Y, Lubensky IA, Zhuang ZP, Boguski MS, Weisemann J, Green J, Guru SC, Manickam P, Olufemi SE, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ. Hum Mol Genet 1997; 6: 1169-1175. Medline 97358593

Positionnal cloning of the gene for Multiple Endocrine Neoplasia type 1. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert- Buck MR, Debelenko LV, Zhuang ZP, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Lee Burns A, Marx SJ. Science 1997; 276: 404-407. Medline 97258940

Menin mutations in patients with multiple endocrine neoplasia type 1. Mayr B, Apenberg S, Rothomel T, von Zur Muhlen A, Brabant G. Eur J Endoc 1997; 137: 684-687. Medline 98099883

Germline mutations of the MEN1 gene in japanese kindreds with multiple

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -205- endocrine neoplasia type 1. Shimizu S, Tsukada T, Futami H, Ui K, Kameya T, Kawanaka M, Uchiyama S, Aoki A, Yasuda H, Kawano S, Ito Y, Kanbe M, Obara T, Yamaguchi K. Jpn J Cancer 1997; 88: 1029-1032. Medline 98102849

Identification of the Multiple Endocrine Neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet 1997; 6: 1177-1183.

Characterization of mutations in patients with multiple endocrine neoplasia type 1. Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH, Thakker RV. Am J Hum Genet 1998; 62: 232-244. Medline 98130524

Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Calender A, Giraud S, Porchet N, Gaudray P, Cadiot G, Mignon M. Ann Endocrinol 1998; 59: 444-451. (Review). Medline 99205984

Genetic testing in multiple endocrine neoplasia and related syndromes. Calender A. Forum (Genova) 1998; 8: 146-159. (Review). Medline 99088397

Novel V184E MEN1 germline mutation in a japanese kindred with familial hyperparathyroidism. Fujimori M, Shirahama S, Sakurai A, Hashizume K, Hama Y, Ito K, Shingu K, Kobayashi S, Amano J, Fukushima Y. Am J Med Genet 1998; 80: 221-222. Medline 99057176

Germ-line mutation analysis in patients with Multiple Endocrine Neoplasia type 1 and related disorders. Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem MC, Assayag M, Peix JL, Pugeat M, Rohmer V, Vallotton M, Lenoir GM, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A, Calender A. Am J Hum Genet 1998; 63: 455-467. Medline 98349969

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -206- Menin, the product of the MEN1 gene, is a nuclear protein. Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS, Chandrasekharappa SC. Proc Natl Acad Sci USA 1998 ; 95 : 1630-1634 Medline 98132642

A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1. Kishi M, Tsukada T, Shimizu S, Futami H, Ito Y, Kanbe M, Obara T, Yamaguchi K. Jpn J Cancer Res 1998 ; 89 : 1-5 . Medline 98169289

Characterization of the mouse Men1 gene and its expression during development.. Stewart C, Parente F, Piehl F, Farnebo F, Quincey D, Silins G, Bergman L, Carle GF, Lemmens I, Grimmond S, Xian CZ, Khodei S, Teh BT, Lagercrantz J, Siggers P, Calender A, Van de Vem V, Kas K, Weber G, Hayward N, Gaudray P, Larsson C. Oncogene 1998 ; 12: 2485-2493 Medline 99039765

A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild type alleles in the parathyroid tumors. Teh BT, Esapa CT, Houlston R, Grandell U, Farnebo F, Nordenskjöld M, Pearse CJ, Carmichael D, Larsson C, Harris PE. Am J Hum Genet 1998; 63: 1544-1549. Medline 99011276

Mutation analysis of the MEN1 gene in Multiple Endocrine Neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. Teh BT, Kytola S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward NK, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Salmela P, Larsson C. J Clin Endoc Metab 1998; 83: 2621-2626. Medline 98373695

Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin. Huang SC, Zhuang Z, Weil RJ, Pack S, Wang C, Krutzsch HC, Pham TA, Lubensky IA. Lab Invest 1999 ; 79: 301-310 Medline 99190487

Menin interacts with the AP1 transcription factor JunD and represses JunD- activated transcription. Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -207- Cell 1999 Jan 8;96(1):143-52 Medline 99142611

Mutation analysis of the MEN1 gene in Belgian patients with Multiple Endocrine Neoplasia type 1 and related diseases. Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ, Verloes A, Meurisse M, Van Gaal L, Verellen C, Koulischer L, Beckers A. Hum Mutat 1999; 13: 54-60. Medline 99103464

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 05- Alain Calender 1999 Citation This paper should be referenced as such : Calender A . MEN1. Atlas Genet Cytogenet Oncol Haematol. May 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MEN1ID148.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -208- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(7;11)(p15;p15)

Identity

t(7;11)(p15;p15) G-banding - Courtesy Diane H. Norback, Eric B. Johnson, and Sara Morrison-Delap, Cytogenetics at the Waisman Center

Clinics and Pathology Disease ANLL mostly; occasionally: CML-like cases without t(9;22), or CML in blast crisis (with t(9;22)) Phenotype / M2 or M4 ANLL mainly; involving maturing leukemic cells in ANLL cell stem cases, might affect trilineage progenitors in CML-like cases origin Epidemiology most cases have been found in Japan; balanced sex ratio Cytology auer rods; low alkaline phosphatase scores; CML like blood features Prognosis CR in most cases; but patients tend to relapse; mean survival: 15 mths Cytogenetics Additional most often (90%) none anomalies Genes involved and Proteins Gene HOXA9 Name Location 7p15 Protein encodes a class I homeodomain protein potentially involved in myeloid differentiation Gene NUP98 Name Location 11p15

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -209- Dna / Rna alternate splicings Protein contains repeated motifs and a RNA binding motif; nucleoporin: role in nucleo-cytoplasmic transport Result of the chromosomal anomaly Hybrid gene 5' NUP98 - 3' HOXA9 Description

Fusion fuses the N-term GLFG repeat domains of NUP98 to the HOXA9 3' Protein homeobox Description Oncogenesis may promote leukaemogenesis through inhibition of HOXA9-mediated terminal differentiation and/or aberrant nucleocytoplasmic transport

External links Other t(7;11)(p15;p15) Mitelman database (CGAP - NCBI) database Other t(7;11)(p15;p15) CancerChromosomes (NCBI) database Bibliography Reciprocal translocation involving the short arms of chromosomes 7 and 11, t(7p-;11p+), associated with myeloid leukemia with maturation. Sato Y, Abe S, Mise K, Sasaki M, Kamada N, Kouda K, Musashi M, Saburi Y, Horikoshi A, Minami Y, et al Blood 70 (5): 1654-1658 (1987) Medline 88025601

Two additional cases of acute myeloid leukemia with t(7;11)(p15;p15) having low neutrophil alkaline phosphatase scores. Fujimura T, Ohyashiki K, Ohyashiki JH, Kawakubo K, Iwabuchi A, Kodama A, Toyama K Cancer Genet Cytogenet 68 (2): 143-146 (1993) Medline 93358284

The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9 Borrow J, Shearman AM, Stanton VP Jr, Becher R, Collins T, Williams AJ, Dube I, Katz F, Kwong YL, Morris C, Ohyashiki K, Toyama K, Rowley J, Housman DE Nat Genet 12 (2): 159-167 (1996) Medline 96154188

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -210- Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP, Jenkins NA, Copeland NG, Shaughnessy JD Jr Nat Genet 12 (2): 154-158 (1996) Medline 96154187

Contributor(s) Written 01- Jean-Loup Huret 1999 Citation This paper should be referenced as such : Huret JL . t(7;11)(p15;p15). Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0711p15.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -211- Atlas of Genetics and Cytogenetics in Oncology and Haematology

-Y (updated: old version not available) Y loss in leukemia

Identity Note Loss of the Y chromosome from individual metaphases is common in metaphase cells from both PHA-stimulated lymphocytes and spontaneously dividing bone marrow cells. The frequency of Y loss is greater in older men, and the size of the 45,X,-Y cell population probably increases gradually with advancing age. (In females, a corollary loss of one X chromosome also occurs with advancing age.) This natural phenomenon challenges our ability to distinguish between a normal and a disease-associated 45,X,-Y clone. Clinics and Pathology Disease -Y is frenquently observed in myeloproliferative diseases (MPD), myelodysplasic syndromes (MDS), acute non lymphocytic leukemias (ANLL), and can also be seen in lymphoproliferations Epidemiology In CML with t(9;22) and in ANLL with a t(8;21), loss of the Y chromosome tends to occurs at a younger age than in the general population Clinics Partial or complete reappearance of the Y chromosome has been described in several cases of ANLL in remission. In most or all of these ANLL cases, the 45,X,-Y cell population represented 80-100% of preremission metaphases. These observations support the interpretation that the leukemia cell karyotype is 45,X,-Y. In MDS, the proportion of -Y cells has been observed to increase, decrease, remain stable, or fluctuate up and down on follow-up studies. In four cases of Hodgkin disease, simultaneous fluorescence immunophenotyping and FISH showed that the -Y cell population was probably independent of the Hodgkin disease in at least two of the patients. It is notable that the -Y cells represented fewer than 10-15% of the metaphase cells in all four cases. Cytology no known association Prognosis In ANLL, a 45,X,-Y karyotype is believed to have an intermediate prognosis. In MDS, the prognosis appears to be neutral or favorable. There are insufficient data for MPD or lymphoproliferative disease Cytogenetics

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -212- Cytogenetics In PHA-stimulated lymphocyte karyotype studies of males, about Morphological 2% have one or more cells with loss of the Y chromosome. Cells with - Y are observed more often in males over age 55 than in younger males. In all age groups, the proportion of -Y cells is usually under 10%. The pattern of Y loss is more striking in bone marrow aspirate karyotype studies. Here, clonal Y chromosome loss as a sole abnormality in the karyotype is a common finding. A 45,X,-Y karyotype is observed in about 6% of bone marrow karyotype studies from males, and it represents 15-20% of abnormal karyotypes. The frequency of -Y cells increases with advancing age and is significantly greater in cases with MDS, MPD, ANLL, or lymphoproliferative disease than in subjects who have no evidence of disease. Subjects with no evidence of disease rarely exhibit more than 75% of cells with 45,X,-Y. Thus, if fewer than 75% of metaphase cells are -Y, the disease association is uncertain. However, if 75-100% of metaphase cells are -Y, the karyotype probably is disease-associated, even in older men. Chromosome rearrangements involving the Y chromosome are rare in cancer and leukemia. Loss of the Y chromosome, in contrast, is a common secondary change in cancer cells and in a few leukemias (see below). Probes all available probe for the Y chromosome Additional In association with t(9;22) in CML and with t(8;21) in FAB-M2 ANLL, anomalies loss of the Y chromosome is generally considered a secondary event of no added clinical significance. Genes involved and Proteins Note genes involved, if any, are unknown

External links Other -Y Mitelman database (CGAP - NCBI) database To be noted It is not known whether the Y chromosome loss is the critical mutational event. Likewise, it is not known whether the Y chromosome loss is a secondary genetic change, or if the critical (submicroscopic) genetic change simply occurs by chance in a -Y cell. Speculatively, loss of the Y could provide a proliferative advantage simply because it tends to replicate late in S-phase. Its loss might therefore shorten the cell cycle slightly. Bibliography Age-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging. Pierre RV, Hoalgland HC.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -213- Cancer 1972; 30: 889-894. Medline 4116908

Y chromosome loss in leukemias. Berger R, Bernheim A. Cancer Genet Cytogenet 1979; 1: 1-8.

Chromosomes and causation of human cancer and leukemia XXXV. The missing Y in acute non-lymphocytic leukemia (ANLL). Abe S, Golomb HM, Rowley JD, Mitelman F, Sandberg AA. Cancer 1980; 45: 84-90. Medline 6985828

Loss of the Y chromosome in acute myelogenous leukemia: a report of 13 patients. Holmes RI, Keating MJ, Cork A, Trujillo JM, McCredie KB, Freireich EJ. Cancer Genet Cytogenet 1985;17:269-278. Medline 3859363

Acute myelogenous with a 8;21 translocation. A report on 148 cases from the Groupe Fran&ccdil;ais de Cytogégétique Hématologique. Groupe Fran&ccdil;ais de Cytogénétique Hématologique. Cancer Genet Cytogenet 1990; 44: 169-179.

The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not reproductive history. Nowinski GP, Van Dyke DL, Tilley B, Babu VR, Worsham MJ, Wilson GN, Weiss L. Am J Hum Genet 1990; 46:1101-1111. Medline 2339703

Loss of the chromosome from normal and neoplastic bone marrows. United Kingdom Cancer Cytogenetics Group (UKCCG). Genes Chromosom Cancer 1992; 5: 83-88.

X and Y chromosome loss as sole abnormality in acute nonlymphocytic leukemia (ANLL). Riske CB, Morgan R, Ondreyco S, Sandberg AA. Cancer Genet Cytogenet 1994; 72: 44-47. Medline 8111738

Y chromosome loss in chronic myeloid leukemia detected in both normal and malignant cells by interphase fluorescence in situ hybridization. Kirk JA, Van Devanter DR, Biderman J, Bryant EM. Genes Chromosom Cancer 1994; 5: 83-88.

Loss of Y Chromosome. An age-related event or a cytogenetic marker of a

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -214- malignant clone? Abelovich D, Yehuda O, Ben-Neriah S, Or R. Cancer Genet Cytogenet 1994:76:70-71.

Clarification of dubious karyotypes in Hodgkin's disease by simultaneous fluorescence immunophenotyping and interphase cytogenetics (FICTION). Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W, Schlegeiberger B. Cytogenet Cell Genet 1995;70:243-245. Medline 7789181

Clinical significance of Y chromosome loss in hematologic disease. Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K, Van Dyke DL. Genes Chromosomes Cancer 2000;27:11-14. Medline 10564581

Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR. Blood 2000;96:4075-4083. Medline 11110676

Contributor(s) Written 01- Fran&ccdeil;ois Desangles 1999 Updated 01- Daniel L. Van Dyke 2001 Citation This paper should be referenced as such : Desangles F . -Y,Y loss in leukemia. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://AtlasGeneticsOncology.org/Anomalies/YlossID1089.html Van Dyke DL . -Y,Y loss in leukemia. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://AtlasGeneticsOncology.org/Anomalies/YlossID1089.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -215- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(8;14)(q24;q32) t(2;8)(p12;q24) t(8;22)(q24;q11)

Identity Note the 3 translocations are variants of each other, and they share the same clinical significance

Top row: t(2;8)(p12;q24) G- banding (left and center) - Courtesy Diane H.Norback, Eric B. Johnson, Sara Morrison-Delap; R- banding - (right) Courtesy Jean-Luc Lai. Middle row: t(8;14)(q24;q32) G- banding - (left) Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap; R- banding - (center Courtesy Jean-Luc Lai; right: Editor). Lower row: t(8;22)(q24;q11) G- banding (left and center) - Courtesy Diane H. Norback, Eric B.Johnson, Sara Morrison-Delap Cytogenetics at the Waisman Center ; R- banding - (right) Courtesy Jacques Boyer.

Clinics and Pathology Disease described both in B-cell acute lymphoblastic leukemia (ALL) and in non-

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -216- Hodgkin lymphomas (NHL), especially in the Burkitt lymphoma Phenotype / cell stem B-cell malignant hemopathies origin Epidemiology of the lymphoma : the translocation is present in both the endemic African Burkitt lymphoma and in the non endemic tumor type (Europe, America, Japan); the L3-ALL represents only 2% of ALLs and is closer to a leukemic stage of a lymphoma than to other ALL types Cytology ALL : L3 morphology according to the FAB classification, very occasionally L1 or L2 cytology reported

Bone marrow sample: the medium-sized cells show a diffuse monotonous pattern of infiltration. The nuclei are round, cytoplasm deeply basophilic and usually contain vacuoles. The morphological feature in this bone marrow smear (Giemsa), quite similar to tumor cells as seen in tissue imprints, is highly characteristic of Burkitt lymphoma - Courtesy Georges Flandrin.

