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 5, Number 2, Apr-Jun 2001 Previous Issue / Next Issue Genes

COL1A1 (collagen, type I, alpha 1) (17q21.31-q22).

Marie-Pierre Simon, Georges Maire, Florence Pedeutour.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 169-177. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/COL1A1ID186.html

NF2 (neurofibromatosis type 2) (22q12.1-12.2) - updated.

James F Gusella.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 178-184. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/NF2117.html

PDGFB (22q12.3-q13.1).

Marie-Pierre Simon, Georges Maire, Florence Pedeutour.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 185-194. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/PDGFBID155.html

XPA (9q22.3-9q22.3).

Anne Stary, Alain Sarasin.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 195-204. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 I URL : http://AtlasGeneticsOncology.org/Genes/XPAID104.html ERCC-3 (Excision repair cross-complementing rodent repair deficiency, complementation group 3) (2q21). Anne Stary, Alain Sarasin.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 205-214. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/XPBID296.html

XPC (3p25.1).

Anne Stary, Alain Sarasin.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 215-224. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/XPCID122.html ERCC2 (Excision repair cross-complementing rodent repair deficiency, complementation group 2) - (19q13.2). Anne Stary, Alain Sarasin.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 225-240. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/XPDID297.html

POLH (polymerase (DNA direct), eta) (6p21.1).

Anne Stary, Alain Sarasin.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 241-248. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/XPVID303.html

FBP17 (Formin Binding Protein 17) (9q34).

Uta Fuchs, Arndt Borkhardt.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 249-252. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/FBP17ID353.html

Ghrelin/MTLRP (3p26-p25).

Catherine Tomasetto.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 253-257. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/GhrelinID327.html

MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1) (4q27).

Atlas Genet Cytogenet Oncol Haematol 2001; 2 II Elizabeth M. Petty, Kenute Myrie.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 258-267. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/MAD2L1ID304.html

TFF3 (21q22.3).

Catherine Tomasetto.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 268-273. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/TFF3ID265.html

WRN (8p12).

Mounira Amor-Guéret.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 274-279. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/WRNID284.html Leukaemias

Burkitt's lymphoma (BL).

Antonio Cuneo, Gianluigi Castoldi.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 281-284. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/BurkittID2077.html

del(13q) in multiple myeloma.

Franck Viguié.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 285-287. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/del13qMMyeloID2094.html

Follicular lymphoma (FL).

Antonio Cuneo, Gianluigi Castoldi.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 288-291. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/FollLymphomID2075.html

t(5;11)(q31;q23).

Stig E Bojesen.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 292-294. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 III URL : http://AtlasGeneticsOncology.org/Anomalies/t0511ID1192.html

Classification of T-Cell disorders.

Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 295-300. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/TcellClassifID2079.html Solid Tumours

Testis: Germ cell tumors - updated.

Leendert H.J. Looijenga.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 301-320. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Tumors/malegermID5005.html Cancer Prone Diseases

Bruton's agammaglobulinemia.

Niels B Atkin.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 321-323. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/BrutonAgammaID10023.html

Familial nervous system tumour syndromes.

Anne Marie Capodano.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 324-326. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/FamilNervousCanID10067.html

Multiple Endocrine Neoplasia type 2 (MEN2).

Sophie Giraud.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 327-331. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/MEN2ID10009.html

Von Hippel-Lindau - updated.

Stéphane Richard.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 332-342. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/VHLKpr10010.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 IV Neurofibromatosis type 2 (NF2) - updated.

James F Gusella.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 343-346. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/NF2Kpr10007.html Deep Insights

Nucleotide excision repair.

Leon H.F. Mullenders, Anne Stary, Alain Sarasin.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 347-352. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Deep/ExcisRepairID20014.html Case Reports Educational Items

Hardy-Weinberg model.

Robert Kalmes, Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (2): 353-362. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Educ/HardyEng.html

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Atlas Genet Cytogenet Oncol Haematol 2001; 2 V Atlas of Genetics and Cytogenetics in Oncology and Haematology

COL1A1 (collagen, type I, alpha 1)

Identity Hugo COL1A1 Location 17q21.31-q22 Telomeric to MEOX1 (mesenchyme homeo box 1), centromeric to

MVWF (Modifier of von Willebrand factor)

COL1A1 (17q21) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA

Description The COL1A1 gene is 18 kb in size and is composed of 52 exons. Exons 6 to 49 encode the alpha helical domain. Most of these exons were 45 bp, 54 bp or multiple of 45 bp or 54 bp Transcription Two RNA of 5,8 kb and 4,8 kb differing by their Ô3 terminus non coding sequence and giving rise to a single 140 kDa protein Protein

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -169- Description 1464 amino acids. The a1 (I) chains of the type I collagen are synthesised as procollagen molecules containing amino and carboxy- terminal propeptides, wich are removed by site-specific endopeptidase. The central triple helical domain is formed by 338 repeats of a Gly-X-Y triplet where X and Y are often a proline. Expression Type I collagen is the most abundant protein in vertebrates and a constituent of the extra cellular matrix in connective tissue of bone, skin, tendon, ligament and dentine. It is mostly produced and secreted by fibroblasts and osteoblasts. Localisation Extra-cellular matrix Function Two pro a1 (I) chain associate in trimers with one pro a2 (I) chain to form the type I collagen fibrils after proteolysis. Homology Member of the collagen family. Implicated in Entity Dermatofibrosarcoma Protuberans (DP), also called Darier Ferrand tumour or Darier-Hoffmann tumour. Giant cell fibrosarcoma (GCF) (juvenile form of DP). Bednar tumour (pigmented variant of DP) Disease Infiltrative skin tumours of intermediate malignancy Prognosis The prognosis is usually favourable. These tumours are locally aggressive and highly recurrent, but metastases or tumour-related deaths are extremely rare. Cytogenetics Dermatofibrosarcoma Protuberans, Giant Cell fibrosarcoma and Bednar tumours present specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13.1) ( Fig A) or, more often, supernumerary ring chromosomes derived from t(17;22) (B). As shown by FISH analysis, the ring chromosomes contain chromosome 22 centromere and low-level amplification of 22cen-q13.1 and 17q22-qter sequences. To note, in most cases, the derivative chromosome 17 is not present. In contrast, several copies of the derivative chromosome 22 are generally observed.in addition to two apparently normal chromosomes 17

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -170-

Hybrid/Mutated Both rings and der(22) translocated chromosomes present a same molecular Gene rearrangement that fuses the collagen type I alpha 1(COL1A1) and the platelet- derived growth factor B chain (PDGFB) genes (C). In all DP and GCF cases studied, the t(17;22)translocation results in chimerical COL1A1/PDGFB mRNA production, in which the PDGFB exon 1 is deleted and replaced by a variable segment of COL1A1 mRNA sequence. In the 32 cases tested the fusion mRNA was an in-frame fusion of one of the COL1A1 exons (varying from exon 7 to exon 47) to PDGFB exon 2 (D). Abnormal COL1A1 and PDGFB are both encoded as pro-peptides, which are Protein processed by proteolytic cleavage at N and C-terminus, to give mature proteins. Sequences analyses of the chimerical COL1A1/PDGFB fusion transcripts showed that the COL1A1/PDGFB putative proteins displayed a pro-peptide structure, which preserved the N-terminus COL1A1 pro-peptide containing the signal peptide and the N and C-terminus PDGFB maturation cleavage sites. The functional and structural properties of the COL1A1/PDGFB fusion protein were characterized by generating stable fibroblastic cell lines that expressed tumour-derived COL1A1/PDGFB chimerical genes. The diagram herein given presents the COL1A1/PDGFB chimerical protein encoded by the T94796 tumour-derived chimerical COL1A1/PDGFB cDNA sequence

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -171-

A chimerical COL1A1/PDGFB cDNA sequence fusing COL1A1 exon 29 to PDGFB exon 2 was isolated from the DP T94796 tumour and stably transfected in the Chinese hamster lung fibroblastic cell line PS200 (E). The T94796 COL1A1/PDGFB chimerical protein sequence retained the COL1A1 N-terminus processing site encoded by the COL1A1 exon 6 and the N and C-terminus PDGFB processing sites encoded by the PDGFB exons 3 and 6 respectively (F). Mutagenesis experiments and immunodetection with anti-PDGFBB and specific anti- COL1A1/PDGFB antibodies showed that COL1A1/PDGFB expressing cells produced 116 kD chimerical COL1A1/PDGFB precursors chains, which formed dimers and were processed to give active 30 kD PDGFB-like dimers (G). Oncogenesis Transfected cells lines expressing the chimerical T94796-COL1A1/PDGFB proteins became independent upon growth factors, including PDGFB, and induced tumours formation in nude mice. In addition, it was shown that the COL1A1/PDGFB stable clones cells contained activated PDGF b-receptors and that the conditioned media from COL1A1/PDGFB transfected cells were able to

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -172- stimulate fibroblastic cells growth. Anti-PDGFBB antibodies neutralized this effect. These results strongly suggest that the COL1A1/PDGFB chimerical gene expression associated with DP, contributes to tumour formation through ectopic production of mature PDGFB and the formation of an autocrine loop.

Breakpoints

External links Nomenclature Hugo COL1A1 GDB COL1A1 Entrez_Gene COL1A1 1277 collagen, type I, alpha 1 Cards Atlas COL1A1ID186 GeneCards COL1A1 Ensembl COL1A1 CancerGene COL1A1 Genatlas COL1A1

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -173- GeneLynx COL1A1 eGenome COL1A1 euGene 1277 Genomic and cartography COL1A1 - chr17:45616456-45633992 - 17q21.33 (hg17- GoldenPath May_2004) Ensembl COL1A1 - 17q21.33 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene COL1A1 Gene and transcription

Genbank AF017178 [ SRS ] AF017178 [ ENTREZ ]

Genbank J02829 [ SRS ] J02829 [ ENTREZ ]

Genbank J03559 [ SRS ] J03559 [ ENTREZ ]

Genbank K03179 [ SRS ] K03179 [ ENTREZ ]

Genbank L47667 [ SRS ] L47667 [ ENTREZ ]

RefSeq NM_000088 [ SRS ] NM_000088 [ ENTREZ ]

RefSeq NT_086883 [ SRS ] NT_086883 [ ENTREZ ] AceView COL1A1 AceView - NCBI TRASER COL1A1 Traser - Stanford

Unigene Hs.172928 [ SRS ] Hs.172928 [ NCBI ] HS172928 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P02452 [ SRS] P02452 [ EXPASY ] P02452 [ INTERPRO ] CluSTr P02452 Blocks P02452 Polymorphism : SNP, mutations, diseases OMIM 120150 [ map ] GENECLINICS 120150

SNP COL1A1 [dbSNP-NCBI]

SNP NM_000088 [SNP-NCI]

SNP COL1A1 [GeneSNPs - Utah] COL1A1 [SNP - CSHL] COL1A1] [HGBASE - SRS] General knowledge Family COL1A1 [UCSC Family Browser] Browser SOURCE NM_000088 SMD Hs.172928 SAGE Hs.172928 Amigo component|collagen

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -174- Amigo component|collagen type I Amigo component|cytoplasm Amigo process|epidermis development Amigo function|extracellular matrix structural constituent Amigo process|perception of sound Amigo process|phosphate transport Amigo process|skeletal development Amigo function|structural constituent of bone PubGene COL1A1 Other databases Probes Probe Cancer Cytogenetics (Bari) Probe COL1A1 Related clones (RZPD - Berlin) PubMed PubMed 63 Pubmed reference(s) in LocusLink Bibliography Brittle bones-fragile molecules: disorders of collagen gene structure and expression. Byers PH. Trends Genet. 1990 Sep;6(9):293-300. Review. Medline 91048866

Ring 22 chromosomes in dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences. Pedeutour F, Simon MP, Minoletti F, Sozzi G, Pierotti MA, Hecht F and Turc-Carel C. Cancer Res. 1995 Jun 1;55(11):2400-3. Medline 95277719

Soft tissue sarcomas in dermatology. Fish FS Dermatol Surg. 1996 Mar;22(3):268-73. REVIEW. Medline 96178090

Translocation, t(17;22)(q22;q13), in dermatofibrosarcoma protuberans: a new tumor-associated chromosome rearrangement. Pedeutour F, Simon MP, Minoletti F, Barcelo G, Terrier-Lacombe MJ, Combemale P, Sozzi G, Ayraud N and Turc-Carel C. Cytogenet Cell Genet. 1996;72(2-3):171-4. Medline 97133368

The human type I collagen mutation database. Dalgleish R.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -175- Nucleic Acids Res. 1997 Jan 1;25(1):181-7. Medline 97169389

Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Simon MP, Pedeutour F, Sirvent N, Grosgeorge J, Minoletti F, Coindre JM, Terrier- Lacombe MJ, Mandahl N, Craver RD, Blin N, Sozzi G, Turc-Carel C, O'Brien KP, Kedra D, Fransson I, Guilbaud C and Dumanski JP. Nat Genet. 1997 Jan;15(1):95-8. Medline 97141927

Transforming activity of the chimeric sequence formed by the fusion of collagen gene COL1A1 and the platelet derived growth factor b-chain gene in dermatofibrosarcoma protuberans. Greco A, Fusetti L, Villa R, Sozzi G, Minoletti F, Mauri P and Pierotti MA. Oncogene. 1998 Sep 10;17(10):1313-9. Medline 98442972

Fibrosarcomatous ("high-grade") dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. Mentzel T, Beham A, Katenkamp D, Dei Tos AP and Fletcher CD. Am J Surg Pathol. 1998 May;22(5):576-87. Medline 98252402

COL1A1-PDGFB fusion in a ring chromosome 4 found in a dermatofibrosarcoma protuberans. Navarro M, Simon MP, Migeon C, Turc-Carel C and Pedeutour F. Genes Chromosomes Cancer. 1998 Nov;23(3):263-6. Medline 99005169

Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas. O'Brien KP, Seroussi E, Dal Cin P, Sciot R, Mandahl N, Fletcher JA, Turc-Carel C and Dumanski JP. Genes Chromosomes Cancer. 1998 Oct;23(2):187-93. Medline 98409403

The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Shimizu A, O'Brien KP, Sjoblom T, Pietras K, Buchdunger E, Collins VP, Heldin CH, Dumanski JP and Ostman A. Cancer Res. 1999 Aug 1;59(15):3719-23. Medline 99374653

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -176-

Detection of COL1A1-PDGFB fusion transcripts in dermatofibrosarcoma protuberans by reverse transcription-polymerase chain reaction using archival formalin-fixed, paraffin-embedded tissues. Wang J, Hisaoka M, Shimajiri S, Morimitsu Y and Hashimoto H. Diagn Mol Pathol. 1999 Sep;8(3):113-9. Medline 20029411

Supernumerary ring chromosome in a Bednar tumor (pigmented dermatofibrosarcoma protuberans) is composed of interspersed sequences from chromosomes 17 and 22: A fluorescence in situ hybridization and comparative genomic hybridization analysis Nishio J, Iwasak H, Ishiguro M, Ohjimi Y, Yo S, Isayama T, Naito M, Kikuchi M. Genes Chromosomes Cancer. in press

Structural and functional analysis of a chimerical protein COL1A1/PDGFB generated by the translocation t(17;22)(q22;q13.1) in Dermatofibrosarcoma Protuberans (DP) Simon M-P, Navarro M, Roux D and PouyssŽgur J. in press

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Marie-Pierre Simon, Georges Maire, Florence Pedeutour 2001 Citation This paper should be referenced as such : Simon MP, Maire G, Pedeutour F . COL1A1 (collagen, type I, alpha 1). Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/COL1A1ID186.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -177- Atlas of Genetics and Cytogenetics in Oncology and Haematology