Cytogenetics

944B18 The figure illustrates the translocation of the c-Myc gene (probe 944B18,

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -217- red) to 14q32.3 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics

Cytogenetics t(8 ;14) is described in 75-85% of the cases, t(2;8) in 5%, and t(8 ;22) Morphological in the remaining 10%; high-quality metaphases are required to detect t(8;14) and t(8;22) Additional reported in 70% cases, especially : structural rearrangements of the anomalies long arm of chromosome 1 (30% cases) resulting in a partial trisomy 1q, rearrangements of 13q34 (15% cases); a t(1;13)(q23;q34) has been described Variants t(2;8)(p12;q24) and t(8;22)(q24;q11) are variants of the t(8;14)(q24;q32); three-way rearrangements and translocations of submicroscopic chromosome fragments have also been described Genes involved and Proteins Note on the molecular point of view, in all these three translocations, the oncogene C-MYC is juxtaposed either with the immunoglobulin heavy chain locus IGH (14q32), the kappa light-chain locus IGK (2p12), or the lambda light-chain locus IGL (22q11); all these translocations share a breakpoint in 8q24 (C-MYC locus) Gene C-MYC Name Location 8q24 the human C-MYC oncogene is the cellular homologue of an avian retrovirus; in vertebrates, it belongs to a small gene family with closely related members (C-MYC, N-MYC, L-MYC); C-MYC has three exons; two promoters P1 and P2 control the C-MYC transcription; the choice of the promoter depends on the myc protein level. P2 promoter is Dna / Rna considered as the most active promoter, generating a 2.25 kb transcript, whereas P1 promoter enrates a 2.4 kb transcript; the main part of 5' first exon corresponds to an untranslated region, MYC1 translation starting at a CUG codon near its 3'end, having 14 additional N-terminal amino- acids compared with MYC2 translation site localized 5' near the second exon beginning Protein Myc protein is a transcription factor of the helix-loop-helix/leucine zipper family that activates transcription as obligate heterodimer with a partner protein, Max Gene Immunoglobulin genes : IGH, IGK, IGL Name Location located in 14q32, 2p12 and 22q11 respectively Result of the chromosomal anomaly Hybrid no hybrid gene but the translocation of C-MYC close to enhancers gene Note constitutively active in this specific cell lineage

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -218- Description C- MYC is translocated to der(14) in the t(8;14), whereas it remains on der(8) in the variant translocations; t(8;14) leads to a head-to-head fusion of C-MYC with the heavy chain immunogloulin locus : 8q24 is close to the 5' extremity of C-MYC exon 2, leading the all translated gene region to 14q32; the 8q24 breakpoint region is variable, scattered over a 190 Kb region, 5' far from C-MYC or within C-MYC; the 14q32 breakpoint region is mainly located in the constant region, very close within the switch or joining regions; C-MYC juxtaposed to the immunoglobin constant regions and enhancer is overexpressed, shutting down the normal remaining C-MYC; in both t(2;8) and t(8;22), the breakpoint is in 3' of or distal to the C-MYC gene which always remains on der(8); the rearrangement with respectively Igk or Igl and C- MYC is head-to-tail.

Fusion the protein c-myc resulting from the translation of the second and third Protein Note exons, through DNA- binding properties, plays a role in regulating cell growth and differentiation Oncogenesis constitutive expression of c-myc induces proliferation even in the absence of growth factors

External links Other t(8;14)(q24;q32) Mitelman database (CGAP - NCBI) database Other t(8;14)(q24;q32) CancerChromosomes (NCBI) database Other t(2;8)(p12;q24) Mitelman database (CGAP - NCBI) database Other t(2;8)(p12;q24) CancerChromosomes (NCBI) database Other t(8;22)(q24;q11) Mitelman database (CGAP - NCBI) database Other t(8;22)(q24;q11) CancerChromosomes (NCBI) database Other c-MYC / IGH t(8;14) (Bari) database

Bibliography Chromosomal abnormalities in adult non-endemic Burkitt's lymphoma and leukemia: 22 new reports and a review of 148 cases from the literature. Kornblau SM, Goodacre A, Cabanillas F. Hematol Oncol. 1991; 9: 63-78. Medline 91331533

Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: a high-grade

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -219- lymphoma responsive to ProMACE-based combination chemotherapy. Longo DL, Duffey PL, Jaffe ES, Raffeld M, Hubbard SM, Fisher RI, Wittes RE, DeVita VT Jr, Young RC J Clin Oncol 1994; 12: 2153-2159. Medline 95016881

World Health Organization classification of neoplastic diseases of hematopoietic and lymphoid tissues: Report of the clinical advisory committee - Airlie House, Virginia, Novembre 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 20044867

Clinicopthogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Kiel-Wien-lymphoma study group. Schlegelberger B, Zwingers T, Harder L, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Muller-Hermelink K, Feller A, Heinz R. Blood 1999; 94: 3114-3120. Medline 20028294

Molecular biology of Burkitt's lymphoma. Hecht JL, Aster JC J Clin Oncol 2000; 18: 3707-3721. Medline 20510198

Contributor(s) Written 02- Chrystèle Bilhou-Nabera 1999 Citation This paper should be referenced as such : Bilhou-Nabera C . t(8;14)(q24;q32),t(2;8)(p12;q24),t(8;22)(q24;q11). Atlas Genet Cytogenet Oncol Haematol. February 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0814ID1050.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -220- Atlas of Genetics and Cytogenetics in Oncology and Haematology

t(5;15)(p15;q11-13)

Clinics and Pathology Disease B-cell, precursor ALL Phenotype / cell stem L1, CD10+/-, CD24+ origin Epidemiology 5 reported cases; Infant ALL, age 1.5-7 months at diagnosis Prognosis CR in all cases; 1 CNS relapse Cytogenetics Cytogenetics t(5;15)(p15;q11-13) Morphological Cytogenetics not done Molecular Additional +14; +22 one case each anomalies Variants none reported 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 Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the children cancer group. Heerema NA, Arthur DC, Sather H, Albo V, Feusner J, Lange BJ, Steinhertz PG, Zeltzer P, Hammond D, Reaman GH. Blood 1994; 83: 2274-2284. Medline 94214141

Contributor(s) Written 03- Nyla A. Heerema 1999

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Citation This paper should be referenced as such : Heerema NA . t(5;15)(p15;q11-13). Atlas Genet Cytogenet Oncol Haematol. March 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0515ID1149.html

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Hodgkin's disease

Clinics and Pathology Disease Hodgkin's disease (HD) is generally considered to involve a clonal expansion of neoplastic B lymphocytes Epidemiology a distinguishing feature with non-Hodgkin's lymphomas (NHLs) is its relative frequency in patients under 20 years Pathology most HDs can be classified as nodular sclerotic (NS) or mixed cellularity (MS) subtypes; two uncommon subtypes, lymphocyte predominance and lymphocyte depletion, present less typical pictures and examples of the former have sometimes been reclassified as low- grade B-cell NHLs Prognosis unlike NHLs, the prognosis of HD has improved in recent decades with a five-year survival rate of over 80% Cytogenetics Cytogenetics the neoplastic cells in typical HD lymph nodes comprise Morphological mononuclear Hodgkin and multilobate, binucleate or multinucleate Reed-Sternberg cells, and that these are clonal with modal chromosome numbers varying from case to case is shown by direct chromosome analysis and DNA measurements the modes are about twice as frequently in the triploid-tetraploid (particularly 65-80 chromosomes) as neardiploid region; the clonal aneuploidy has been demonstrated by simultaneous fluorescence immunophenotyping and interphase chromosomal analysis to occur in the Hodgkin and Reed-Sternberg cells unlike NHLs, where a number of chromosomal translocations specific for histopathological types of tumour have been discovered, similarly specific changes have unfortunately not been reported for HD; occasionally, translocations such as t(l4;18) and t(2;5) that are common in specific types of NHL have been found; deletions and duplications, common in other types of tumour, including NHLs, have been described in HD, such as del(lp),dup(lq),del(6q) and del(7q); a nonrandom change involving chromosome 4, with breakpoints in the region 4q25-28, has been found on several occasions and merits further investigation in chromosome studies, both direct and after culturing, diploid as well as aneuploid metaphases are commonly found in HD, not unexpectedly since histopathological studies usually reveal a considerable excess of lymphocytes and other cells with normal morphology compared to the aneuploid Hodgkin and Reed-Sternberg

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -223- cells; a recent intriguing finding using FISH, however, has been that 1- 12% of "normal" nuclei in HD have abnormalities, most commonly trisomies for various chromosomes External links Association Leukemia Society of America

Bibliography Hodgkin's disease. Kaplan HS: Second Edition. Harvard University Press, Massachusetts 1980.

Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed-Sternberg cells in 100% of analyzed cases of Hodgkin's disease. Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W, Schlegelberger B. Blood 1995; 86: 1464-1468 Medline 95359446

Hodgkin's disease - Time for a change. Schwartz RS. New Engl J Med 1997; 337: 495-496. Medline 97382707

Cytogenetics of Hodgkin's disease. Atkin NB. Cytogenet Cell Genet 1998; 80: 23-27. Medline 98341469

Chromosomal abnormalities in Hodgkin's disease are not restricted to Hodgkin/Reed-Sternberg cells. Jansen MPHM, Hopman AHN, Haesevoets AM, Gennotte IAF, Bot FJ, Arends JW, Ramaekers FCS, Schouten HC. J Pathol 1998; 185: 145-152. Medline 98378962

Precursors of Hodgin's disease and B-cell lymphomas. Manis JP. New Engl J Med 1999; 340: 1280-1281. Medline 99211823

Contributor(s) Written 05- Niels B Atkin 1999

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Citation

This paper should be referenced as such : Atkin NB . Hodgkin's disease. Atlas Genet Cytogenet Oncol Haematol. May 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/HodgkinID2068.html

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Infant leukaemias Congenital leukaemias Neonatal leukaemias

Identity infant or congenital leukaemias are defined by a diagnosis within either the first month, the first year, or the first two years of life, according to different workers; recent data have shown that patients, diagnosed to have a leukaemia at age 5 mths and 2 yrs, already had a MLL-AF4 fusion gene in their neonatal blood spots/Guthrie cards infant leukaemias have been suspected to have an environmental component: 1- some of the leukaemias known to be often related to genotoxic exposure, such as the 11q23 leukaemias and the t(8;16) leukaemia, may also be found in infants; 2- there has been a significant increase in infant acute leukaemias incidence of around 2.5% per year for 15 yrs, suggesting the presence of an environmental factor; 3- infants with leukaemia (excluding Down syndrome cases) have more Pathology Disease Infant myelodysplasia Note they most often exhibit a normal karyotype or a monosomy 7 Etiology exhibit a genetic background or is considered as idiopathic Epidemiology annual incidence : about 1 case per 106 Prognosis has herein been calculated from 3 large studies (n= 47) : median survival was 31 mths; 6 yr survival was 43%

Disease Down syndrome with M7 Note Down syndrome patients have been known for long to be at increased risk (10 to 30 fold) of both ALL and ANLL; ALL is similar in Down syndrome (DS) and in the general population, whereas ANLL in DS is most often a specific entity of acute megakaryoblastic leukaemia (M7- ANLL); at least 20% of leukaemias in DS are M7, and other cases of M7-ANLL may also be misclassified as undifferentiated leukaemias or as ALL; therefore, the risk of M7 may well be 500 to 1000 times greater when the child has a DS; in other words, it may be that half of infants with M7 are DS ... and also that the risk of ALL in DS may not be as increased as previously claimed Epidemiology M7 leukaemia in Down syndrome infants annual incidence : 0.2 case per 106; median age at diagnosis is 22-23 mths Clinics there is often a preceeding myelodysplasia, or history of transient leukemoid reaction (a disease of the megakaryocytic lineage) Prognosis M7-ANLL has proved to be of better prognosis when in DS, with a recent study on 65 DS patients with M7, showing a 4 yr event free survival of 73%

Disease 11q23 abnormalities Phenotype / M4 or M5 acute non lymphocytic leukaemia (ANLL) or CD19+ B-cell cell stem acute lymphocytic leukaemia (ALL); origin Epidemiology 25% of 11q23 rearrangements cases are infant (<1 yr) cases; as much as 2/3 of cases of infant ALL leukaemias have been found in some studies to carry a 11q23 rearrangement, especially in infants < 6 mths old; a third to a half of infant ANLL cases also have a 11q23 rearrangement; however, 11q23 leukaemias can also be seen in children and in adults Clinics organomegaly; frequent CNS involvement; high WBC Prognosis median survival of 1yr, and a 3yr event free survival of 13% in a study and a 4 yr event free survival of 15% in another

t(4;11)(q21;q23) : CD19+ B-ALL; unbalanced sex ratio < 4 yrs (1M/2F); infants (<1 yr) accounting for 1/3 of t(4;11) cases; annual incidence could be 0.3-0.5 case per 106; prognosis: med EFS 7 mths;

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -227- med survival 29mths; 3yr survival 40%; 3yr EFS: 30%; the gene involved in 4q21 is AF4

t(9;11)(p23;q23) : found in M5a or M4 ANLL; the rare ALL cases of t(9;11) are most often found in infants; infants cases (<1 yr) account for 15% of all t(9;11) cases; med EFS: 1yr, 3yr EFS 20%; the gene involved in 9p22 is AF9 t(10;11)(p12;q23) : rare; M4 or M5 ANLL; ALL at times; infants represent 40% of cases; the gene involved in 10p12 is AF10 t(11;19)(q23;p13.3): ALL, biphenotypic AL and M4 or M5 ANLL; half cases of t(11;19)(q23;p13.3) are infant cases; a study on 40 cases showed that med survival was 5 mths, with a 2yr survival of 20% (unpublished observation); the gene involved in 19p13.3 is ENL other 11q23 rearrangements are rarely found in infants leukaemias in 11q23 sits MLL, which encodes a 431 kDa protein; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation; wide expression; homology with trithorax (drosophila); the fusion protein includes the N-term AT hook and DNA methyltransferase from MLL fused to (little or most of) the partner C- term part from the other chromosome

Disease t(1;22)(p13;q13) Phenotype / cell stem M7 ANLL origin Epidemiology 39 cases so far described; <0.1 case per 106 (perhaps much less); the only leukaemia (nearly) restricted to infant cases; median age is 4 mths Clinics organomegaly, bone marrow fibrosis; misdiagnosis of a solid tumour is frequent Prognosis remission is obtained in only half cases, median survival is 7 mths

Disease 12p abnormalities Phenotype / cell stem B lineage ALL mainly (CD10+); M5 ANLL at times origin Epidemiology at least 9 cases Prognosis no sufficient data

Disease inv(16)(p13q22) Phenotype / cell stem M4 ANLL origin Epidemiology at least 3 cases reported

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -228- Clinics high WBC, CNS involvement Prognosis is very poor so far (remission duration : 0, 2, 6 mths), in contrast with the usual inv(16) prognosis

Disease t(5;15)(p15;q11) Phenotype / cell stem B lineage ALL origin Epidemiology 5 known cases Prognosis unknown; CR in 5/5