NF2 (neurofibromatosis type 2) (updated: old version not available)

Identity Other SCH names Hugo NF2 Location 22q12.1-12.2 22q12.1-12.2 junction, incidentally not far from EWS DNA/RNA Description exons 17 exons (1-15, 17 constitutive, 16 alternatively spliced); spans 120 kb; open reading frame: 1.8 kb Transcription alternate splicing, in particular after exon 15 Protein

Description called merlin, schwannomin, or SCH; isoform 1 595 amino acids, isoform 2 590 amino acids (due to inclusion of exon 16 in transcript) ; 66 KDa; NH2 -- FERM domain -- large a helix domain -- COOH Expression wide: in lung, kidney, ovary, breast, placenta, neuroblasts; high in fetal brain Localisation membrane associated interacts with integral membrane proteins and actin-cytoskeleton Function membrane-cytoskeleton anchor (as APC also appears to be); role in the development of extraembryonic structures before gastrulation; has characteristics of a tumour suppressor, as has been found in sporadic as well as neurofibromatosis type 2 induced schwannomas and meningiomas Homology ezrin, radixin, moesin, members of the erythrocytes band 4.1 family, especially in the N-terminal FERM domain Mutations Germinal inborn condition of neurofibromatosis type 2 patients: protein truncations due to various frameshift deletions or insertions or nonsense mutations; splice-site or missense mutations are also found; phenotype-genotype correlations are observed (i.e. that severe phenotype are found in cases with protein truncations rather than those with amino acid substitution) Somatic mutation and allele loss events in tumours in neurofibromatosis type 2 and in sporadic schwannomas and meningiomas are in accordance with the two-hit model for neoplasia, as is found in retinoblastoma

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -178- Implicated in Entity neurofibromatosis type 2 Disease autosomal dominant tumor prone disease; neurofibromatosis type 2 (NF2: the same symbol is used for the disease neurofibromatosis type 2 and the gene) is an hamartoneoplastic syndrome Prognosis hamartomas have a potential towards neoplasia; those, in NF2, are The tumors of NF2 are slow-growing benign schwannomas which do not progress to malignancy and meningiomas

Entity sporadic meningioma

Entity sporadic schwannoma

Entity other tumours: ependymoma; mesothelioma

External links Nomenclature Hugo NF2 GDB NF2 Entrez_Gene NF2 4771 neurofibromin 2 (bilateral acoustic neuroma) Cards Atlas NF2117 GeneCards NF2 Ensembl NF2 CancerGene NF2 Genatlas NF2 GeneLynx NF2 eGenome NF2 euGene 4771 Genomic and cartography GoldenPath NF2 - chr22:28324119-28419137 + 22q12.2 (hg17-May_2004) Ensembl NF2 - 22q12.2 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene NF2 Gene and transcription

Genbank AF165426 [ SRS ] AF165426 [ ENTREZ ]

Genbank X72655 [ SRS ] X72655 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -179- Genbank X72670 [ SRS ] X72670 [ ENTREZ ]

Genbank AF113694 [ SRS ] AF113694 [ ENTREZ ]

Genbank AF122827 [ SRS ] AF122827 [ ENTREZ ]

RefSeq NM_000268 [ SRS ] NM_000268 [ ENTREZ ]

RefSeq NM_016418 [ SRS ] NM_016418 [ ENTREZ ]

RefSeq NM_181825 [ SRS ] NM_181825 [ ENTREZ ]

RefSeq NM_181826 [ SRS ] NM_181826 [ ENTREZ ]

RefSeq NM_181827 [ SRS ] NM_181827 [ ENTREZ ]

RefSeq NM_181828 [ SRS ] NM_181828 [ ENTREZ ]

RefSeq NM_181829 [ SRS ] NM_181829 [ ENTREZ ]

RefSeq NM_181830 [ SRS ] NM_181830 [ ENTREZ ]

RefSeq NM_181831 [ SRS ] NM_181831 [ ENTREZ ]

RefSeq NM_181832 [ SRS ] NM_181832 [ ENTREZ ]

RefSeq NM_181833 [ SRS ] NM_181833 [ ENTREZ ]

RefSeq NM_181834 [ SRS ] NM_181834 [ ENTREZ ]

RefSeq NM_181835 [ SRS ] NM_181835 [ ENTREZ ]

RefSeq NT_086921 [ SRS ] NT_086921 [ ENTREZ ] AceView NF2 AceView - NCBI TRASER NF2 Traser - Stanford

Unigene Hs.187898 [ SRS ] Hs.187898 [ NCBI ] HS187898 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P35240 [ SRS] P35240 [ EXPASY ] P35240 [ INTERPRO ] CluSTr P35240 Blocks P35240 Polymorphism : SNP, mutations, diseases OMIM 607379 [ map ] GENECLINICS 607379

SNP NF2 [dbSNP-NCBI]

SNP NM_000268 [SNP-NCI]

SNP NM_016418 [SNP-NCI]

SNP NM_181825 [SNP-NCI]

SNP NM_181826 [SNP-NCI]

SNP NM_181827 [SNP-NCI]

SNP NM_181828 [SNP-NCI]

SNP NM_181829 [SNP-NCI]

SNP NM_181830 [SNP-NCI]

SNP NM_181831 [SNP-NCI]

SNP NM_181832 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -180- SNP NM_181833 [SNP-NCI]

SNP NM_181834 [SNP-NCI]

SNP NM_181835 [SNP-NCI]

SNP NF2 [GeneSNPs - Utah] NF2 [SNP - CSHL] NF2] [HGBASE - SRS] General knowledge Family NF2 [UCSC Family Browser] Browser SOURCE NM_000268 SOURCE NM_016418 SOURCE NM_181825 SOURCE NM_181826 SOURCE NM_181827 SOURCE NM_181828 SOURCE NM_181829 SOURCE NM_181830 SOURCE NM_181831 SOURCE NM_181832 SOURCE NM_181833 SOURCE NM_181834 SOURCE NM_181835 SMD Hs.187898 SAGE Hs.187898 Amigo component|cytoplasm Amigo function|cytoskeletal protein binding Amigo component|cytoskeleton Amigo component|cytoskeleton Amigo process|negative regulation of cell cycle Amigo process|negative regulation of cell proliferation Amigo process|perception of sound Amigo component|plasma membrane Amigo function|structural molecule activity PubGene NF2 Other databases Probes Probe NF2 Related clones (RZPD - Berlin) PubMed PubMed 34 Pubmed reference(s) in LocusLink Bibliography

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -181- A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, et al Cell 1993 Mar 12;72(5):791-800 Medline 8453669

Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B, et al Nature 1993 Jun 10;363(6429):515-21 Medline 93281181

Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N Am J Med Genet 1994 Oct 1;52(4):450-61 Medline 95266606

Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF Am J Hum Genet 1996 Sep;59(3):529-39 Medline 96354546

Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn JM, Hall BD, Propping P, Rouleau GA Am J Hum Genet 1996 Aug;59(2):331-42 Medline 96335702

The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T Genes Dev 1997 May 15;11(10):1253-65 Medline 97315196

Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane. Deguen B, Merel P, Goutebroze L, Giovannini M, Reggio H, Arpin M, Thomas G Hum Mol Genet 1998 Feb;7(2):217-26 Medline 98087573

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -182-

Merlin: the neurofibromatosis 2 tumor suppressor.(REVIEW) Gusella JF, Ramesh V, MacCollin M, Jacoby LB Biochim Biophys Acta 1999 Mar 25;1423(2):M29-36 Medline 10214350

Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M, Abramowski V, Goutebroze L, Woodruff JM, Berns A, Thomas G. Genes Dev 2000 Jul 1;14(13):1617-30 Medline 10887156

The parental origin of new mutations in neurofibromatosis 2 Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella J, Davis K, Stavrou D, MacCollin M Neurogenetics 2000 Sep;3(1):17-24 Medline 11085592

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 09- Jean-Loup Huret 1997 Updated 03- Jean-Loup Huret 1998 Updated 02- James F Gusella 2001 Citation This paper should be referenced as such : Huret JL . NF2 (neurofibromatosis type 2). Atlas Genet Cytogenet Oncol Haematol. September 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NF2117.html Huret JL . NF2 (neurofibromatosis type 2). Atlas Genet Cytogenet Oncol Haematol. March 1998 .

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -183- URL : http://www.infobiogen.fr/services/chromcancer/Genes/NF2117.html Gusella JF . NF2 (neurofibromatosis type 2). Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/NF2117.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -184- Atlas of Genetics and Cytogenetics in Oncology and Haematology

PDGFB

Identity Other V-sis platelet-derived growth factor beta (simian sarcoma viral names oncogene homolog) Hugo PDGFB Location 22q12.3-q13.1 Telomeric to TXN2 (thioredoxin, mitochondrial), centromeric to DMC1(dosage suppressor of mck1, yeast homologue meiosis-specific homologous recombination) DNA/RNA

Description The PDGFB gene encodes the human platelet-derived growth factor (PDGF) B chain precursor and is the cellular homologue of the v-sis oncogene. PDGFB gene is 22 kb in size and is composed of 7 exons. The exon 7 and most part of the exon 1 are non coding sequences (white boxes). Transcription The PDGFB chain precursor is usually translated from a 3.5 kb transcript. The first exon contains the sequence for the signal peptide preceeded by a 1 kb-long untranslated sequence with potent translation inhibitory activity. A 2.6 kb mRNA which initiates at an alternative exon 1, exon 1A, was described in the human choriocarcinoma cell line JEG-3. It initiates an open reading frame that is continuous with the code for the PDGF B chain precursor but lacks the code for the signal peptide. Protein

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -185-

Description The PDGFB chains are synthesised as 240 amino acids precursors molecules containing amino and carboxy-terminal propeptides, which are removed by site-specific endopeptidases. Two PDGFB precursor chains associate in dimers to form the mature PDGFBB after proteolysis. Expression First isolated from human platelets, the PDGFBB is synthesized by a variety of different cell lineages. Localisation Secreted in the extra-cellular medium Function The homodimer PDGFBB is a potent growth factor that acts as a mitogen and chemo-attractant for a variety of cells from mesenchymal origin. It has various roles in embryonic development, tissue regeneration, osteogenesis, fibrosis, atherosclerosis, and neoplasia. Homology Member of the PDGF/VEGF family Implicated in Entity Dermatofibrosarcoma Protuberans (DP), also called Darier Ferrand tumour or Darier-Hoffmann tumour. Giant cell fibrosarcoma (GCF) (juvenile form of DP). Bednar tumour (pigmented variant of DP) Disease Infiltrative skin tumours of intermediate malignancy Prognosis The prognosis is usually favourable. These tumours are locally aggressive and highly recurrent, but metastases or tumour-related deaths are extremely rare. Cytogenetics Dermatofibrosarcoma Protuberans, Giant Cell fibrosarcoma and Bednar tumours present specific cytogenetic features such as reciprocal translocations t(17;22)(q22;q13.1) ( Fig A) or, more often, supernumerary ring chromosomes derived from t(17;22) (B). As shown by FISH analysis, the ring chromosomes

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -186- contain chromosome 22 centromere and low-level amplification of 22cen-q13.1 and 17q22-qter sequences. To note, in most cases, the derivative chromosome 17 is not present. In contrast, several copies of the derivative chromosome 22 are generally observed.in addition to two apparently normal chromosomes 17

Hybrid/Mutated Both rings and der(22) translocated chromosomes present a same Gene molecular rearrangement that fuses the collagen type I alpha 1(COL1A1) and the platelet-derived growth factor B chain (PDGFB) genes (C). In all DP and GCF cases studied, the t(17;22)translocation results in chimerical COL1A1/PDGFB mRNA production, in which the PDGFB exon 1 is deleted and replaced by a variable segment of COL1A1 mRNA sequence. In the 32 cases tested the fusion mRNA was an in-frame fusion of one of the COL1A1 exons (varying from exon 7 to exon 47) to PDGFB exon 2 (D). Abnormal COL1A1 and PDGFB are both encoded as pro-peptides, which are Protein processed by proteolytic cleavage at N and C-terminus, to give mature proteins. Sequences analyses of the chimerical COL1A1/PDGFB fusion transcripts showed that the COL1A1/PDGFB putative proteins displayed a pro- peptide structure, which preserved the N-terminus COL1A1 pro-peptide containing the signal peptide and the N and C-terminus PDGFB maturation cleavage sites.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -187- The functional and structural properties of the COL1A1/PDGFB fusion protein were characterized by generating stable fibroblastic cell lines that expressed tumour-derived COL1A1/PDGFB chimerical genes. The diagram herein given presents the COL1A1/PDGFB chimerical protein encoded by the T94796 tumour-derived chimerical COL1A1/PDGFB cDNA sequence

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -188- Oncogenesis Transfected cells lines expressing the chimerical T94796-COL1A1/PDGFB proteins became independent upon growth factors, including PDGFB, and induced tumours formation in nude mice. In addition, it was shown that the COL1A1/PDGFB stable clones cells contained activated PDGF b-receptors and that the conditioned media from COL1A1/PDGFB transfected cells were able to stimulate fibroblastic cells growth. Anti-PDGFBB antibodies neutralized this effect. These results strongly suggest that the COL1A1/PDGFB chimerical gene expression associated with DP, contributes to tumour formation through ectopic production of mature PDGFB and the formation of an autocrine loop.

Breakpoints

External links Nomenclature Hugo PDGFB GDB PDGFB PDGFB 5155 platelet-derived growth factor beta polypeptide Entrez_Gene (simian sarcoma viral (v-sis) oncogene homolog) Cards Atlas PDGFBID155 GeneCards PDGFB Ensembl PDGFB CancerGene PDGFB Genatlas PDGFB GeneLynx PDGFB eGenome PDGFB

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -189- euGene 5155 Genomic and cartography PDGFB - chr22:37944219-37965490 - 22q13.1 (hg17- GoldenPath May_2004) Ensembl PDGFB - 22q13.1 [CytoView]

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

Genbank A37537 [ SRS ] A37537 [ ENTREZ ]

Genbank A37562 [ SRS ] A37562 [ ENTREZ ]

Genbank K01401 [ SRS ] K01401 [ ENTREZ ]

Genbank K01913 [ SRS ] K01913 [ ENTREZ ]

Genbank K01914 [ SRS ] K01914 [ ENTREZ ]

RefSeq NM_002608 [ SRS ] NM_002608 [ ENTREZ ]

RefSeq NM_033016 [ SRS ] NM_033016 [ ENTREZ ]

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

Unigene Hs.1976 [ SRS ] Hs.1976 [ NCBI ] HS1976 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P01127 [ SRS] P01127 [ EXPASY ] P01127 [ INTERPRO ]

Prosite PS00249 PDGF_1 [ SRS ] PS00249 PDGF_1 [ Expasy ]

Prosite PS50278 PDGF_2 [ SRS ] PS50278 PDGF_2 [ Expasy ]

Interpro IPR002400 GF_cysknot [ SRS ] IPR002400 GF_cysknot [ EBI ] Interpro IPR000072 PD_growth_factor [ SRS ] IPR000072 PD_growth_factor [ EBI ]

Interpro IPR006782 PDGF_N [ SRS ] IPR006782 PDGF_N [ EBI ] CluSTr P01127 Pfam PF00341 PDGF [ SRS ] PF00341 PDGF [ Sanger ] pfam00341 [ NCBI-CDD ] Pfam PF04692 PDGF_N [ SRS ] PF04692 PDGF_N [ Sanger ] pfam04692 [ NCBI-CDD ]