Disease t(8;16)(p11;p13) Phenotype / cell stem M5/M4 ANLL origin Epidemiology at least 3 cases Prognosis survival : 0.5 mth, 22 mths+, 24 mths+

Disease +19 and/or +21 Phenotype / cell stem ANLL and ALL origin Epidemiology at least 5 cases Prognosis no survival data available

Disease other chromosome rearrangements : +8 (solely or not), found in a few cases, del(6q), , and non recurring anomalies, found in at least one case each; finally, the kayotype has been found to be normal in a percentage of cases PHENOTYPE_STEM_CELL_ORIGIN Bibliography An analysis of leukemic cell chromosomal features in infants. Pui CH, Raimondi SC, Murphy SB, Ribeiro RC, Kalwinsky DK, Dahl GV, Crist WM, Williams DL. Blood 1987; 69: 1289-1293. Medline 87185810

Clinical characteristics of infant leukemia with or without 11q23 translocations. Kaneko Y, Shikano T, Maseki N, Sakurai M, Sakurai M, Takeda T, Hiyoshi Y, Mimaya JI, Fujimoto T. Leukemia 1988; 2: 672-676. Medline 89013230

Phenotypic and genotypic heterogeneityin infant acute leukemia. II. Acute

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -229- nonlymphoblastic leukemia. Köller U, Haas OA, Ludwig WD, Bartram CR, Harbott J, Panzer_Grümayer R, Hansen_Hagge T, Ritter J, Creutzig U, Knapp W, Gadner H. Leukemia 1989;3:708-714. Medline 89383528

Acute myeloid leulemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on pediatric oncology group AML study 8498. Ravindranath Y, Abella E, Krischer JP, Wiley J, Inoue S, Harris M, Chauvenet A, Alvarado CS, Dubowy R, Ritchey AK, Land V, Steuber CP, Weinstein H. Blood 1992; 80: 2210-2214. Medline 93043333

11q23/MLL rearrangement confers a poor prognosis in infants withacute lymphoblastic leukemia. Pui CH, BEhm FG, Downing JR, Hancock ML, Shurtleff SA, Ribeiro RC, Head DR, Mahmoud HH, Sandlund JT, Furman WL, Roberts WM, Crist WM, Raimondi SC. J Clin Oncol 1994; 12: 909-915. Medline 94216939

Myelodysplasia and acute megakaryoblastic leukemia in Down's syndrome Zipursky A, Thorner P, De Harven E, Christensen H, Doyle J. Leuk Res. 1994 Mar;18(3):163-71. Medline 94187373

Akute myeloische leukämie bei kindern mit Down-syndrom. [Acute myeloid leukemia in children with Down syndrome] Creutzig U, Ritter J, Ludwig WD, Niemeyer C, Reinisch I, Stollmann-Gibbels B, Zimmermann M, Harbott J. Klin Pädiatr 1995: 207: 136-144. Medline 96018542

Acute megakaryoblastic leukemia. Gassman W, Löffler H. Leukemia Lymphoma 1995;18 Suppl 1:61-63. Medline 96077760

Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Passmore SJ, Hann IM, Stiller CA, Ramani P, Swansbury GJ, Gibbons B, Reeves BR, Chessells JM. Blood. 1995 Apr 1;85(7):1742-50 Medline 95218172

Ultrastructural studies of the megakaryoblastic leukemias of Down syndrome. Zipursky A, Christensen H, De Harven E. Leuk Lymphoma. 1995 Jul;18(3-4):341-7. Medline 96077743

Infant leukemia biology, aetiology and treatment. Greaves MF. Leukemia 1996; 10: 372-377. Medline 96200153

Pathogenesis, biology, and management of myelodysplastic syndromes in children. Haas OA, Gadner H. Semin Hematol. 1996 Jul;33(3):225-35. Review.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -231- Medline 96416331

Myelodysplastic syndrome in children: differenciation from acute myeloid leukemia with a low blast count. Chan GCF, Wang WC, Raimondi SC, Behm FG, Krance RA, Chen G, Freiberg A, IN gram L, Butler D Head DR. Leukemia 1997; 11: 206-211. Medline 97162095

Spontaneous remission of congenital leukemia. Dionulos JG, Hawkins DS, Clark BS, Francis JS. J Pediatr 1997; 131: 300-303. Medline 97435953

Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Gale KB, Ford AM, Repp R, Borkhardt A, Keller C, Eden OB, Greaves MF. Proc Natl Acad Sci USA 1997; 94: 13950-13954. Medline 98054341

Forty four cases of childhood myelodysplasia with cytogenetics, documented by the Groupe Français de Cytogénétique Hématologique. Groupe Français de Cytogénétique Hématologique Leukemia 1997; 11: 1478-1485 Medline 97449105

Hematologic malignancies with t(4;11)(q21;q23) - a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases. Johansson B, Moorman AV, Haas OA, Watmore AE, Cheung KL, Swanton S, Secker-Walker LM. Leukemia 1998 May;12(5): 779-787. Medline 98254113

The t(10;11)(p12;q23) translocation in acute leukaemia: a cytogenetic and clinical study of 20 patients. European 11q23 Workshop participants Lillington DM, Young BD, Berger R, Martineau M, Moorman AV, Secker-Walker LM. Leukemia 1998; 12: 801- 804. Medline 98254116

Hematological malignancies with t(9;11)(p21;q23) - a laboratory and clinical study of 125 cases. Swansbury GL, Slater R, Bain BJ, Moorman AV, Secker-Walker LM. H Leukemia. 1998 May;12(5):792-800 . Medline 98254115

Distinctive demography, biology, and outcome of acute myeloid leukemia and

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -232- myelodysplastic syndrome in children with Down syndrome/ children's cancer group studies 2861 and 2891. Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, Howells WB, Gold S, Sanders J, Neudorf S, Smith FO, Woods WG. Blood. 1998 Jan 15;91(2):608-15 Medline 98102443

Congenital abnormalities in children with acute leukemia: a report from the children's cancer group. Mertens AC, Wen W, Davies SM, Steinbuch M, Buckley JD, Potter JD, Robison LL. J pediatr 1998; 133: 617-623. Medline 99038858

The translocations t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3): a cytogenetic and clinical profile of 53 patients. Moorman AV, Hagemeijer A, Charin C, Rieder H, Secker-Walker LM , on behalf of the European 11q23 workshop participants. Leukemia 1998; 12: 805-810. Medline 98254117

General reports on the European concerted action workshop on 11q23. Secker-Walker LM, on behalf of the European 11q23 workshop participants. Leukemia 1998; 12: 776-778. Medline 98254112

Fifteen New Cases of the t(1;22)(p13;q13) Acute Megakaryoblastic Leukaemia of Infants and a Review of 39 Cases : Report from a t(1;22) Study Group. Bernstein J , Dastugue N, Haas OA, Harbott J, Heerema NA, Huret JL, Landman- Parker J, LeBeau MM, Léonard C, Mann G,Pages MP, Pérot C, Pirc-Danoewinata H, Roitzheim B, Rubin CM, Slociak M, Viguié F. submitted

Contributor(s) Written 05- Jean-Loup Huret 1999 Citation This paper should be referenced as such : Huret JL . Infant leukaemias,Congenital leukaemias,Neonatal leukaemias. Atlas Genet Cytogenet Oncol Haematol. May 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/InfantLeukID1084.html

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t(17;19)(q22;p13)

Clinics and Pathology Disease acute lymphoblastic leukemia (ALL) Phenotype / precursor-B cell immunophenotype; characteristic expression of cell stem surface markers CD10, CD19, TdT, HLA-DR origin Epidemiology less than 1% of ALL cases; 1% of childhood B-ALL ; sex ratio 1M/1F; more frequent in children Clinics frequent disseminated intravascular coagulation at diagnosis (not observed in ALL with other translocations) Cytology pro-B lymphocytes Prognosis poor; no response to intensive chemotherapy and short survival Cytogenetics Cytogenetics presents usually as a balanced translocation t(17;19)(q22;p13); in Morphological some cases, only the der(19)t(17;19) is observed, but not the der(17); the same unbalanced form occurs in the closely related t(1;19) Additional found in appproximately 50% of cases anomalies Variants the translocation t(1;19)(q23;p13) and the t(17;19)(q22;p13) can be considered as variants of each other Genes involved and Proteins Gene HLF (Hepatic Leukemia Factor) Name Location 17q22

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -234- Protein basic leucine zipper (bZIP) transcription factor; normally expressed in hepatocytes and, at lower level, in lung and renal cells but not in hematopoietic cells Gene E2A Name Location 19p13

Protein E2A encodes the basic helix loop helix (bHLH) transcription factors E12 and E47; expressed in most cell types Result of the chromosomal anomaly Hybrid gene

Description fusion gene E2A-HLF on der(19); two types of genomic rearrangements: type 1 results from a crossover between E2A intron 13 and HLF intron 3, type 2 from a crossover between E2A intron 12 and HLF intron 3 - t(17;19) type I: 5' E2A exons 1 to 13 <-> cryptic exon formed by E2A intron/HLF intron sequences to reestablish a reading frame <-> HLF exon 4 in 3' - t(17;19) type II: 5' E2A exons 1 to 12 <-> HLF exon 4 in 3' Transcript expression of two mRNAs of 4.4 and 4.8kb with the same coding sequence Detection RT-PCR

Fusion the fusion results in linking the amino-terminal transactivation domains Protein 1 and 2 of E2A to the carboxy-terminal leucine zipper and basic Description domain of HLF; the minor structural difference induced in both types of proteins does not appear to have any functional consequence Oncogenesis the fusion gene encodes a chimeric transcription factor E2A-HLF with altered DNA binding affinity compared with native HLF; it functions as an antiapoptotic transcription factor in leukemic cell transformation; when E2A-HLF protein was introduced into murine pro-B lymphocytes, it reverted both interleukin-3-dependent and p53-mediated apoptosis; E2A-HLF could act by regulating expression of downstream target genes : possible activation of target genes normally repressed in B-cell precursors by another bZIP protein gene, E4BP4 (dominant negative effect by heterodimerization with endogenous proteins?)

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External links Other t(17;19)(q22;p13) Mitelman database (CGAP - NCBI) database Other t(17;19)(q22;p13) CancerChromosomes (NCBI) database Bibliography Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis. Hunger SP Blood. 1996 Feb 15;87(4):1211-24. Medline 96190033

New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Raimondi SC, Privitera E, Williams DL, Look AT, Behm F, Rivera GK, Crist WM, Pui CH. Blood 1991; 77: 2016-2022. Medline 91208418

Fusion of the leucine zipper gene HLF to the E2A gene in human acute B- lineage leukemia. Inaba T, Roberts WM, Shapiro LH, Jolly KW, Raimondi SC, Smith SD, Look AT. Science 1992; 257: 531-534 Medline 92342953

E2 A/HLF fusion cDNAs and the use of RT-PCR for the detection of minimal residual disease in t(17;19)(q22;p13) acute lympho blastic leukemia. Devaraj PE, Foroni L, Sekhar M, Butler T, Wright F, Mehta A, Samson D, Prentice HG, Hoffbrand AV, Secker-Walker LM. Leukemia 1994; 8: 1131-1138. Medline 94309294

Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor. Inaba T, Inukai T, Yoshihara T, Seyschab H, Ashmun RA, Canman CE, Laken SJ, Kastan MB, Look AT. Nature 1996; 382: 541-544 Medline 96320558

Cell transformation mediated by homodimeric E2A-HLF transcription factors. Inukai T, Inaba T, Yoshihara T, Look AT. Mol Cell Biol 1997; 17: 1417-1424. Medline 97184466

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -236- Contributor(s) Written 05- Franck Vigiué 1999

Citation This paper should be referenced as such : Viguié F . t(17;19)(q22;p13). Atlas Genet Cytogenet Oncol Haematol. May 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t1719ID1078.html

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+15 or trisomy 15 (as sole autosomal abnormality)

Clinics and Pathology Disease myeloid and lymphoid lineages (myelodysplastic syndromes (MDS), acute nonlymphocytic leukaemia (ANLL), acute lymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL)); also reported in patients free of haematological malignancy Phenotype / cell stem most commonly seen in low grade MDS, usually RA origin Epidemiology frequency: rare; marked male predominance; found mostly in adults; med age: 77 Prognosis not known Cytogenetics Additional sex chromosome aneuploidy, particularly -Y in males anomalies Genes involved and Proteins Note is/are not known

External links Other +15 or trisomy 15 (as sole autosomal Mitelman database (CGAP - database abnormality) NCBI) To be noted proposed association between loss of Y chromosome and trisomy 15, which may reflect an underlying age effect in some cases Bibliography Trisomy 15 in hematological malignancies: six cases and review of the literature. Smith SR, Rowe D Cancer Genet Cytogenet. 1996 Jul 1;89(1):27-30. Review. Medline 96280752

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -238- Trisomy 15 associated with loss of the Y chromosome in bone marrow: a possible new aging effect. Sinclair EJ, Potter AM, Watmore AE, Fitchett M, Ross F Cancer Genet Cytogenet. 1998 Aug;105(1):20-3. Review. Medline 98354363

Contributor(s) Written 05- Elizabeth J Sinclair and Anthony M Potter 1999 Citation This paper should be referenced as such : Sinclair EJ and Potter AM . +15 or trisomy 15 (as sole autosomal abnormality). Atlas Genet Cytogenet Oncol Haematol. May 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/tri15ID1144.html

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

Breast tumors : an overview (updated: old version not available)

Classification Benign epithelial lesions with no significant tendency to malignant transformation include : adenoma:

o ductal o lactating o tubular

adenosis:

o apocrine o blunt duct o microglandular o sclerosing

fibroadenoma radial scar/complex sclerosing lesions Invasive breast carcinomas are divided into two major categories on the basis of their cytoarchitectural features: Invasive ductal carcinoma :

o acinic cell carcinoma o adenoid cystic carcinoma o apocrine carcinoma o cribriform carcinoma o glycogen-rich/clear cell o inflammatory carcinoma o lipid-rich carcinoma o medullary carcinoma o metaplastic carcinoma o micropapillary carcinoma o mucinous carcinoma o neuroendocrine carcinoma o oncocytic carcinoma o papillary carcinoma o sebaceous carcinoma o Secretory Breast Carcinoma o tubular carcinoma

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -240- lobular carcinoma

o pleomorphic o signet ring cell

The recognized precursor lesions of invasive breast carcinoma are : intraductal proliferative lesions:

o atypical ductal hyperplasia o ductal carcinoma in situ o florid o usual

lobular neoplasia/atypical lobular The terminology Invasive ductal/lobular carcinoma does not imply an origin form ducts and lobules, respectively, but the presence of cytoarchitectural and phenotypical features of ductal-type and lobular- type, respectively. Ductal adenocarcinoma is the most common. Lobular carcinoma is the second malignant breast tumour. Medullary carcinoma is rare. Hyperplasia is a proliferation without criteria of malignancy. Fibroadenomas are benign breast tumours. Clinics and Pathology Etiology The etiology is multifactorial. It involves diet, genetic and reproductive factors, and related hormone imbalances. Epidemiology The annual incidence of breast cancer is about 43/100 000 per year in France, and the mortality rate is about 18/100 000 per year. Invasive breast cancer is the most common carcinoma in women, accounting for 22% of all female cancers. One million women worldwide are diagnosed with breast cancer every year. The main factors of risk are: gender : women's risk for the development of invasive breast carcinoma is approximately 400 times that of men. age : breast cancer incidence increases rapidly with age. The mean age at diagnosis is around 60 yrs genetic factors : rare (3 to 5% of cancers and 1/500-800 women) but highly predictive of the disease. The areas of higher risk are the affluent populations of North America, Europa and Australia, where 6% of women develop invasive breast carcinoma before age 75. Pathology The most common histologic type of invasive breast carcinoma is designated as ductal, NOS (not otherwise specified). It comprises about 80% of all cases. It is a proliferation of epithelial cells from galactophoral ducts; it may be preceded and accompanied by an in situ component characterized by a proliferation of cells within the ducts without interuption of the basal membrane; when this membrane is

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -241- altered, the carcinoma is invasive. It can be graded on the basis of the architecture (amount of tubule formations), nuclear atypia and mitotic activity. The score resulting from the sum of these criteria (NottinghamÕs score) has been show to be an important prognostic indicator. A 3-grade system has been developed for in situ ductal carcinoma. Grade III in situ ductal carcinoma corresponds to the classic comedocarcinoma, whereas Grade I in situ ductal carcinoma merges with atypical ductal hyperplasia, to the point that some authors regard the two process as one and the same. Recently, a proposal has been made to embrace all of the various types of intraductal proliferative lesions under the term ductal intraepithelial neoplasia (DIN) and to divide this into 3 grades, having increasingly higher risk for the development of invasive carcinoma.