Prodom PD001629 PD_growth_factor[INRA-Toulouse] Prodom P01127 PDGB_HUMAN [ Domain structure ] P01127 PDGB_HUMAN [ sequences sharing at least 1 domain ] Blocks P01127

PDB 1PDG [ SRS ] 1PDG [ PdbSum ], 1PDG [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 190040 [ map ]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -190- GENECLINICS 190040

SNP PDGFB [dbSNP-NCBI]

SNP NM_002608 [SNP-NCI]

SNP NM_033016 [SNP-NCI]

SNP PDGFB [GeneSNPs - Utah] PDGFB [SNP - CSHL] PDGFB] [HGBASE - SRS] General knowledge Family PDGFB [UCSC Family Browser] Browser SOURCE NM_002608 SOURCE NM_033016 SMD Hs.1976 SAGE Hs.1976 Amigo process|cell proliferation Amigo component|extracellular region Amigo function|growth factor activity Amigo component|membrane Amigo function|platelet-derived growth factor receptor binding Amigo process|regulation of cell cycle Amigo process|response to wounding BIOCARTA Transcriptional activation of dbpb from mRNA PubGene PDGFB Other databases Probes Probe PDGFB Related clones (RZPD - Berlin) PubMed PubMed 35 Pubmed reference(s) in LocusLink Bibliography Brittle bones-fragile molecules: disorders of collagen gene structure and expression. Byers PH. Trends Genet. 1990 Sep;6(9):293-300. Review. Medline 91048866

Biology of the platelet-derived growth factor. Westermark B and Sorg C. Cytokines 1993, 5, Sorg C (ed): Karger S, Basel: 1-167.

Ring 22 chromosomes in dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences. Pedeutour F, Simon MP, Minoletti F, Sozzi G, Pierotti MA, Hecht F and Turc-Carel C.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -191- Cancer Res. 1995 Jun 1;55(11):2400-3. Medline 95277719

Soft tissue sarcomas in dermatology. Fish FS Dermatol Surg. 1996 Mar;22(3):268-73. REVIEW. Medline 96178090

The human type I collagen mutation database. Dalgleish R. Nucleic Acids Res. 1997 Jan 1;25(1):181-7. Medline 97169389

Signal transduction via platelet-derived growth factor receptors. Heldin CH, Ostman A and Ronnstrand L. Biochim Biophys Acta. 1998 Aug 19;1378(1):F79-113. Review. Medline 98412078

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -192- Medline 98252402

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

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -193- BiblioGene - INIST Contributor(s) Written 02- Marie-Pierre Simon, Georges Maire, Florence Pedeutour 2001 Citation This paper should be referenced as such : Simon MP, Maire G, Pedeutour F . PDGFB. Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PDGFBID155.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -194- Atlas of Genetics and Cytogenetics in Oncology and Haematology

XPA

Identity Other XPAC xeroderma pigmentosum, complementation group A names Hugo XPA Location 9q22.3-9q22.3 DNA/RNA Description human xeroderma pigmentosum group A 25kbp, six exons, 2 polyadenylation signals Transcription 1377 b mRNA; suggestion of 1 major transcript; promoter G+C rich (73%); one CAAT box and no TATA box. Protein

Description 273 amino acids, 31 kDa. DNA excision repair protein. The functional domain for damaged DNA recognition contains a zinc-finger motif with 4 cysteine residues : Cys-X2-Cys-X17-Cys-X2-Cys motif and a glutamic acid cluster encoded by Exon 2. The nuclear localization signal is located in Exon 1. Expression ubiquitous Localisation nuclear Function Initiates DNA repair by binding to damaged sites with various affinities, depending upon the chemical structure of the lesion Two proteins have been identified and implicated in (one of) the first steps of Nucleotide Excision Repair (NER), i.e. the recognition of lesions in the DNA: the XPA gene product and the XPC gene product. Cells from XPA patients are extremely sensitive to UV and have very low nucleotide excision repair activity. In vitro the XPA protein binds preferentially to damaged DNA compared to nondamaged DNA. The XPA protein binds to replication protein A (RPA) which enhances the affinity of XPA for damaged DNA and is essential for NER. The XPA protein has been shown to bind to ERCC1 and TFIIH. It is possible that the complex XPA/RPA may tell to the repair machinery which strand contained the damage and therefore should be eliminated. Homology Xpac (FlyBase ID) ; Xpa (MGI) Mutations Germinal 13 nucleotide substitutions and 5 small insertion/deletion in patients

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -195- Implicated in Entity xeroderma pigmentosum XPA Disease predisposition to skin cancer: early skin tumours ( basal cell carcinoma, squamous cell carcinoma and melanoma); early internal tumours

External links Nomenclature Hugo XPA GDB XPA Entrez_Gene XPA 7507 xeroderma pigmentosum, complementation group A Cards Atlas XPAID104 GeneCards XPA Ensembl XPA CancerGene XPA Genatlas XPA GeneLynx XPA eGenome XPA euGene 7507 Genomic and cartography GoldenPath XPA - chr9:97516747-97539194 - 9q22.33 (hg17-May_2004) Ensembl XPA - 9q22.33 [CytoView]

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

Genbank AF503166 [ SRS ] AF503166 [ ENTREZ ]

Genbank U10347 [ SRS ] U10347 [ ENTREZ ]

Genbank U16815 [ SRS ] U16815 [ ENTREZ ]

Genbank BC014965 [ SRS ] BC014965 [ ENTREZ ]

Genbank BT019518 [ SRS ] BT019518 [ ENTREZ ]

RefSeq NM_000380 [ SRS ] NM_000380 [ ENTREZ ]

RefSeq NT_086754 [ SRS ] NT_086754 [ ENTREZ ] AceView XPA AceView - NCBI TRASER XPA Traser - Stanford

Unigene Hs.288867 [ SRS ] Hs.288867 [ NCBI ] HS288867 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P23025 [ SRS] P23025 [ EXPASY ] P23025 [ INTERPRO ]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -196- Prosite PS00752 XPA_1 [ SRS ] PS00752 XPA_1 [ Expasy ]

Prosite PS00753 XPA_2 [ SRS ] PS00753 XPA_2 [ Expasy ] Interpro IPR009061 Putativ_DNA_bind [ SRS ] IPR009061 Putativ_DNA_bind [ EBI ]

Interpro IPR000465 XPA [ SRS ] IPR000465 XPA [ EBI ] CluSTr P23025 Pfam PF05181 XPA_C [ SRS ] PF05181 XPA_C [ Sanger ] pfam05181 [ NCBI- CDD ] Pfam PF01286 XPA_N [ SRS ] PF01286 XPA_N [ Sanger ] pfam01286 [ NCBI- CDD ] Blocks P23025

PDB 1D4U [ SRS ] 1D4U [ PdbSum ], 1D4U [ IMB ]

PDB 1XPA [ SRS ] 1XPA [ PdbSum ], 1XPA [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 278700 [ map ] GENECLINICS 278700

SNP XPA [dbSNP-NCBI]

SNP NM_000380 [SNP-NCI]

SNP XPA [GeneSNPs - Utah] XPA [SNP - CSHL] XPA] [HGBASE - SRS] General knowledge Family XPA [UCSC Family Browser] Browser SOURCE NM_000380 SMD Hs.288867 SAGE Hs.288867 Amigo function|damaged DNA binding Amigo process|nucleotide-excision repair Amigo component|nucleus Amigo function|protein binding PubGene XPA Other databases Probes Probe XPA Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia Nishigori, C., Zghal, M., Yagi, T., Imamura, S., Komoun, M. R., and Takebe, H.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -197- Am J Hum Genet. 53: 1001-6, 1993. Medline 8105686

The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage Asahina, H., Kuraoka, I., Shirakawa, M., Morita, E. H., Miura, N., Miyamoto, I., Ohtsuka, E., Okada, Y., and Tanaka, K. Mutat Res. 315: 229-37, 1994. Medline 7526200

Mutation and expression of the XPA gene in revertants and hybrids of a xeroderma pigmentosum cell line Cleaver, J. E., McDowell, M., Jones, C., Wood, R., and Karentz, D. Somat Cell Mol Genet. 20: 327-37, 1994. Medline 7974007

Siblings with xeroderma pigmentosum complementation group A with different skin cancer development: importance of sun protection at an early age Kondoh, M., Ueda, M., Nakagawa, K., and Ichihashi, M. J Am Acad Dermatol. 31: 993-6, 1994. Medline 7962783

Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins Park, C. H. and Sancar, A. Proc Natl Acad Sci U S A. 91: 5017-21, 1994. Medline 8197175

Mammalian DNA nucleotide excision repair reconstituted with purified protein components Aboussekhra, A., Biggerstaff, M., Shivji, M. K., Vilpo, J. A., Moncollin, V., Podust, V. N., Protic, M., Hubscher, U., Egly, J. M., and Wood, R. D. Cell. 80: 859-68, 1995. Medline 7697716

Development of a new easy complementation assay for DNA repair deficient human syndromes using cloned repair genes Carreau, M., Eveno, E., Quilliet, X., Chevalier-Lagente, O., Benoit, A., Tanganelli, B., Stefanini, M., Vermeulen, W., Hoeijmakers, J. H., Sarasin, A., and et al. Carcinogenesis. 16: 1003-9, 1995. Medline 7767957

Overexpression of the XPA repair gene increases resistance to ultraviolet radiation in human cells by selective repair of DNA damage Cleaver, J. E., Charles, W. C., McDowell, M. L., Sadinski, W. J., and Mitchell, D. L. Cancer Res. 55: 6152-60, 1995.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -198- Medline 8521407

A deletion and an insertion in the alleles for the xeroderma pigmentosum (XPA) DNA-binding protein in mildly affected patients Cleaver, J. E., Charles, W. C., Thomas, G. H., and McDowell, M. L. Hum Mol Genet. 4: 1685-7, 1995. Medline 8541864

Expression of a transfected DNA repair gene (XPA) in xeroderma pigmentosum group A cells restores normal DNA repair and mutagenesis of UV-treated plasmids Levy, D. D., Saijo, M., Tanaka, K., and Kraemer, K. H. Carcinogenesis. 16: 1557-63, 1995.

DNA repair protein XPA binds replication protein A (RPA) Matsuda, T., Saijo, M., Kuraoka, I., Kobayashi, T., Nakatsu, Y., Nagai, A., Enjoji, T., Masutani, C., Sugasawa, K., Hanaoka, F., and et al. J Biol Chem. 270: 4152-7, 1995. Medline 7876167

The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor Park, C. H., Mu, D., Reardon, J. T., and Sancar, A. J Biol Chem. 270: 4896-902, 1995. Medline 7876263

Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA de Vries, A., van Oostrom, C. T., Hofhuis, F. M., Dortant, P. M., Berg, R. J., de Gruijl, F. R., Wester, P. W., van Kreijl, C. F., Capel, P. J., van Steeg, H., and et al. Nature. 377: 169-73, 1995. Medline 7675086

Two novel splicing mutations in the XPA gene in patients with group A xeroderma pigmentosum Satokata, I., Uchiyama, M., and Tanaka, K. Hum Mol Genet. 4: 1993-4, 1995. Medline 8595429

Identification of a damaged-DNA binding domain of the XPA protein Kuraoka, I., Morita, E. H., Saijo, M., Matsuda, T., Morikawa, K., Shirakawa, M., and Tanaka, K. Mutat Res. 362: 87-95, 1996.

Sequential binding of DNA repair proteins RPA and ERCC1 to XPA in vitro Saijo, M., Kuraoka, I., Masutani, C., Hanaoka, F., and Tanaka, K.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -199- Nucleic Acids Res. 24: 4719-24, 1996. Medline 8972858

Splice site mutations in a xeroderma pigmentosum group A patient with delayed onset of neurological disease States, J. C. and Myrand, S. P. Mutat Res. 363: 171-7, 1996. Medline 8765158

Xpa knockout mice de Vries, A. and van Steeg, H. Semin Cancer Biol. 7: 229-40, 1996.

Relative susceptibilities of XPA knockout mice and their heterozygous and wild-type littermates to UVB-induced skin cancer Berg, R. J., de Vries, A., van Steeg, H., and de Gruijl, F. R. Cancer Res. 57: 581-4, 1997. Medline 9044829

Human nucleotide excision repair protein XPA: expression and NMR backbone assignments of the 14.7 kDa minimal damaged DNA binding domain (Met98- Phe219) Buchko, G. W., Ni, S., Thrall, B. D., and Kennedy, M. A. J Biomol NMR. 10: 313-4, 1997. Medline 9390412

Human nucleotide excision repair protein XPA: 1H NMR and CD solution studies of a synthetic peptide fragment corresponding to the zinc- binding domain (101-141) Buchko, G. W. and Kennedy, M. A. J Biomol Struct Dyn. 14: 677-90, 1997. Medline 9195337

The DNA damage-recognition problem in human and other eukaryotic cells: the XPA damage binding protein Cleaver, J. E. and States, J. C. Biochem J. 328: 1-12, 1997.

Loss of the xeroderma pigmentosum group A gene (XPA) enhances apoptosis of cultured cerebellar neurons induced by UV but not by low-K+ medium Enokido, Y., Inamura, N., Araki, T., Satoh, T., Nakane, H., Yoshino, M., Nakatsu, Y., Tanaka, K., and Hatanaka, H. J Neurochem. 69: 246-51, 1997. Medline 9202316

Quantification of XPA gene expression levels in human and mouse cell lines by

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -200- competitive RT-PCR Layher, S. K. and Cleaver, J. E. Mutat Res. 383: 9-19, 1997. Medline 9042415

DNA damage recognition by XPA protein promotes efficient recruitment of transcription factor II H Nocentini, S., Coin, F., Saijo, M., Tanaka, K., and Egly, J. M. J Biol Chem. 272: 22991-4, 1997.

Induction of DNA adducts and mutations in spleen, liver and lung of XPA- deficient/lacZ transgenic mice after oral treatment with benzo[a]pyrene: correlation with tumour development de Vries, A., Dolle, M. E., Broekhof, J. L., Muller, J. J., Kroese, E. D., van Kreijl, C. F., Capel, P. J., Vijg, J., and van Steeg, H. Carcinogenesis. 18: 2327-32, 1997. Medline 9450477

Spontaneous liver tumors and benzo[a]pyrene-induced lymphomas in XPA- deficient mice de Vries, A., van Oostrom, C. T., Dortant, P. M., Beems, R. B., van Kreijl, C. F., Capel, P. J., and van Steeg, H. Mol Carcinog. 19: 46-53, 1997. Medline 9180928

Retrovirus-mediated gene transfer corrects DNA repair defect of xeroderma pigmentosum cells of complementation groups A, B and C Zeng, L., Quilliet, X., Chevallier-Lagente, O., Eveno, E., Sarasin, A., and Mezzina, M. Gene Ther. 4: 1077-84, 1997. Medline 9415314

Solution structure of the DNA- and RPA-binding domain of the human repair factor XPA Ikegami, T., Kuraoka, I., Saijo, M., Kodo, N., Kyogoku, Y., Morikawa, K., Tanaka, K., and Shirakawa, M. Nat Struct Biol. 5: 701-6, 1998.