Many morphologic variants of invasive ductal carcinoma exist, some of them extremely rare. They include: tubular, cribriform, medullary, mucinous, neuroendocrine, papillary, micropapillary, apocrine, metaplastic, lipid-rich, secretory, oncocytic, adenoid cystic, acinic cell, glycogen-rich (clear cell), sebaceous, and inflammatory carcinoma. The prognosis of these subtypes varies, some of them having a better and some a worse outcome than invasive ductal carcinoma, NOS.

Invasive lobular carcinoma is the second major type (5-10%) of breast cancer. Like its ductal counterpart, it may be preceded or accompanied by an in situ component. It is histologically more homogeneous than ductal carcinoma, but some morphologic variation exist, such as pleomorphic and signet ring cell. Medullary carcinoma, already mentioned above as a rare subtype of invasive ductal carcinoma (1%) with a better prognosis, it has a very distinctive form: sharply circumscribed, accompanied by a heavy lymphoid infiltrate, of high nuclear grade, with a syncytial pattern of growth, and lacking in situ or microglandular features. When one of these features is lacking, the tumor is referred to as Òatypical medullary carcinoma". A high frequency of medullary carcinoma has been reported in patients with BRCA1 germ line mutation. The different steps in the progression of breast cancer are not well individualized. Hyperplasia is a proliferation of ductal or lobular epithelial cells, without criteria of malignancy; in contrast, atypical hyperplasia has incomplete malignant features and can be difficult to distinguish from in situ carcinoma. Fibroadenomas are the most common form of benign breast tumors.

These different forms of breast cancer may occur with (hereditary or familial forms) or without (sporadic forms) a familial background. Prognosis There are over 100 factors that have been identified as having prognostic significance in breast carcinoma , but only a minority of them will retain this property when subjected to a multivariate analysis.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -242- The most important prognostic factors are: presence and number of positive lymph nodes; tumor size; microscopic grade; and presence of lymphovascular invasion. Other parameters examined pathologically - such as hormone receptors and ERBB2/Neu - have more of a predictive than a prognostic value, in the sense of anticipating a certain type of response to specific forms of therapy. Upon diagnosis, the different presentations are classified upon morphological study, and the gravity and prognosis of the disease is estimated with several parameters that are : tumor size, tumor grade: it is calculated from assessment of tubular differentiation, number of mitoses, and nuclear polymorphism, the absence of estrogen and progesterone receptors, the presence of lymph node metastasis, peritumoral vascular invasion. Other parameters such as the proliferating index (Ki 67, S-phase), the ploidy, and the presence of P53 or ERBB2 alteration may also be useful for prognostic evaluation or as predictive factors for therapeutic response. Genetics Note Familial breast cancers are thought to represent about 5 to 10% of all breast cancers. Cytogenetics Cytogenetics Many of the chromosomal aberrations observed in breast carcinomas Morphological are not specific of this type of tumour; karyotypes of breast tumours frequently show multiclonality, suggesting the existence of a high degree of intratumoural heterogeneity.

Alterations of chromosome arms 1q, 3p, 6q, 8p are often present; i(1q) and der t(1;16) are frequent as sole anomalies; +7, +8 and +20 are also frequent; cytogenetic signs of DNA amplification, such as homogeneously staining regions (HSR), are commonly observed in breast carcinomas and seem preferentially associated to 8p. Cytogenetics LOH studies : loss of heterozygosity (LOH) has been associated with Molecular physical deletion of large genomic segments containing tumour suppressor genes; common regions of LOH in breast cancer are located on several chromosomes: 1p, 1q, 3p, 6q, 8p, 11q, 13q, 16q, 17p, 17q; almost all breast tumours show LOH in one or several regions; some regions are lost in more than 50% of tumors: 8p, 16q, 17p; precancerous lesions also show LOH.

CGH : Comparative genomic hybridization (CGH) is a molecular cytogenetics method designed to detect and map chromosomal regions showing abnormal copy numbers in tumors; theoretically, it is possible to detect equally copy number gains (DNA amplification or polyploidies) or losses using this approach; it appears, however, that CGH has a greater sensitivity for gains than for losses; this could be related to the fact that gains are generally of higher magnitude than losses and that losses can be obscured by intratumoral heterogeneity;

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -243- Overall CGH data show that breast tumor genomes undergo severe rearrangements; on average, breast tumors show 5-7 copy number changes/tumor; less than 10% of the tumors analyzed by CGH show neither gains nor losses; almost every chromosome presents at least one site with aberrant copy numbers, however, gains or losses are not evenly distributed throughout the genome.

Hot spots for gains are routinely observed at 1q (50-55% of the tumors), 8q (60%), 17q (25-30%), 20q (20-25%); gains generally involve subregions of each chromosomal arm and most prevalent regions are 1q31-q32, 8q12 and 8q24 (with MYC and other genes), 17q12 (ERBB2) and 17q23-q24, and 20q13; other regions of recurrent gains are 11q13 (20%, with CCND1), 8p12 (10-15%, and FGFR1), 16p (10-15%); recurrent losses are observed at 1p, 6q, 8p, 11q23- qter, 13q, 16q, 17p and 22q

CGH has revealed that copy number gains are common in breast tumors and involve 26 (!) chromosomal arms; these data somewhat contradict karyotypical analysis and LOH studies which indicate that losses are more frequent that gains; furthermore, it appears from CGH data that the number of events (gains and losses) increases in advanced cancer. Genes involved and Proteins Gene HRAS Name Location 11p15.5

Gene KRAS Name Location 12p12.1

Gene NRAS Name Location 1p13.2 Protein H, K, and NRAS genes are a subfamily of the huge RAS/RHO/RAB superfamily and encode ubiquitous cytoplasmic GTP binding p21 proteins involved in signal transduction. Somatic RAS genes are mutated at codons 12, 13 and 61in different types of mutation cancers; the frequency of mutations in breast cancer is rather low (<10%) compared to colorectal cancer or pancreatic cancer for instance.

Gene P53 Name Location 17p13

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -244- Dna / Rna 11 exons Protein The tumor suppressor gene P53 encodes an ubiquitous nuclear protein involved in the control of genome integrity by preventing cells from dividing before DNA damage is repaired; it has 5 conserved regions containing a transactivation domain, a DNA-binding domain, a tetramerization domain. Somatic 20-25% of breast cancers show P53 mutations and these correspond mutation to aggressive breast tumors (loss of estrogen receptor expression). 90% of P53 mutations are found within exons 5 through 9, portions correspondig to codons 165-185 (exon 5) and 235-252 (exon 7) concentrating 50% of the mutations (mutational hot spots); most frequently involved are codons 175, 248 and 273; mutations affecting residues 165-185 and 235-252 bear worse prognostic significance than others; these amino acid residues are located in the L2 and L3 domains of the p53 protein; both these domains bind a Zinc atom and convey contact to DNA; it may thus be of greater phenotypic significance. The majority of P53 mutations (80%) in breast cancer are missense, while nonsense mutations, deletions, insertions or, splice site mutations, which result in the truncation of the protein, make the rest (20%). Prolonged half-life of the protein can also be detected by immunohistochemistry and shows correlation with missense mutations.

Gene ERBB2 Name Location 17q21.2 Protein The ERBB2 (also called HER2 or NEU) gene encodes an integral type I protein of 185 kDa with a cysteine-rich extracellular region, a transmembrane domain and an intracellular region endowed with a tyrosine kinase activity. Somatic HER2 somatic mutations are reported in lung cancer, glioblastoma and mutation ovarian tumor. No somatic mutations in human breast carcinoma are described. Amplification : the ERBB2 gene is amplified and overexpressed in 20- 25% of breast tumors; tumors showing ERBB2 amplification have predominantly lost estrogen receptor expression (ER-) and are of ductal invasive type; interestingly, 70% of intraductal comedo carcinomas show ERBB2 expression, suggesting a role of this gene in the etiology of this breast tumor subtype ; Although ERBB2 amplification and overexpression are related to a worsened course of the disease, they do not represent independent prognostic indicators; However, the p185-ERBB2 protein being a transmembrane receptor with low levels of expression in normal tissues has turned out to be a very interesting target for therapeutical approaches; several protocols using engineered anti-ERBB2 antibodies have shown a good success rate.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -245- Gene CCND1 Name Location 11q13.3 Protein The CCND1 gene codes for a cell cycle protein specifically acting in the G1 phase; upon interaction with cyclin dependent kinases (CDK4 or CDK6) cyclin D1 phosphorylates the p105-RB protein and thereby promotes progression in late G1 thus favoring entry into S phase; ectopic overexpression of CCND1 has been shown to result in shortened G1 phase and increased genetic instability, possibly due to a bypass of cell cycle checkpoints. Somatic Amplification : the CCND1 gene is amplified in approximately 15% mutation breast cancers; CCND1 amplification is strongly correlated to expression of ER and is prevalent in invasive lobular carcinomas; univariate analysis and Cox model studies show that CCND1 amplification is an independent prognostic factor, however, it bears greatest significance in node positive patients.

Gene FGFR1 Name Location 8p11-12 Protein The FGFR1 gene encodes an integral type I protein of 145 kDa with an extracellular region made of three immunoglobulin-like domains, a transmembrane domain and an intracellular region endowed with a tyrosine kinase activity; alternative splicing create a large number of isoforms; it is a receptor for different members of the fibroblast growth factor family (FGF), which has about 20 members known to date. Somatic Amplification : the 8p11-12 region is amplified in about 10% of breast mutation carcinomas; the FGFR1 gene is overexpressed as a consequence of the amplification, and is a good candidate for being the driver gene of the 8p11-12 amplicon; FGFR1 is frequently amplified concomitantly with CCND1 (40% of FGFR1 amplified tumors also show CCND1 amplification); this coamplification of FGFR1 and CCND1 chromosomal regions results in the formation of a hybrid chromosomal structure in which amplified FGFR1 and CCND1 sequences are sequentially arranged.

Gene BRCA1 Name Location 17q21 Dna / Rna Large gene of 22 coding exons spaning more than 70 kb of genomic DNA; exon 11 corresponds to almost 50% of the total coding sequence (5592 nucleotides); the BRCA1 mRNA has a size of 7.8 kb, and a complex pattern of alternative splicing has been reported; it is expressed in numerous tissues (breast, ovary, testis, spleen, thymus ...). Protein the corresponding protein has 1863 amino acids, and 190-220 kDa;

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -246- BRCA1 is not a member of any known gene family; there is only two stretches of evolutionary conserved sequences between humans and mice: at the N-terminus (the RING finger motif), and at the C-terminus (the BRCT domain); the function of BRCA1 is still unknown but it seems to act as a tumor suppressor gene with transcriptional activity; it is involved in cell proliferation processes of mammary epithelial cells in response to hormonal stimulation, in apoptosis, control of recombination and genome integrity after binding to proteins involved in these activities. Germinal more than 300 sequence variations at the germline level have been mutation reported; a list is available on the BIC website:

the germline mutations are dispersed throughout the coding sequence; although a majority of these variations are unique, recurrent mutations such as 185delAG and 5382insC are observed; they were initially described in the Ashkenazy Jewish population; more than 80% of the sequence variants lead to a truncated protein; in contrast, the majority of missense mutations are of unknown clinical significance, excepted those in the RING finger region; in the BRCA1 families, an excess of breast, ovarian, and prostate cancers are seen; all mutations combined, penetrance at age 70 years works out at 56% to 87% in the case of breast cancer, and 16% to 63% in that of ovarian cancer

BRCA1-associated breast cancers have specific morphological features; they are more frequently of histoprognostic grade 3, highly proliferating and poorly differentiated tumors with a very pleomorphotic nuclear pattern; high frequencies of P53 alterations and negativity of steroid receptors are found in these tumors; a high rate of medullary breast carcinomas is observed among BRCA1-associated breast cancers; evidence for possible genotype-phenotype correlations have been provided concerning the tumor spectrum (breast/ovarian cancer incidence rate), the penetrance, and the proliferation rate of tumors Somatic in contrast, somatic mutations of BRCA1 coding sequence are rare in mutation breast/ovarian cancers

Gene BRCA2 Name Location 13q12-13 Dna / Rna like BRCA1 it is a large gene spanning more than 70 kb of genomic DNA; the coding sequence comprises 26 exons (10254 nucleotides) with three large ones (exons 10, 11, 27); the mRNA is of 11-12 Kb long; like BRCA1, it is expressed in various tissues. Protein The coresponding protein has 3418 amino acid residues (384 kDa), and is poorly conserved, exepted for the BRC repeats region in exon 11 (8 copies of 20-30 aa); like BRCA1, its function remains unknown; however, it acts as a tumor suppressor gene; transcriptional activation properties have been reported as well as involvement in the DNA repair system.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -247- Germinal more than 100 unique germ-line mutations are reported and are mutation dispersed throughout the coding sequence (cf the BIC website, address above); recurrent mutations are seen: 6174delT (of Ashkenazy Jewish origin), 999del5 (Icelandic), and 6503delTT (in France and in the UK); the majority lead to a truncated protein and are considered as disease- associated mutations, except for a polymorphic stop codon in exon 27; missense mutations are of uncertain clinical significance

BRCA2 germline mutations are associated with a high risk of male and female breast cancer; initially, the breast cancer risk was considered as equivalent to that of BRCA1, but in a recent work based only on the Icelandic recurrent BRCA2 999del5 mutation, the estimated risk of breast cancer at age 70 years is considered of only 37%; the ovarian cancer risk is lower than that of BRCA1; in addition, an excess of prostate and pancreas cancers is also seen

at the morphological level, BRCA2 breast cancers seem to be different from both BRCA1-associated breast cancers and sporadic cases, with a poor differentiation but no high proliferation rate; evidence for possible genotype-phenotype correlation has been provided concerning the tumor spectrum (breast/ovarian cancer incidence rate) Somatic somatic mutations of BRCA2 coding sequence are rare in mutation breast/ovarian cancers.

Gene BRCA3 Name Location An important breakthrough in the understanding of breast carcinogenesis came with the identification of the two major genes BRCA1 and BRCA2, correponding to 52% and 32% of hereditary breast cancer families, respectively; however, the germline mutations of these genes do not account for all familial cases; additional genes may be involved.