Mutational analysis of a function of xeroderma pigmentosum group A (XPA) protein in strand-specific DNA repair Kobayashi, T., Takeuchi, S., Saijo, M., Nakatsu, Y., Morioka, H., Otsuka, E., Wakasugi, M., Nikaido, O., and Tanaka, K. Nucleic Acids Res. 26: 4662-8, 1998. Medline 9753735

Interactions of the transcription/DNA repair factor TFIIH and XP repair proteins with DNA lesions in a cell-free repair assay

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -201- Li, R. Y., Calsou, P., Jones, C. J., and Salles, B. J Mol Biol. 281: 211-8, 1998. Medline 9698541

Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein States, J. C., McDuffie, E. R., Myrand, S. P., McDowell, M., and Cleaver, J. E. Hum Mutat. 12: 103-13, 1998. Medline 9671271

Strand specificity and absence of hot spots for p53 mutations in ultraviolet B- induced skin tumors of XPA-deficient mice Takeuchi, S., Nakatsu, Y., Nakane, H., Murai, H., Hirota, S., Kitamura, Y., Okuyama, A., and Tanaka, K. Cancer Res. 58: 641-6, 1998. Medline 9485015

Retrovirus-mediated DNA repair gene transfer into xeroderma pigmentosum cells: perspectives for a gene therapy Zeng, L., Sarasin, A., and Mezzina, M. Cell Biol Toxicol. 14: 105-10, 1998. Medline 9553721

Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition de Boer, J., van Steeg, H., Berg, R. J., Garssen, J., de Wit, J., van Oostrum, C. T., Beems, R. B., van der Horst, G. T., van Kreijl, C. F., de Gruijl, F. R., Bootsma, D., Hoeijmakers, J. H., and Weeda, G. Cancer Res. 59: 3489-94, 1999. Medline 10416615

A novel function of emodin: enhancement of the nucleotide excision repair of UV- and cisplatin-induced DNA damage in human cells Chang, L. C., Sheu, H. M., Huang, Y. S., Tsai, T. R., and Kuo, K. W. Biochem Pharmacol. 58: 49-57, 1999. Medline 10403518

A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy Cleaver, J. E., Thompson, L. H., Richardson, A. S., and States, J. C. Hum Mutat. 14: 9-22, 1999. Medline 10447254

Neurodegeneration in hereditary nucleotide repair disorders Itoh, M., Hayashi, M., Shioda, K., Minagawa, M., Isa, F., Tamagawa, K., Morimatsu,

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -202- Y., and Oda, M. Brain Dev. 21: 326-33, 1999. Medline 10413020

Functional studies on the interaction between human replication protein A and Xeroderma pigmentosum group A complementing protein (XPA), Lee, B. E., Sung, J. W., Kim, D. K., Lee, J. R., Kim, N. D., and Kang, S. W. Mol Cells. 9: 185-90, 1999. Medline 10340474

Order of assembly of human DNA repair excision nuclease Wakasugi, M. and Sancar, A. J Biol Chem. 274: 18759-68, 1999. Medline 10373492

Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK Araujo, S. J., Tirode, F., Coin, F., Pospiech, H., Syvaoja, J. E., Stucki, M., Hubscher, U., Egly, J. M., and Wood, R. D. Genes Dev. 14: 349-59, 2000.

Stable Binding of Human XPC Complex to Irradiated DNA Confers Strong Discrimination for Damaged Sites Batty, D., Rapic'-Otrin, V., Levine, A. S., and Wood, R. D. J Mol Biol. 300: 275-290, 2000.

Damage recognition in nucleotide excision repair of DNA Batty, D. P. and Wood, R. D. Gene. 241: 193-204, 2000. Medline 10675030

Identification of four single nucleotide polymorphisms in DNA repair genes: XPA and XPB (ERCC3) in Polish population Butkiewicz, D., Rusin, M., Harris, C. C., and Chorazy, M. Hum Mutat. 15: 577-8, 2000. Medline 10862089

Three-dimensional structural views of damaged-DNA recognition: T4 endonuclease V, E. coli Vsr protein, and human nucleotide excision repair factor XPA Morikawa, K. and Shirakawa, M. Mutat Res. 460: 257-275, 2000. Medline 10946233

XAB2, a novel tetratricopeptide repeat protein, involved in transcription- coupled DNA repair and transcription

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -203- Nakatsu, Y., Asahina, H., Citterio, E., Rademarkers, S., Vermeulen, W., Kamiuchi, S., Yeo, J. P., Khaw, M. C., Saijo, M., Kodo, N., Matsuda, T., Hoeijmakers, J. H., and Tanaka, K. J Biol Chem, 2000.

Mutagenesis and carcinogenesis in nucleotide excision repair-deficient XPA knock out mice van Steeg, H., Mullenders, L. H., and Vijg, J. Mutat Res. 450: 167-80, 2000. Medline 10838141

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Anne Stary and Alain Sarasin 2001 Citation This paper should be referenced as such : Stary A, Sarasin A . XPA. Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/XPAID104.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -204- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ERCC-3 (Excision repair cross-complementing rodent repair deficiency, complementation group 3)

Identity Other XPB names XPBC Hugo ERCC3 Location 2q21

XPB (2q21) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA Description 2751 b mRNA Protein

Description 782 amino acids Expression ubiquitous Localisation nuclear

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -205- Function DNA excision repair protein. 3'-5' ATP-dependent helicase activity involved in excision DNA repair and initiation of basal transcription The XPB protein displays a 3'-5' helicase activity. This protein is a subunit of the basal transcription factor TFIIH involved in both Nucleotide Excision Repair (NER) and the initiation of RNA polymerase II . Indeed, TFIIH fulfills a dual role in transcription initiation and NER and the role of TFIIH in NER might closely mimic its role in the transcription initiation process. In transcription initiation TFIIH is thought to be involved in unwinding of the promoter site to allowing promoter clearance. In the NER process TFIIH causes unwinding of the lesion- containing region that has been localized by XPC-HR23B and XPA- RPA, enabling the accumulation of NER proteins around the damaged site. Among the Xeroderma pigmentosum (XP) patients, XPB patients are extremely rare (only 3 patients known in the world) due to the fact that the XPB gene product is essential for transcription initiation and in all cases, these patients show the double symptoms of Xeroderma pigmentosum and Cockayne syndrome (CS) (see below). Homology haywire gene (FLYBASE, hay) ; Ercc3 (MGI : 95414) Mutations Germinal F99S (T296C) is found in two XPB/CS patients; T119P (A355C) is found in two TTD/XPB patients; FS740 is found in one XPB/CS patient Implicated in Entity ERCC3/XPB Disease Xeroderma pigmentosum and Cockayne syndrome in the same patient or Trichothiodystrophy. Early skin cancers

External links Nomenclature Hugo ERCC3 GDB ERCC3 ERCC3 2071 excision repair cross-complementing rodent repair Entrez_Gene deficiency, complementation group 3 (xeroderma pigmentosum group B complementing) Cards Atlas XPBID296 GeneCards ERCC3 Ensembl ERCC3 CancerGene ERCC3 Genatlas ERCC3 GeneLynx ERCC3 eGenome ERCC3

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -206- euGene 2071 Genomic and cartography ERCC3 - 2q21 chr2:127731096-127767982 - 2q14.3 (hg17- GoldenPath May_2004) Ensembl ERCC3 - 2q14.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ERCC3 Gene and transcription

Genbank AY163769 [ SRS ] AY163769 [ ENTREZ ]

Genbank AK091500 [ SRS ] AK091500 [ ENTREZ ]

Genbank AK095557 [ SRS ] AK095557 [ ENTREZ ]

Genbank AK127469 [ SRS ] AK127469 [ ENTREZ ]

Genbank BC008820 [ SRS ] BC008820 [ ENTREZ ]

RefSeq NM_000122 [ SRS ] NM_000122 [ ENTREZ ]

RefSeq NT_086627 [ SRS ] NT_086627 [ ENTREZ ] AceView ERCC3 AceView - NCBI TRASER ERCC3 Traser - Stanford

Unigene Hs.469872 [ SRS ] Hs.469872 [ NCBI ] HS469872 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P19447 [ SRS] P19447 [ EXPASY ] P19447 [ INTERPRO ]