One such gene might be located on chromosome arm 8p; a positive linkage has first been found in a small set of French families, and then a lod score of almost 3 was obtained in one German family; in addition, the chromosome 8p12-22 region seems to be frequently involved in breast carcinogenesis as well as in different types od tumors (lung, prostate, ovarian); while the 8p12-22 region remain a strong candidate locus, whole-genome linkage studies are in progress to identify the other gene(s) that predispose to breast cancer.

Gene PTEN Name Location 10q23 Dna / Rna 9 exons Protein The PTEN protein (also called MMAC1) is an evolutionary conserved

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -248- dual-specificity phosphatase sharing extensive similarity with the cytoskeletal protein tensin; PTEN appears to be a tumor suppressor since biallelic inactivations are observed in several types of tumors; inactivating germline mutations are responsible for a cancer prone syndrome, the Cowden disease (see below); also, PTEN -/- ES cells are highly tumorigenic in syngeneic mice whereas PTEN +/- are not. Germinal Heterozygous germline mutations are responsible for the Cowden mutation disease, a cancer prone syndrome with high susceptibility to breast carcinoma, and, to a lesser degree, to thyroid carcinoma; most of the mutations are inactivating mutations, either by leading to protein truncation, or by introducing alterations in the phosphatase catalytic domain; germline mutations are also seen in the Bannayan-Riley- Ruvalcaba syndrome Somatic In spite of the initial description of PTEN homozygous deletion in two mutation breast tumor xenografts and biallelic inactivation of PTEN in two breast carcinoma cell lines, very few PTEN mutations have been observed in sporadic breast carcinoma (1 described mutation in more than 100 analyzed tumors).

Gene ATM Name Location 11q23 Dna / Rna The ATM gene covers 150 kb of DNA and is spread over 64 exons. It codes for a 13.000 bp transcript, translated into a 3500 aa protein. Protein Nuclear protein showing homology at its carboxy terminus with PI-3 kinase; belongs to a family of DNA damage signaling proteins characterized in either yeast or Drosophila; ATM interacts with the ABL protein and is known to transmit a signal to the P53 protein. ATM activity seems restricted to double strand DNA breaks induced by ionising radiations or radio-mimetics; it is noteworthy that the phenotype of Atm KO mice is very similar to that of ATM patients, but that heterozygous Atm +/- mutant mice do not show an increased incidence of cancer. Germinal The ATM gene is the genetic determinant to ataxia telangiectasia, a rare mutation recessive disorder, which among other clinical signs, is characterized by an extreme sensitivity to ionising radiations; it has been hypothesized that ATM could play a role in cancer predisposition because AT patients show a 100 fold increased risk of cancer, particularly hematological malignancies; furthermore, epidemiological studies have suggested that AT heterozygotes were also at increased risk of developing cancer, specially breast cancer in women; this, added to the fact that the ATM gene maps to 11q23, a region frequently affected by losses of heterozygosity, suggested that heterozygous mutations in the ATM gene may favor breast cancer development; ATM heterozygotes have been estimated to represent 1% of the total population. Most mutations reported in ATM kindreds result in the truncation of the protein.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -249- Gene Mismatch repair genes : MSH2 (2p21), MLH1 (3p21), PMS1 (2q31-33), Name PMS2 /GTBP/MSH6 (7p22), MSH3 (5q) Protein The proteins encoded by the mismatch repair genes are analogues of the bacteria Mut HLS system which is involved in the reparation of DNA replication errors; their defect leads to genomic instability, the most visible consequence of which is the presence of additional alleles at microsatellite markers; the latter are prone to replication errors; their alteration is a hallmark of genomic instability, also called RER (replication error) or MSI (microsatellite instability) phenotype. Somatic Frequencies of genomic instability varies from 0 to 40% in breast mutation cancer, depending on studies; however, mutations of mismatch repair genes are uncommon in breast cancer; thus, the high frequencies observed may be due to unknown genes involved in the control of DNA integrity.

Gene E-Cadherin Name Location 16q22.1 Somatic Mutations and loss of expression of the E-cadherin gene, located on mutation chromosome arm 16q, is very frequentlly observed in breast lobular carcinomas.

External links Orphanet Breast cancer, familial Other On-Line Breast Cancer Mutation DataBase database

Bibliography FGFR1 and PLAT genes and DNA amplification at 8p12 in breast and ovarian cancers. Theillet C, Adelaide J, Louason G, Bonnet-Dorion F, Jacquemier J, Adnane J, Longy M, Katsaros D, Sismondi P, Gaudray P, Birnbaum D. Genes Chromosom Cancer 1993; 7: 219-226. Medline 94031964

E-cadherin is a tumour/invasion suppresor gene mutated in human lobular bbreast cancers Berx G, Cleton-Jansen AM, Nollet F, de Leeuw JF, Van de Vijver M, Cornelisse C, Van Roy F. EMBO J 1995; 14: 6107-6115. Medline 96134909

Genetic alterations in breast cancer. Bieche I and Lidereau R.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -250- Genes Chromosom Cancer 1995; 14: 227-251. Medline 96187122

Tumors of the breast. Heim S and Mitelman F. Cancer Cytogenetics, Wiley-Liss, 1995.

Loss of heterozygosity and linkage analysis in breast carcinoma : indication for a putative third susceptibility gene on the short arm of chromosome 8. Kerangueven F, Essioux L, Dib A, Noguchi T, Allione F, Geneix J, Longy M, Lidereau R, Eisinger F, Pebusque MJ, et al. Oncogene 1995; 10: 1023-1026. Medline 95206771

Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors : definition of phenotypic groups. Courjal F, Cuny M, Simony-LafontaineJ, Louason G, Speiser P, Zeillinger R, Rodriguez C, Theillet C. Cancer Res 1997; 57: 4360-4367. Medline 97470639

Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Kerangueven F, Noguchi T, Coulier F, Allione F, Wargniez V, Simony-Lafontaine J, Longy M, Jacquemier J, Sobol H, Eisinger F, Birnbaum D. Cancer Res 1997; 57: 5469-5474. Medline 98069841

Chromosomal imbalance maps of malignant solid tumors. Mertens F, Johansson B, H–glund M, Mitelman F. Cancer Res 1997; 57: 2765-2780. Medline 97349085

Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Rhei E, Bogomolniy F, Federici M, Borgen P, Boyd J. Cancer Res 1997; 57: 3657-3659. Medline 97433097

CCND1 and FGFR1 coamplification results in the colocalization of 11q13 and 8p12 sequences in breast tumor nuclei. Bautista S and Theillet C. Genes Chromosom Cancer 1998; 22: 268-277. Medline 98332327

Characterization of recurrent homogeneously staining regions in 72 breast

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -251- carcinomas. Bernardino J, Apiou F, Gerbault-Seureau M, Malfoy B, Dutrillaux B. Genes Chromosom Cancer 1998; 23: 100-108. Medline 98409392

Functions of the BRCA1 and BRCA2 genes. Bertwistle D and Ashworth A. Curr Op Genet Develop 1998; 8: 14-20. Medline 98190437

Recent advances in breast cancer biology. Eisen A and Weber B. Curr Op Oncol 1998; 10: 486-491. Medline 99035631

Mutations at BRCA1: the medullary breast carcinoma revisited. Eisinger F, Jacquemier J, Charpin C, Stoppa-Lyonnet D, Bressac-de Paillerets B, Peyrat JP, Longy M, Guinebretiere JM, Sauvan R, Noguchi T, Birnbaum D, Sobol H. Cancer Res 1998; 58: 1588-1592. Medline 98222929

Pathology and Genetics of Tumours the Breast and Female Genital Organs F.Tavassoli and P.Devilee . "World Health Organisation Classification of Tumours". IARC Press, Lyon,2003

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Daniel Birnbaum, Francois Eisinger, Jocelyne Jacquemier, 1999 Michel Longy,Hagay Sobol and Charles Theillet Updated 05- Maria Luisa Carcangiu, Patrizia Casalini, Sylvie Ménard 2005 Citation This paper should be referenced as such : Birnbaum D, Eisinger F, Jacquemier J, Longy M, Sobol H, Theillet C . Breast tumors : an overview. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://AtlasGeneticsOncology.org/Tumors/breastID5018.html Carcangiu ML, Casalini P, Ménard S . Breast tumors : an overview. Atlas Genet Cytogenet Oncol Haematol. May 2005 . URL : http://AtlasGeneticsOncology.org/Tumors/breastID5018.html

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Atlas of Genetics and Cytogenetics in Oncology and Haematology

Uterus: Endometrial carcinoma

Classification the modified WHO classification distinguishes: endometrioid adenocarcinoma serous carcinoma clear cell carcinoma mucinous carcinoma serous carcinoma mixed types of carcinoma undifferentiated carcinoma Clinics and Pathology Disease It is an heterogeneous entity, comprising at least two types : type I: endometrioid carcinoma : pre- and perimenopausal, estrogen dependent, associated to endometrial hyperplasia, low grade, indolent behaviour, representing about 80 % of the cases type II: serous carcinoma : post-menopausal, estrogen independent, associated to atrophic endometrium, high grade, aggressive behaviour, representing about 10 % of the cases among other histologic types, type I includes mucinous and secretory carcinomas, whereas type II includes clear-cell carcinomas and adenosquamous carcinomas Embryonic tumour developped from the epithelium of the endometrial mucosa origin Etiology a strong association between unopposed estrogen stimulation and the development of endometrial carcinoma has been demonstrated; this may be related to replacement estrogen therapy, obesity, or chronic anovulation Epidemiology It is the most common malignancy of the female genital tract in developped countries (33.000 new cases per year in the USA); the incidence is 4 to 5 times lower in developping countries Genetics Note besides the common sporadic form, there are two forms of hereditary endometrial carcinoma: a predisposition to endometrial carcinoma; Lynch syndrome , which associates a risk of colon cancer, and ovarian carcinoma in women

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -253- Cytogenetics Cytogenetics the results of conventional cytogenetic techniques and Comparative Morphological Genomic Hybridisation (CGH) show that the two types of endometrial carcinoma differ by their karyotypic features : endometrioid carcinomas are characterised by relatively simple chromosome aberrations whereas serous carcinomas show complex abnormalities endometrioid carcinomas are generally slightly hyperdiploid; chromosome gains concern mainly the long arm of chromosome 1 (70 % of the cases) through isochromosomes or unbalanced translocations; it can be observed as sole abnormality; trisomies 10 (40 % of the cases), 2, 7, and 12 are, in decreasing order, the most frequently associated abnormalities; trisomy 10 can exist as sole imbalance; loss of chromosome 22 has also been recurrently observed; Comparative Genomic Hybridization (CGH) confirms the low rate of copy number changes (mean of 1,5 aberrations per tumour); it roughly shows the same imbalances, and, in addition, gains of 8q (18 % of cases), and of the region 13q21-->qter (3 cases); loss of chromosome 22 has not be detected using this method; high level amplification was found in 3 cases, in 1q and in 6p due to their low incidence and to the complexity of their chromosome abnormalities serous carcinomas are less documented; a CGH sudy, carried out on 24 case showed a higher rate of chromosome imbalances (mean of 5,7 aberrations per tumour); the most frequent regions of gain were 3q26.1-->qter (50 % of cases), 8q (33 %), and 1q, 2q, 5p, 6p; high level amplifications were found in 30 % of the cases in 2q, 3q, 5p, 6p, 8q, 15q, 18 p and 18q, 20 The distinct patterns of chromosome changes observed in serous and endometrioid carcinomas suggest that these two types belong to two genetic entities. A comparison of these results with those of a CGH study of serous ovarian carcinoma (cited in 5) shows that the serous endometrial carcinoma should be genetically related to this tumour. Bibliography Chromosome imbalances in endometrial adenocarcinoma. Couturier J, Vielh Ph, Salmon RJ, Lombard M, Dutrillaux B. Cancer Genet Cytogenet 1988; 33: 67-76. Medline 88253200

Blaustein's Pathology of the Female Genital Tract. Kurman R.J. 4th ed. Springer-Verlag. New-York 1994.

Near-diploid karyotypes with recurrent chromosome changes characterize early-stage endometrial cancer. Bardi G, Pandis N, Schousboe C, Holund B, Heim S. Cancer Genet Cytogenet 1995; 80: 110-114. Medline 95254471

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -254-

Distinct chromosomal imbalances in uterine serous and endometrioid carcinomas. Pere H, Tapper J, Wahlstr–m T, Knuutila S, Butzow R. Cancer Res 1998, 58: 892-895. Medline 98160081

Detection of DNA gains and losses in primary endometrial carcinomas by comparative genomic hybridization Sonoda G, du Manoir S, Godwin AK, Bell DW, Liu Z, Hogan M, Yakushiji M, Testa JR. Genes Chromosomes Cancer 1997 Feb;18(2):115-25 Medline 97187367

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Jérome Couturier 1999 Citation This paper should be referenced as such : Couturier J . Uterus: Endometrial carcinoma. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://AtlasGeneticsOncology.org/Tumors/endometrID5045.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -255- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Kidney: t(X;1)(p11.2;p34) in renal cell carcinoma

Identity Note must not be confused with the t(X;1)(p11.2;q21), also found in renal cell carcinoma Classification renal cell carcinoma (RCC) are classified into two main clinicopathologic entities clear-cell RCC (also called non-papillary RCC, found in 80% of cases) chromophilic RCC (also called papillary RCC, in 15-20% of cases) Clinics and Pathology Disease t(X;1)(p11.2;p34) is found in very rare (n<5) cases of papillary renal cell carcinoma Phenotype / cell stem may not be restricted to the papillary subtype of renal cell carcinoma origin Genes involved and Proteins Gene TFE3 Name Location Xp11.2 Protein contains a transcriptional activation domain , a helix-loop-helix, and a leucine zipper; member of the basic helix-loop-helix family (b-HLH) of transcription factors

Gene PSF Name Location 1p34 Protein contains RNA binding domains; involved in pre-m RNA splicing; form complexes with DNA topoisomerase I

Result of the chromosomal anomaly

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -256- Hybrid Gene Description 5' PSF- 3' TFE3 Fusion

Protein Description N-term PSF and most of it fused to the DNA binding domains of TFE3 (excluding the acidic transcriptional activation domain, including the C- term helix-loop-helix, and the leucine zipper); no TFE3-PSF reciprocal transcript, as the der(X) t(X;1) is missing; the normal TFE3 transcript is found

Bibliography Specific chromosome aberration in human renal cell carcinoma. Kovacs G, Szucs S, De Riese W, Baumgartel H Int J Cancer. 1987 Aug 15;40(2):171-8 Medline 87278685

Distinct Xp11.2 breakpoints in two renal cell carcinomas exhibiting X;autosome translocations. Dijkhuizen T, van den Berg E, Wilbrink M, Weterman M, Geurts van Kessel A, Storkel S, Folkers RP, Braam A, de Jong B Genes Chromosomes Cancer. 1995 Sep;14(1):43-50. Review. Medline 96076342

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Jean-Loup Huret 1999

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -257- Citation This paper should be referenced as such : Huret JL . Kidney: t(X;1)(p11.2;p34) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://AtlasGeneticsOncology.org/Tumors/tX1ID5056.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -258- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Rhabdoid tumor

Classification primarily described as rhabdoid tumor of the kidney (RTK), further extended to tumors of other primary sites : extrarenal rhabdoid tumor (ERRT, or malignant extrarenal rhabdoid tumor MERT) they present a wide histological, ultrastructural, and immunocytochemical spectrum may represent a heterogeneous group of neoplasms and also invite confusion with other renal or extrarenal neoplasms, of which is the Favorable Histology Wilms' tumor (with a fair prognosis) finally "composite" extrarenal rhabdoid tumors (CERT) with a recognizable "parent" neoplasm admixed with MERT appear to be of various origin the recent finding that hSNF5/INI1is involved in true rhabdoid tumors is of paramount importance in this context Clinics and Pathology Embryonic uncertain histiogenesis origin Epidemiology RTK occurs in infancy and early childhood, median age is 11 mths; unbalanced sex ratio (1.5M/1F); ERRT have been observed in a broader range of patient ages Clinics often located in the kidney, may occur in various anatomic sites, such as the central nervous system or soft tissues Prognosis highly aggressive; 80% mortality rate with frequent metastases, predominantly pulmonary; a large study 10 yrs ago found a better outcome for girls (> 50% survival) than for boys (10%) Cytogenetics Cytogenetics normal karyotype or 22q11.2 involvement in a t(Var; 22)(-;q11.2) or Morphological in del(22q). loss of heterozygosity (LOH) on chromosome 22; LOH can also occur at chromosome band 11p15.5, indicating that a second gene may also be involved in addition in a subset of rhabdoid tumors Genes involved and Proteins Gene hSNF5/INI1 Name Location 22q11.2

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -259- Germinal found in the rhabdoid tumor predisposition syndrome. mutation Somatic mutation and allele loss events in sporadic rhabdoid tumors are in mutation accordance with the two-hit model for neoplasia, as is found in retinoblastoma

Bibliography Rabdoid tumor of kidney: a report of 111 cases from the National Wilm Tumor Study Pathology center. Weeks DA,Beckwith JB, Mierau GW, Luckey DW. Am J Surg Pathol 1989; 13: 439-458. Medline 89270848

Renal neoplasms mimicking rhabdoid tumor of kidney. A report from the National Wilms' Tumor Study Pathology Center. Weeks DA, Beckwith JB, Mierau GW, Zuppan CW. Am J Surg Pathol 1991; 15: 1042-1054. Medline 92026688

The clinicopathologic spectrum of putative extrarenal rhabdoid tumors. An analysis of 42 cases studied with immunohistochemistry or electron microscopy. Parham DM,Weeks DA, Beckwith JB. Am J Surg Pathol 1994; 18: 1010-1029. Medline 94379315

Clinicopathologic and cytogenetic analysis of malignant rhabdoid tumor of the central nervous system. Hasserjian RP, Folkerth RD, Scott RM, Schofield DE. J Neurooncol 1995; 25: 193-203. Medline 96139760

Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Wick MR, Ritter JH, Dehner LP. Semin Diagn Pathol 1995; 12: 233-248. Medline 96050185

Loss of heterozygosity at chromosome regions 22q11-12 and 11p15.5 in renal rhabdoid tumors. Schofield DE, Beckwith JB, Sklar J. Genes Chromosomes Cancer 1996; 15: 10-17 . Medline 96422103

Cytogenetic and molecular analysis of a t(1;22)(p36;q11.2) in a rhabdoid tumor with a putative homozygous deletion of chromosome 22.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -260- Rosty C, Peter M, Zucman J, Validire P, Delattre O, Aurias A. Genes Chromosom Cancer 1998; 21: 82-89. Medline 98152018

Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O. Nature 1998; 394: 203-206. Medline 98334382

Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Cancer Res 1999; 59: 74-79. Medline 99107207

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 03- Jean-Loup Huret 1999 Citation This paper should be referenced as such : Huret JL . Rhabdoid tumor. Atlas Genet Cytogenet Oncol Haematol. March 1999 . URL : http://AtlasGeneticsOncology.org/Tumors/rhabdoidID5037.html

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Hereditary papillary renal cell carcinoma Identity Note other (well known) classes of inherited renal cell carcinomas are: the Von Hippel-Lindau syndrome, and the Lynch syndrome II Inheritance some familly trees resemble autosomal recessive transmission (affected sibs with unaffected parents), other exhibit typical autosomal dominant trasmission with a vertical parent-to-child pattern; the situation is not that of (recessive) tumour suppressor genes as in the retinoblastoma, nor that of a recessive DNA replication/repair gene like in Bloom's, but the overexpression of the mutant allele through (acquired) chromosome imbalance (see below) Clinics Note no phenotypic sign Neoplastic multiple and/or bilateral papillary renal cell carcinomas, with median age risk 45 yrs at diagnosis (range 18-79 yrs, most cases being between 35 and 55 yrs old), sex ratio 29M/12F, the presence of asymptomatic cases (mutations have also been detected in tumour-free individuals in these pedigrees pointing to a low expressivity), and still a median age at death of affected individuals at 52 yrs Cytogenetics Note similar to what is found in sporadic papillary renal cell carcinoma, in particular trisomy 7 and 17 Other findings Note no loss of heterozygosity at loci on 3p in the tumours; this contrasts with clear-cell renal cell carcinomas which are associated with deletions of 3p Genes involved and Proteins

Gene MET Name Location 7q31 Protein Expression wide

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -262- Localisation membrane Function transmembrane tyrosine kinase receptor for the hepatocyte growth factor/scatter factor (HGF/SF) Mutations Germinal found mutated in half of the cases of hereditary papillary renal cell carcinoma so far studied; mutations were in exons 16-19 (tyrosine kinase domain); cases without a detected mutation may either have a mutation in non-tested parts of MET, or mutations in another gene Somatic the mutant MET allele is duplicated (via the trisomy 7) in the tumours; might lead to a constitutive kinase activation

External links GeneCards MET GDB MET OMIM 164860 HGMD 120178 Bibliography Hereditary papillary renal cell carcinoma. Zbar B, Tory K, Merino M, Schmidt L, Glenn G, Choyke P, Walther MM Lerman M, Linehan WM. J Urol 1994; 151: 561-566. Medline 8308957

Hereditary papillary renal cell carcinoma: clinical studies in 10 families. Zbar B, Glenn G, Luensky I, Choyke P, Walther MM, Magnusson G, Bergerheim USR, Pettersson S, Amin M, Hurley K, Linehan WM. J Urol 1995; 153: 907-912. Medline 7853572

Chromosome imbalances in papillary renal cell carcinoma and first cytogenetical data of familial cases analysed by comparative genomic hybridization Bentz M, Bergerheim USR, Li C, Joos S, Werner CA, Baudis M, Gnarra J, Merino MJ, Zbar B, Lineham WM, Lichter P. . Cytogenet. Cell Genet. 1996; 75: 17-21. Medline 8995481

Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Schmidt L, Duh FM, Chen F, et al. Nature Genetics 1997; 16: 68-73. Medline 9140397

Duplication and overexpression of the mutant allele of the MET proto-

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -263- oncogene in multiple hereditary papillary renal cell tumours. Fischer J, Palmedo G, Knobloch RV, Bugert P, Prayer-Galetti T, Pagano F, Kovacs G. Oncogene 1998; 17: 733-739. Medline 9715275

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 04- Jean-Loup Huret 1999 Citation This paper should be referenced as such : Huret JL . Hereditary papillary renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. April 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/papilrenalkpron10053.html

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Rhabdoid predisposition syndrome (updated: old version not available) Clinics Note the following observations have suggested that a new cancer-prone disease, related to the gene hSNF5/INI, could be delineated: two siblings with a paravertebral malignant rhabdoid tumor in the first year of life and a poor outcome; no family history; renal rhabdoid tumors associated with tumors of the central nervous system in a given patient germ-line mutations of INI1 identified in four children, three with renal rhabdoid tumors and one with an atypical teratoid tumor of the brain (out of 18 atypical teratoid and rhabdoid tumors studied) and 4 recent pedigrees with - malignant rhabdoid tumor, choroid plexus carcinoma, atypical teratoid tumor, medulloblastoma, and/or primitive neuroectodermal tumor, - either occurring in sibs or in a given patient, - with a INI1 point mutation in the tumor DNA and loss of wild type allele and/or heterozygosity for the mutation in constitutional DNA Phenotype no apparent stigmata and clinics Neoplastic malignant rhabdoid tumors and atypical teratoid tumors, choroid plexus risk carcinomas, medulloblastomas, and primitive neuroectodermal tumors; highly aggressive tumors; very early onset in children or infants, and, apparently , high penetrance Genes involved and Proteins

Gene hSNF5/INI1 Name Location 22q11.2 Mutations Germinal found in this syndrome Somatic mutation and allele loss events in sporadic rhabdoid tumors, primitive neurectodermal tumors, medulloblastoma, or choroid plexus carcinoma are in accordance with the two-hit model for neoplasia, as is found in retinoblastoma

External links GeneCards SMARCB1

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -265- GDB SMARCB1 OMIM 601607 HGMD 593871 Bibliography Paravertebral malignant rhabdoid tumor in infancy. In vitro studies of a familial tumor. Lynch HT, Shurin SB, Dahms BB, Izant RJ Jr, Lynch J, Danes BS. Cancer 1983; 52: 290-296. Medline 83232583

Rhabdoid tumor of the kidney with primitive neuroectodermal tumor of the central nervous system: associated tumors with different histologic, cytogenetic, and molecular findings. Fort DW, Tonk VS, Tomlinson GE, Timmons CF, Schneider NR. Genes Chromosomes Cancer 1994; 11: 146-152. Medline 95134706

Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Cancer Res 1999; 59: 74-79. Medline 99107207

Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety of Cancers SÈvenet N, Sheridan E, Amram D, Schneider P, Handgretinge Rupert, Delattre O. Am J Hum Genet 1999; 65:1342-1348. Medline 99452595

Spectrum of hSNF5/INI1 mutations in human cancer and genotype-phenotype correlations. SÈvenet N, Lellouch-Tubiana A, Schofield D, Hoang-Xuan K, Gessler M, Birnbaum D, Jeanpierre C, Jouvet A, Delattre O. Human Molecular Genetics 1999; 8: 2359-2368. Medline 20025744

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 03- Jean-Loup Huret 1999 Updated 01- Jean-Loup Huret 2000

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -266- Updated 02- Nicolas SÈvenet 2000 Citation This paper should be referenced as such : Huret JL . Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol. March 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/rhabdKpronID10051.html Huret JL . Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol. January 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/rhabdKpronID10051.html SÈvenet N . Rhabdoid predisposition syndrome. Atlas Genet Cytogenet Oncol Haematol. February 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/rhabdKpronID10051.html

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -267- Atlas of Genetics and Cytogenetics in Oncology and Haematology

An Introduction to Chromosomal Aberrations

John R K Savage March 1999 (MRC Radiation and Genome Stability Unit, Harwell, Didcot, OX11 0RD, UK) Introduction Visible changes to chromosome structure and morphology have played a very important part as indicators of genetic damage in both clinical and cancer studies. Most of the changes encountered in clinical studies are "secondary" or "derived" aberrations. This is true also in cancer studies, except that here, there is an ongoing production of aberrations, so that in some cells, a mixture of primary and secondary changes is present, and a continuously changing karyotype (true chromosomal instability). To appreciate these observed secondary changes we need to understand the primary changes from which they are derived, and it is the purpose of this article to provide a brief introduction to them. Observation Primary aberrations are those seen at the first post-induction division, when all the parts are present and there has been no selection by passage through mitosis, nor any modification by subsequent chromosome duplication [7]. Most commonly, observation is made at metaphase, using "solid-staining" with dyes which give high-contrast chromatin staining and negligible cytoplasmic coloration. For more critical work, the chromosomes are banded in various ways, which allows chromosome identification, detection of some forms invisible with solid-staining, and offers more precise positioning of the lesion interaction points [8]. Recently, resolution and classification of transmissible forms has been considerably improved by the introduction of fluoresence in situ hybridisation (FISH) chromosome "painting" [5] [15] [18]. Classification of Primary changes For purely pragmatic and diagrammatic purposes, we can regard the chromosomal changes we see down the microscope as being the result of "breaks" followed by "re- joins" of the chromosome thread. However, we must always remember that, in reality, their origin is much more complicated [11][12]. Since the chromosome we see and score at metaphase has two (sister-) chromatids, it is convenient (and conventional) to divide all aberrations into two broad types: Chromosome-type where the breaks and re-joins always affect both sister- chromatids at any one locus. Examples in Figure 1. Chromatid-type where the breaks and re-joins affect only one of the sister-chromatids at any one locus (Fig 2).

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -268- Figure 1

Figure 2 The distinction is important. For some aberration-inducing agents, like ionizing radiation, the type of aberration recovered at metaphase reflects the duplication status of the chromosomes in the treated cell. But, for the majority of chemical agents which can induce aberrations, for ultra-violet light, and most probably all "spontaneous" (and de novo aberrations) only primary chromatid-types are recovered. When, at subsequent interphase, the chromatids duplicate, surviving

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -269- aberrations (and bits of aberrations) are converted into apparent chromosome-types, some of which are then transmitted almost indefinitely to further cell generations. These are the "derived" aberrations, and many are so modified that it is impossible to deduce their primary origin. Thus, following an "acute" treatment with any clastogen, surviving cells in later generations carry only chromosome-type changes. The presence in such cells of chromatid-type aberrations is, therefore, an indicator of an ongoing production of primary structural changes, i.e. of some form of chromosome instability. Nearly all the aberrations we see with solid staining appear to result from the interaction ("re-joining") of two breaks, so we can further classify them on the basis of where these breaks are situated in relation to the chromosome arms [7]. - If the breaks are situated in the arms of different (non-homologous or homologous) chromosomes we have the category of INTERCHANGES. - If the breaks are in the opposite arms of the same chromosome, we have the category of INTER-ARM INTRACHANGES. - If the two breaks are both in the same arm of a chromosome, we have the category of INTRA-ARM INTRACHANGES. These three categories are often referred to collectively as EXCHANGES. - Finally, some aberrations appear to arise from a single, open break in just one arm. This category we term "BREAKS" or "DISCONTINUITIES". Many (perhaps all) of them are, in reality, intra-arm intrachanges where one end has failed to join up properly, though the limitations of microscopical resolution do not permit us to be certain that the re-joining is really incomplete. The newer techniques, like FISH chromosome painting, are telling us that a lot of the chromosome-type aberrations we see and score as "simple" two-break interactions actually involve more than two breaks, and often more than two chromosomes, i.e. they are COMPLEX EXCHANGES [14]

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -271- facilitate transport of the genetic material to the daughter cells at mitosis. This condensation and packing readily obscures, modifies and disguises aberrations which are produced during interphase - a point that should always be borne in mind when interpreting what we see down the microscope. Most aberration-inducing agents can introduce lesions into the chromatin at all stages of the cell cycle, but relatively few of them can produce actual structural changes in G1,( and therefore give rise to primary chromosome-type changes) or in S and G2 (producing primary chromatid-types ). Ionising radiation, restriction endonucleases, and a few chemicals like bleomycin and some antibiotics are amongst those that can. Almost all remaining aberration producing agents are "S-dependent" ; surviving unrepaired lesions from G1 or G2 have to pass through a scheduled S-phase to convert them into exclusively chromatid-type aberrations. Any interference with or abnormality in the processes of chromatin replication also leads to chromatid-type aberrations visible at next mitosis. It is almost certain that the vast majority of "spontaneous" and de novo aberrations arise in this way. Chromosome instability syndromes also probably produce aberrations via defective S-phase pathways. However they are produced, the resulting chromatid-type aberrations are qualitatively (but not quantitatively) identical. Meaningful quantitative work with chromatid-types is extremely difficult because observed frequencies fluctuate with time of sample after treatment, and are subject to dramatic modifications as the result of mitotic perturbation and differential cell selection. This makes comparison between different treatments, or the production of sensible dose-response curves, virtually impossible [13]. Aberration transmission and stability Although there is an enormous range of primary aberration forms, very few of them are transmissible to future cell generations long term, so only a handful of secondary ( or "derived" ) forms are recovered [7][10]. The following paragraphs list the kinds most likely to be encountered, together with comments and a note about probable primary origin. RECIPROCAL TRANSLOCATION : Involves no mechanical separation problems at anaphase, and usually no genetic loss or imbalance. Problems can occur at meiosis because of multivalent formation, and degrees of sterility may arise. At the molecular level, the re-joining points can disrupt important genetic sequences, leading to inactivation, mutation or position effects (e.g. the t(9;22) Ph1 chromosome of CML). Derived directly from chromosome-type reciprocal translocations or from one segregation sequence of symmetrical chromatid-type interchanges. (Note that the alternative interchange segregation leads to imbalance and cell lethality). PERICENTRIC INVERSION : Very similar properties to those for reciprocal translocations given above. Large inversions lead to meiotic bridges, sterility and cell death. Derived directly from chromosome-type or chromatid-type pericentric inversions. PARACENTRIC INVERSION : Very difficult to detect at the chromosome level unless they are very large (many megabases of DNA). Again the re-joining points can disrupt important genetic sequences, and reverse segments of the reading frame. Large inversions will give problems at meiosis.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -272- Derived directly from chromosome-type paracentric inversions, or from one form of chromatid-type intra-chromatid intra-arm intrachange (Revell-type 3 [6] [7][9]). INTERSTITIAL DELETION : The loss of small segments of a chromosome (usually in only one homologue) is not uncommon. Many mutations that have been genetically sequenced have been shown to be actually small deletions. Very occasionally, the loss of quite large segments appears to be compatible with cell survival. Derived directly from chromosome-type interstitial deletions ("double minutes") and from the alternative form of chromatid-type intra-chromatid intra-arm intrachange (Revell-type 2 [6] [7] [9]) to that which produces paracentric inversions. Segregation products from some complex chromatid-type interchanges can also carry deletions. TERMINAL DELETION : It is now questionable whether true stable terminal deletions actually exist. All those that have been investigated using the new fluorescent telomere probes are found to be "capped" by telomere sequences. This either means that they are disguised interstitial deletions, where one re-join point was almost terminal, or that survival has been rendered possible by de novo telomere synthesis. The recent development of end-specific telomere probes should be able to solve this question [2][3]. Derivation, if genuine, from various forms of incomplete chromosome-type or chromatid-type intrachanges and interchanges, followed by telomerase activity to achieve capping. INTERSTITIAL DUPLICATION : Segments of a chromosome repeated in tandem, sometimes in reverse sequence. This may not necessarily arise from a pre-existing structural aberration ; segment amplification and re-duplication is a well attested phenomenon under certain conditions (e.g. HSR regions following chronic methotrexate exposure). Nevertheless, there are primary aberrations which can survive as segmental duplication. Most likely derived from one form chromatid-type inter-chromatid intra-arm intrachange (Revell-type 1 [6][7] [9]). Some forms of complex chromatid-type interchanges can segregate to give surviving chromosomes with duplicated segments. INTERSTITIAL INSERTION : Deletion of a segment and its insertion into another chromosome within the same cell is a fairly common transmitted aberration. Much less common is the insertion of a segment additional to the two complete homologues within a cell. All insertions are derived from complex exchanges, since, by definition, their production requires the interaction of a minimum of 3 lesions. Either chromosome- type or chromatid-type complex interchanges may be involved, the range of inter- intrachanges in the latter being particularly productive of insertions. Occasionally, a surviving dicentric may be found, usually without the related acentric fragment. Very often, the two centromeres lie very close together, because, under these circumstances, only one of the centromeres is active, so anaphase bridges do not form. Likewise, an occasional centric-ring may survive, again usually very small so that "fall-free" separation always happens. Larger rings are very unstable with respect to size, and the positive selection pressure towards very small rings soon eliminates the big ones. Most of the above comments apply to the situation in normal individuals and cells. When we turn to cancer-derived cells, or to transformed cell lines growing in culture,

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -273- the situation is somewhat different. These cells are inherently chromosomally unstable. There is a continuous production of structural change so that new primary changes are superimposed on the already existing background of secondary aberrations, and these new ones, in their turn, become secondary. Moreover, some of the new changes are being produced in already abnormal chromosomes, so the observed aberrations are often very complicated and bizarre. On top of this, it is clear that most cancer cells are very tolerant of chromosomal loss, or gain, as is evidenced by considerable numerical variations and multiple chromosome copies. These facts make cancer cytogenetics a very difficult and uncertain field for investigation, and considerable credit goes to those workers whose careful and painstaking efforts have produced meaningful advances. References

1. Aghamohammadi SZ, Savage JRK. BrdU pulse/reverse staining protocols for investigating chromosome replication. Chromosoma 1990; 99: 76-82. 2. Boei JJWA, Natarajan AT. Combined use of chromosome painting and telomere detection to analyse radiation induced chromosomal aberrations in mouse splenocytes. Int J Radiat Biol 1998; 73: 125-133. 3. Boei JJWA, Vermeulen S, Fomina J, Natarajan AT. Detection of incomplete exchanges and interstitial fragments in X-irradiated human lymphocytes using telomeric PNA probe. Int J Radiat Biol 1998; 73: 599-603. 4. Lea DE. Actions of radiations on living cells, 1st edn., Cambridge University Press. 1946. 5. Lucas JN, Awa A, Straume T, Poggensee M, Kodama Y, Nakano M, Ohtaki K, Weier HU, Pinkel D, Gray J. Rapid translocation frequency analysis in humans decades after exposure to ionizing radiation. Int J Radiat Biol 1992; 62: 53-63. 6. Revell SH. The accurate estimation of chromatid breakage, and its relevance to a new interpretation of chromatid aberrations induced by ionizing radiations. Proc Roy Soc B 1959; 150: 563-589. 7. Savage JRK. Annotation: Classification and relationships of induced chromosomal structural changes. J Med Genet 1976; 13: 103-122. 8. Savage JRK. Application of chromosome banding techniques to the study of primary chromosome structural changes. J Med Genet 1977; 14: 362-370. 9. Savage JRK. The production of chromosome structural changes by radiation: An update of Lea (1946), Chapter VI. Brit J Radiol 1989; 62: 507-520. 10. Savage JRK. The transmission of FISH-painted patterns derived from complex chromosome exchanges. Mutation Res 1995; 347: 87-95. 11. Savage JRK. A brief survey of aberration origin theories. Mutation Res 1998; 404: 139-147. 12. Savage JRK, Harvey AN. Investigations of aberration origins using BrdU. In: "Chromosomal Alterations; Origin and Significance". 1994; (Obe G, Natarajan AT, eds.) pp 76-91. Springer-Verlag, Berlin. 13. Savage JRK, Papworth DG Excogitations about the quantification of structural chromosomal aberrations. Advan Mutagen Res 3: 1991; (Obe G ed.) pp 162- 189. Springer-Verlag, Berlin. 14. Savage JRK, Simpson PJ. FISH "painting" patterns resulting from Complex Exchanges.Mutation Res 1994; 312: 51-60. 15. Savage JRK, Tucker JD. Nomenclature systems for Fish-painted chromosome aberrations. Mutation Res 1996; 366: 153-161.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -274- 16. Savage JRK, Prasad R, Papworth DG. Subdivision of S-phase and its use for comparative purposes in cultured human cells. J Theoret Biol 1984; 111: 355- 367. 17. Simpson PJ, Savage JRK. Detecting "hidden" exchange events within X-ray- induced aberrations using multicolour chromosome paints. Chromosome Res 1995; 3: 69-72. 18. Tucker JD, Morgan EF, Awa AA, Bauchinger M, Blakey D, Cornforth MN, Littlefield GL, Natarajan AT, Shassere C. A proposed system for scoring structural aberrations detected by chromosome painting. Cytogenet Cell Genet 1995; 68: 211-221.

Contributor(s) Written 03- John R K Savage 1999 Citation This paper should be referenced as such : Savage JRK . An Introduction to Chromosomal Aberrations. Atlas Genet Cytogenet Oncol Haematol. March 1999 . URL : http://AtlasGeneticsOncology.org/Deep/Chromaber.html

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RAS family

Franz Watzinger, Thomas Lion March 1999 (Children Cancer Reserch Institute, St. Anna Children's Hospital, A-1090 Vienna, AUSTRIA)

DNA/RNA

The establishment of an in vitro assay to screen for active transformation of mouse NIH 3T3 fibroblasts has revealed transforming genes identified as human homologs of Harvey or Kirsten murine sarcoma virus oncogenes (v-Ha-ras, or v-Ki-ras, respectively). Thereupon, an additional transforming gene was found in human neuroblastoma and fibrosarcoma cell lines that has been identified as the third functional member of the ras gene family. This gene have been termed N-ras. Thus, the human ras family consists of three proto-oncogenes, c-Harvey (H)-ras, c-Kirsten (K)-ras, and N-ras, no c-prefix was added because no viral counterpart was found. Additionally, genes were found in the genome of human and other mammalian species that display high homology to the functional ras genes but lack intervening sequences (introns). These genes were identified as processed and inactivated pseudogenes. Functional ras genes differ greatly in length due to large differences in the size of their introns ranging from about 6kb to 50kb, but they each have 4 coding exons. The human K-ras gene contain an alternative fourth coding exon. Alternative RNA splicing specifies either of two isomorphic proteins differing by 25 amino acid residues at their carboxy-terminus. Ras genes are expressed in all tissues, have a promotor region with multiple GC boxes, but lack a TATA- or CCAT-box; features resembling the promotors of housekeeping genes (11). A comparison of human H-, K-, and N-ras nucleotide sequences with the corresponding regions in other mammalian species reveals a remarkable sequence similarity (29). All differences are synonymous changes with no effect on the amino acid sequence of RAS proteins, indicating a strong evolutionary pressure on the amino acid sequence of these genes. The ras oncogenes in various human tumors harbor point mutations that confer transforming activity. Mutations leading to an amino acid substitution at the positions 12, 13, and 61 are the most common in naturally occurring (i.e. non-experimental) (9) neoplasms and experimentally induced animal tumors (12, 27) (see following

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -276- sections). In addition to the most frequent mechanism of point-mutational activation, overexpression of non-mutated ras genes can also convert normal ras genes into oncogenes. The increased amount of the corresponding mRNA derives either from high transcriptional activity of heterologous promotors and enhancers (7) or results from amplified ras genes located either intrachromosomally as homogeneously staining regions or extrachromosomally as double minute chromosomes (18).

Functional aspects of RAS proteins

Mammalian ras genes code for closely related, small proteins of 189 amino acids with a molecular weight of 21,000 Daltons (p21). When the alternative exon of H- or K-ras is used, proteins of 170 or 188 amino acids are synthesized. The molecular weight of the H-ras protein variant is 19,000 Daltons and that of the K-ras variant is not distinguishable from the normal RAS proteins. RAS proteins are localized in the inner plasma membrane, bind GDP and GTP and possess an intrinsic GTPase activity, implicated in the regulation of their activity. Because of the functional resemblance to G-Proteins, p21RAS have been hypothesized to be also involved in different types of ligand-mediated signal transduction pathways. Later, RAS proteins were shown to influence proliferation, differentiation, transformation, and apoptosis by relaying mitogenic and growth signals into the cytoplasm and the nucleolus (10). In a normal cell most of the RAS molecules are present in an inactive GDP-bound conformation. An extracellular stimulus initiates the release of GDP and the subsequent binding of GTP. This conformational change enables the interaction with the putative effector molecules and permits the transmission of signals. Finally, the active GTP-bound state is turned off by hydrolysis of GTP to GDP and inorganic phosphate. The intrinsic GTPase activity is rather weak, not sufficiently effective for signal transduction pathways where rapid inactivation is required. In order to accelerate this low rate of hydrolysis (which is about 10-2 min-1) and to enable a transient burst of signalling activity, regulatory proteins like GAPs (GTPase activating proteins) (1) or NF-1(Neurofibromatosis Type 1) protein (13), bind to the GTP-containing conformation and stimulate the GTPase activity more than 100-fold. The decreasing level of RAS-GTP, and hence, increasing level of RAS-GDP complexes result in a loss of the biological activity of RAS (see Fig. 1). In a normal cell, GAPs help to keep most of p21RAS in an inactive GDP-bound state. The finding that overexpression of non-mutated ras genes can also transform cells supports the idea that the abundance of GAPs is limited. Overexpression of p21RAS could lead to saturation of the regulatory proteins, resulting in a constitutive, deregulated activation of RAS proteins and oncogenic transformation. Another group of regulatory proteins involved in stimulating the transition of RAS proteins from the inactive- to the active GTP-bound state are designated Guanine Nucleotide Exchange Factors (GEFs) or RAS-GRFs (guanine nucleotide releasing factors) (22). Normally, the release of GDP is regulated by the intracellular concentration of GTP. An increase in the GTP concentration leads to an enhanced dissociation of GDP. GEFs catalyze the dissociation of GDP (see Fig.1). A ligand-

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -277- free RAS protein immediately binds GTP, because it is 10-fold more abundant in the cytosol than GDP.

Figure 1 Figure 1 Mechanism of RAS regulation The activity of RAS proteins is regulated by a cycle of guanine nucleotide binding and hydrolysis. In the active state p21 is bound to GTP, in the inactive to GDP. GEF (Guanine Nucleotide Exchange Factor) promotes dissociation of GDP and acts as a positive regulator; GAP (GTPase activating protein) promotes hydrolysis of GTP and acts as a negative regulator. Pi, inorganic phosphate.

Structure of RAS proteins

The alignment of their primary amino acid sequence clearly indicates the presence of four domains within the RAS molecules. The first domain includes 85 amino acids at the N-terminus which are found to be identical in H-, K-, and N-ras, demonstrating a high degree of conservation. The following 80 amino acids form a second domain, showing less conservation (70-80%) within the RAS proteins. The third domain spans the rest of the molecule, except for the last four amino acids, and represents a hypervariable region. The highly conserved carboxy-terminal motif CAAX (where C stands for cysteine, A for any aliphatic residue, and X for any uncharged amino acid) is the result of posttranslational modifications and forms the last domain.

For more accurate identification of biologically relevant regions of p21RAS and for the interpretation of activating mutations, X-crystallographic analysis of GDP- and GTP-bound RAS molecules and in vitro mutagenesis studies with mutated or truncated RAS proteins were performed. As a result of these studies, the catalytic domain was identified between residues 1 to 171, including the region involved in guanine nucleotide binding where residues 10-16 and 56-59 interact with b- and c- phosphate, and residues 116-119 and 152-165 interact with the guanine base., The so called core effector region (located between residues 32-40), represents an essential element for all interactions with putative downstream effectors and the

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -278- GAPs. A region encompassing the last four amino acids at the C-terminus (residues 186-189), was shown to be essential for the attachment of p21RAS to the plasma membrane.

Comparison of the crystal structure of RAS-GTP (as indicated in Fig.2) and RAS- GDP complexes revealed that switching between the active and the inactive state is associated with a conformational change of two regions, designated as switch I (residues 30-38), overlapping with the core effector region, and switch II (60-76). Binding of the neutralizing antibody Y13-259 to residues 63-73, inhibits the GTP-GDP change, indicating that this conformational change is necessary for the transition of RAS from the GDP- to the GTP-bound state and vice versa (14, 23).

Figure 2 Figure 2 Topological structure of p21 The polypeptide chain of RAS p21 consists of six b-strands and five a-helices. Loop 1, alias phosphate-binding (P-) loop (residues 10 to 16), switch regions I (30 to 37), including loop 2 with adjacent residues, and II (60 to 67), including loop 4 and a-helix 2, represent the active center of the molecule and are involved in the binding interaction between p21RAS and GTP. N stands for the amino terminal, C for the carboxy terminal end. (modified figure reprinted from Seminars in Cancer Biology vol 3, (4), F Wittinghofer, Tree-dimentional structure of p21H-ras and its implications, p189-198, 1992, by permission of the publisher Academic Press).

Activating point mutations have been localized in codons 12, 13, 59, 61, 63, 116, 117, 119, and 146 (4). All of these alterations occur at or near the guanine nucleotide binding sites. The effects of point mutations are either reduced GTPase activity (if amino acids 12, 13, 59, 61, 63 are involved), so that oncogenic RAS mutants are locked in the active GTP-bound state, or decreased nucleotide affinity, and hence, increased exchange of bound GDP for cytosolic GTP (if amino acids 116, 117, 119 or 146 are affected). The inefficient deactivation of the active GTP-bound RAS proteins is intensified by the inability of GAPs to stimulate the conversion to the inactive, GDP- bound state. All point mutations cause an accumulation of activated RAS-GTP complexes, leading to continuous signal transduction by facilitating accumulation of

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -279- constitutively active, GTP-bound RAS protein, and thus contributing to a malignant cell phenotype.

Incidence of ras mutations

(see also the appendix)

Activating ras mutations can be found in human malignancies with an overall frequency of 15-20%. A high incidence of ras gene mutations has been reported in malignant tumors of the pancreas (80-90%, K-ras) (2, 24), in colorectal carcinomas (30-60%, K-ras) (5, 26), in non-melanoma skin cancer (30-50%, H-ras) (4, 21), in hematopoietic neoplasia of myeloid origin (18-30%, K-and N-ras) (5, 16, 17, 22), and in seminoma (25-40%, K-ras) (15, 19). In other tumors, a mutant ras gene is found at a lower frequency: for example, in breast carcinoma (0-12%, K-ras) (20, 25), glioblastoma and neuroblastoma (0-10%, K- and N-ras) (3, 6, 8).

References

1. Ahmadian MR et al. J Biol Chem 1996; 271: 16409. 2. Almoguera C et al. Cell 1988; 53: 549. 3. Ballas K et al. Eur J Pediatr 1988; 147: 313. 4. Barbacid M. Eur J Clin Invest 1990; 20: 225. 5. Breivik J et al. Br J Cancer 1994; 69: 367. 6. Brustle O et al. Cancer 1996; 69: 2385. 7. Chakraborty AK et al. Proc Natl Acad Sci U S A 1991; 88: 2217. 8. Ireland CM. Cancer Res 1989; 49: 5530. 9. Kiaris H, Spandidos DA. Int J Oncol 1999; 7: 413. 10. Khosravi Far R, Der CJ. Cancer Metastasis Rev 1994; 13: 67. 11. Lowndes NF et al. Mol Cell Biol 1989; 9: 3758. 12. Mangues R, Pellicer A. Semin Cancer Biol 1992; 3: 229. 13. McCormick F. Curr Opin Genet Dev 1995; 5: 51. 14. Milburn MV et al. Science 1990; 247: 939. 15. Mulder MP et al. Oncogene 1989; 4: 1345. 16. Nakagawa T et al. Oncology 1992; 49: 114. 17. Neubauer A et al. Blood 1994; 83: 1603. 18. Nishimura S, Sekiya T. Biochem J 1987; 243: 313. 19. Ridanpaa M et al. Environ Health Perspect 1993; 101 Suppl 3: 185-7: 185. 20. Rochlitz CF et al. Cancer Res 1989; 49: 357. 21. Rodenhuis S. Semin Cancer Biol 1992; 3: 241. 22. Satoh T, Kaziro Y. Semin Cancer Biol 1992; 3: 169. 23. Scheffzek K et al. Science 1997; 277: 333. 24. Smit VT et al. Nucleic Acids Res 1988; 16: 7773. 25. Spandidos DA. Anticancer Res 1987; 7: 991. 26. Spandidos DA et al. Tumori 1996; 81: 7. 27. Stanley LA. Toxicology 1995; 96: 173. 28. Syvanen AC et al. Int J Cancer 1992; 50: 713. 29. Watzinger F et al. Mamm Genome 1998; 9: 214.

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Appendix : RAS mutations in various cancers and bibliography

H-RAS mutations

Tumor Frequency (%) Reference Stomach 0-40 (6, 11, 17, 18, 28) Urinary Bladder 0-65 (9, 16, 19, 21, 29) Prostate 0-10 (4, 8, 12, 23) Skin 0-45 (2, 26) Thyroid 0-60 (1, 3, 7, 14, 15, 25) Breast 0-10 (13, 24) Head and neck 0-30 (5, 10, 20, 22) Endometrium 5 (27) H-RAS MUTATIONS REFERENCE LIST

1. Bouras M et al. Eur J Endocrinol 1998; 139: 209. 2. Campbell C et al. Br J Dermatol 1993; 128: 111. 3. Capella G et al. Diagn Mol Pathol 1996; 5: 45. 4. Carter BS et al. Cancer Res 1990; 50: 6830. 5. Clark LJ et al. Br J Cancer 1993; 68: 617. 6. Deng GR et al. Oncogene Res 1991; 6: 33. 7. Fusco A et al. Nature 1987; 328: 170. 8. Gumerlock PH et al. Cancer Res 1991; 51: 1632. 9. Hong SJ et al. Yonsei Med J 1996; 37: 371. 10. Kiaris H et al. Br J Cancer 1995; 72: 123. 11. Kim TY et al. Anticancer Res 1997; 17: 1335. 12. Konishi N et al. Prostate 1997; 30: 53. 13. Kraus MH et al. Proc Natl Acad Sci U S A 1984; 81: 5384. 14. Lemoine NR et al. Cancer Res 1988; 48: 4459. 15. Lemoine NR et al. Oncogene 1989; 4: 159. 16. Malone PR et al. Br J Urol 1985; 57: 664. 17. Miki H et al. Cancer Lett 1991; 58: 107. 18. Nanus DM et al. Gastroenterology 1990; 98: 955. 19. Olderoy G et al. Anticancer Res 1998; 18: 2675. 20. Rumsby G et al. Br J Cancer 1990; 61: 365. 21. Saito S et al. Int J Urol 1997; 4: 178. 22. Saranath D et al. Br J Cancer 1991; 63: 573. 23. Shiraishi T et al. Anticancer Res 1998; 18: 2789. 24. Spandidos DA. Anticancer Res 1987; 7: 991.

Atlas Genet Cytogenet Oncol Haematol 1999; 2 -281- 25. Suarez HG et al. Oncogene 1988; 2: 403. 26. Tormanen VT, Pfeifer GP. Oncogene 1992; 7: 1729. 27. Varras MN et al. Oncology 1996; 53: 505. 28. Victor T et al. Cancer Res 1990; 50: 4911. 29. Visvanathan KV et al. Oncogene Res 1988; 3: 77.

K-RAS mutations

Tumor Frequency (%) Reference Pancreas 80-90 (2, 52, 61) Colon and rectum 25-60 (5, 6, 8, 19, 24, 38, 53, 60, 62) Lung 25-60 (20, 42, 43, 45, 55) Prostate 0-25 (9, 11, 18, 25, 26, 49) Skin 0-25 (1, 50) Thyroid 0-60 (10, 17, 27, 28, 54) Liver 10-25 (12, 30, 56, 57) Ovary 0-50 (15, 21, 58) Endometrium 10-40 (14, 16, 22, 31, 46, 47, 59) Kidney 0-50 (34, 51) Brain 0-15 (3, 4, 7, 23, 29) Testis (Seminoma) 10-45 (32, 33, 41) Leukemia (ANLL, MDS) 5-15 (35, 36, 39, 48) Urinary Bladder 5 (37) Head and neck 10 (40, 44) Breast 10 (13) K-RAS MUTATIONS REFERENCE LIST

1. Albino AP et al. J Cutan Pathol 1991; 18: 273. 2. Almoguera C et al. Cell 1988; 53: 549. 3. Ballas K et al. Eur J Pediatr 1988; 147: 313. 4. Bos JL. Mutat Res 1988; 195: 255. 5. Boughdady IS et al. Surg Oncol 1992; 1: 275. 6. Breivik J et al. Br J Cancer 1994; 69: 367. 7. Brustle O et al. Cancer 1996; 69: 2385. 8. Burmer GC et al. Environ Health Perspect 1991; 93: 27-31: 27. 9. Capella G et al. Environ Health Perspect 1991; 93: 125-31: 125. 10. Capella G et al. Diagn Mol Pathol 1996; 5: 45. 11. Carter BS et al. Cancer Res 1990; 50: 6830. 12. Challen C et al. J Hepatol 1992; 14: 342. 13. Dawson PJ et al. Mod Pathol 1996; 9: 367.

Atlas Genet Cytogenet On 14. Duggan BD et al. Cancer Res 1994; 54: 1604. 15. Enomoto T et al. Am J Pathol 1991; 139: 777. 16. Enomoto T et al. Cancer Res 1991; 51: 5308. 17. Fusco A et al. Nature 1987; 328: 170. 18. Gumerlock PH et al. Cancer Res 1991; 51: 1632. 19. Halter SA et al. Mod Pathol 1992; 5: 131. 20. Husgafvel-Pursiainen K et al. Environ Health Perspect 1992; 98: 183-5: 183. 21. Ichikawa Y et al. Cancer Res 1994; 54: 33. 22. Ignar-Trowbridge D et al. Am J Obstet Gynecol 1992; 167: 227. 23. Ireland CM. Cancer Res 1989; 49: 5530. 24. Kojima M et al. Dis Colon Rectum 1997; 40: 161. 25. Konishi N et al. Cancer 1992; 69: 2293. 26. Konishi N et al. Prostate 1997; 30: 53. 27. Lemoine NR et al. Cancer Res 1988; 48: 4459. 28. Lemoine NR et al. Oncogene 1989; 4: 159. 29. Maltzman TH et al. Cancer Epidemiol Biomarkers Prev 1997; 6: 239. 30. Marion MJ et al. Mol Carcinog 1991; 4: 450. 31. Mizuuchi H et al. Cancer Res 1992; 52: 2777. 32. Moul JW et al. Genes Chromosomes Cancer 1992; 5: 109. 33. Mulder MP et al. Oncogene 1989; 4: 1345. 34. Nagata Y et al. Jpn J Cancer Res 1990; 81: 22. 35. Nakagawa T et al. Oncology 1992; 49: 114. 36. Neubauer A et al. Blood 1994; 83: 1603. 37. Olderoy G et al. Anticancer Res 1998; 18: 2675. 38. Oudejans JJ et al. Int J Cancer 1991; 49: 875. 39. Padua RA et al. Leukemia 1998; 12: 887. 40. Rathcke IO et al. Laryngorhinootologie 1996; 75: 465. 41. Ridanpaa M et al. Environ Health Perspect 1993; 101 Suppl 3: 185-7: 185. 42. Rodenhuis S, Slebos RJ. Cancer Res 1992; 52: 2665s. 43. Rodenhuis S et al. J Clin Oncol 1997; 15: 285. 44. Rumsby G et al. Br J Cancer 1990; 61: 365. 45. Sagawa M et al. Br J Cancer 1998; 77: 720. 46. Sasaki H et al. Cancer Res 1993; 53: 1906. 47. Semczuk A et al. Eur J Gynaecol Oncol 1997; 18: 80. 48. Sheng XM et al. Leuk Res 1997; 21: 697. 49. Shiraishi T et al. Anticancer Res 1998; 18: 2789. 50. Shukla VK et al. Oncogene Res 1989; 5: 121. 51. Skalkeas GD et al. Anticancer Res 1991; 11: 2091. 52. Smit VT et al. Nucleic Acids Res 1988; 16: 7773. 53. Spandidos DA et al. Tumori 1996; 81: 7. 54. Suarez HG et al. Oncogene 1988; 2: 403. 55. Suzuki Y et al. Oncogene 1990; 5: 1037. 56. Tada M et al. Cancer Res 1990; 50: 1121. 57. Tada M et al. Cancer 1992; 69: 1115. 58. Teneriello MG et al. Cancer Res 1993; 53: 3103. 59. Varras MN et al. Oncology 1996; 53: 505. 60. Ward R et al. Am J Pathol 1998; 153: 373. 61. Watanabe H et al. Pancreas 1996; 12: 18. 62. Yamagata S et al. Jpn J Cancer Res 1994; 85: 147.

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N-RAS mutations

Tumor Frequency (%) Reference Leukemia ANLL, MDS 20-40 (7, 17, 18, 19, 22, 24) Leukemia CML,ALL 0-10 (28, 29) Brain 0-15 (2, 3, 4, 9, 13) Skin 0-20 (1, 14, 21, 27) Thyroid 0-60 (5, 8, 11, 12, 23) Testis 0-40 (15, 16, 20) Stomach (gastric tumors) 5 (10) Liver 0-15 (6, 25, 26) N-RAS MUTATIONS REFERENCE LIST

1. Albino AP et al. Nature 1984; 308: 69. 2. Ballas K et al. Eur J Pediatr 1988; 147: 313. 3. Bos JL. Mutat Res 1988; 195: 255. 4. Brustle O et al. Cancer 1996; 69: 2385. 5. Capella G et al. Diagn Mol Pathol 1996; 5: 45. 6. Challen C et al. J Hepatol 1992; 14: 342. 7. De Melo MB et al. Leuk Lymphoma 1997; 24: 309. 8. Fusco A et al. Nature 1987; 328: 170. 9. Ireland CM. Cancer Res 1989; 49: 5530. 10. Kim TY et al. Anticancer Res 1997; 17: 1335. 11. Lemoine NR et al. Cancer Res 1988; 48: 4459. 12. Lemoine NR et al. Oncogene 1989; 4: 159. 13. Maltzman TH et al. Cancer Epidemiol Biomarkers Prev 1997; 6: 239. 1 14. Mooy CM et al. Br J Cancer 1991; 64: 411. 15. Moul JW et al. Genes Chromosomes Cancer 1992; 5: 109. 16. Mulder MP et al. Oncogene 1989; 4: 1345. 17. Nakagawa T et al. Oncology 1992; 49: 114. 18. Neubauer A et al. Blood 1994; 83: 1603. 19. Padua RA et al. Leukemia 1998; 12: 887. 20. Ridanpaa M et al. Environ Health Perspect 1993; 101 Suppl 3: 185-7: 185. 21. Soparker CN et al. Invest Ophthalmol Vis Sci 1993; 34: 2203. 22. de Souza Fernandez T et al. Leuk Res 1998; 22: 125. 23. Suarez HG et al. Oncogene 1988; 2: 403. 24. Syvanen AC et al. Int J Cancer 1992; 50: 713. 25. Tada M et al. Cancer Res 1990; 50: 1121. 26. Tada M et al. Cancer 1992; 69: 1115. 27. van't Veer LJ et al. Mol Cell Biol 1989; 9: 3114. 28. Watzinger F et al. Cancer Res 1994; 54: 3934. 29. Yokota S et al. Int J Hematol 1998; 67: 379.

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Contributor(s) Written 03- Franz Watzinger, Thomas Lion 1999 Citation This paper should be referenced as such : Watzinger F, Lion T . RAS family. Atlas Genet Cytogenet Oncol Haematol. March 1999 . URL : http://AtlasGeneticsOncology.org/Deep/Ras.html

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