Interpro IPR001650 Helicase_C [ SRS ] IPR001650 Helicase_C [ EBI ]

Interpro IPR006935 ResIII [ SRS ] IPR006935 ResIII [ EBI ] Interpro IPR001161 XPB_DNA_repair [ SRS ] IPR001161 XPB_DNA_repair [ EBI ] CluSTr P19447

PF00271 Helicase_C [ SRS ] PF00271 Helicase_C [ Sanger Pfam ] pfam00271 [ NCBI-CDD ] Blocks P19447 Polymorphism : SNP, mutations, diseases OMIM 133510 [ map ] GENECLINICS 133510

SNP ERCC3 [dbSNP-NCBI]

SNP NM_000122 [SNP-NCI]

SNP ERCC3 [GeneSNPs - Utah] ERCC3 [SNP - CSHL] ERCC3] [HGBASE - SRS] General knowledge Family ERCC3 [UCSC Family Browser] Browser SOURCE NM_000122

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -207- SMD Hs.469872 SAGE Hs.469872

Enzyme 3.6.1.- [ Enzyme-SRS ] 3.6.1.- [ Brenda-SRS ] 3.6.1.- [ KEGG ] 3.6.1.- [ WIT ] Amigo function|3' to 5' DNA helicase activity Amigo function|ATP binding Amigo function|ATP-dependent DNA helicase activity Amigo process|DNA topological change Amigo function|damaged DNA binding Amigo function|helicase activity Amigo function|hydrolase activity Amigo process|induction of apoptosis Amigo component|nucleus Amigo process|perception of sound Amigo function|protein binding Amigo process|regulation of transcription, DNA-dependent Amigo component|transcription factor TFIIH complex Amigo process|transcription from Pol II promoter Amigo process|transcription-coupled nucleotide-excision repair BIOCARTA CARM1 and Regulation of the Estrogen Receptor BIOCARTA Chromatin Remodeling by hSWI/SNF ATP-dependent Complexes Nuclear receptors coordinate the activities of chromatin remodeling BIOCARTA complexes and coactivators to facilitate initiation of transcription in carcinoma cells PubGene ERCC3 Other databases Probes Probe Cancer Cytogenetics (Bari) Probe ERCC3 Related clones (RZPD - Berlin) PubMed PubMed 33 Pubmed reference(s) in LocusLink Bibliography Molecular cloning and biological characterization of the human excision repair gene ERCC-3. Weeda G., van Ham R. C., Masurel R., Westerveld A., Odijk H., de Wit J., Bootsma D., van der Eb A. J. Hoeijmakers J. H. Mol Cell Biol 1990; 10: 2570-81. Medline 2167179

A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -208- Weeda G., van Ham R. C., Vermeulen W., Bootsma D., van der Eb A. J. Hoeijmakers J. H. Cell 1990; 62: 777-91. Medline 2167179

Characterization of the mouse homolog of the XPBC/ERCC-3 gene implicated in xeroderma pigmentosum and Cockayne's syndrome. Weeda G., Ma L., van Ham R. C., Bootsma D., van der Eb A. J. Hoeijmakers J. H. Carcinogenesis 1991; 12: 2361-8. Medline 1747940

Structure and expression of the human XPBC/ERCC-3 gene involved in DNA repair disorders xeroderma pigmentosum and Cockayne's syndrome. Weeda G., Ma L. B., van Ham R. C., van der Eb A. J. Hoeijmakers J. H. Nucleic Acids Res 1991; 19: 6301-8. Medline 1956789

Localization of the xeroderma pigmentosum group B-correcting gene ERCC3 to human chromosome 2q21. Weeda G., Wiegant J., van der Ploeg M., Geurts van Kessel A. H., van der Eb A. J. Hoeijmakers J. H. Genomics 1991; 10: 1035-40. Medline 1916809

Molecular and functional analysis of the XPBC/ERCC-3 promoter: transcription activity is dependent on the integrity of an Sp1-binding site. Ma L., Weeda G., Jochemsen A. G., Bootsma D., Hoeijmakers J. H. van der Eb A. J. Nucleic Acids Res 1992; 20: 217-24. Medline 1741247

A Drosophila model for xeroderma pigmentosum and Cockayne's syndrome: haywire encodes the fly homolog of ERCC3, a human excision repair gene. Mounkes L. C., Jones R. S., Liang B. C., Gelbart W. Fuller M. T. Cell 1992; 71: 925-37. Medline 1458540

DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor [see comments]. Schaeffer L., Roy R., Humbert S., Moncollin V., Vermeulen W., Hoeijmakers J. H., Chambon P. Egly J. M. Science 1993; 260: 58-63. Medline 8465201

Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II. Drapkin R., Reardon J. T., Ansari A., Huang J. C., Zawel L., Ahn K., Sancar A.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -209- Reinberg D. Nature 1994; 368: 769-72. Medline 8152490 p44 and p34 subunits of the BTF2/TFIIH transcription factor have homologies with SSL1, a yeast protein involved in DNA repair. Humbert S., van Vuuren H., Lutz Y., Hoeijmakers J. H., Egly J. M. Moncollin V. Embo J 1994; 13: 2393-8. Medline 8194529

Mutational analysis of ERCC3, which is involved in DNA repair and transcription initiation: identification of domains essential for the DNA repair function. Ma L., Westbroek A., Jochemsen A. G., Weeda G., Bosch A., Bootsma D., Hoeijmakers J. H. van der Eb A. Mol Cell Biol 1994; 14: 4126-34. Medline 8196650

The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. Schaeffer L., Moncollin V., Roy R., Staub A., Mezzina M., Sarasin A., Weeda G., Hoeijmakers J. H. Egly J. M. Embo J 1994; 13: 2388-92. Medline 8194528

Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH). van Vuuren A. J., Vermeulen W., Ma L., Weeda G., Appeldoorn E., Jaspers N. G., van der Eb A. J., Bootsma D., Hoeijmakers J. H., Humbert S. et al. Embo J 1994; 13: 1645-53.

Comparative analyses of relative ERCC3 and ERCC6 mRNA levels in gliomas and adjacent non-neoplastic brain. Dabholkar M. D., Berger M. S., Vionnet J. A., Overton L., Thompson C., Bostick- Bruton F., Yu J. J., Silber J. R. Reed E. Mol Carcinog 1996; 17: 1-7. Medline 8876669

A 3' --> 5' XPB helicase defect in repair/transcription factor TFIIH of xeroderma pigmentosum group B affects both DNA repair and transcription. Hwang J. R., Moncollin V., Vermeulen W., Seroz T., van Vuuren H., Hoeijmakers J. H. J. Egly J. M. J Biol Chem 1996; 271: 15898-904. Medline 8663148

Functional interactions between p53 and the TFIIH complex are affected by tumour-associated mutations.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -210- Leveillard T., Andera L., Bissonnette N., Schaeffer L., Bracco L., Egly J. M. Wasylyk B. Embo J 1996; 15: 1615-24. Medline 8612585

Hepatitis B virus transactivator protein, HBx, associates with the components of TFIIH and stimulates the DNA helicase activity of TFIIH. Qadri I., Conaway J. W., Conaway R. C., Schaack J. Siddiqui A. Proc Natl Acad Sci U S A 1996; 93: 10578-83. Medline 8855220

The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. Wang X. W., Vermeulen W., Coursen J. D., Gibson M., Lupold S. E., Forrester K., Xu G., Elmore L., Yeh H., Hoeijmakers J. H. Harris C. C. Genes Dev 1996; 10: 1219-32. Medline 8675009

TFIIH functions in regulating transcriptional elongation by RNA polymerase II in Xenopus oocytes. Yankulov K. Y., Pandes M., McCracken S., Bouchard D. Bentley D. L. Mol Cell Biol 1996; 16: 3291-9. Medline 8668144

Reduced RNA polymerase II transcription in extracts of cockayne syndrome and xeroderma pigmentosum/Cockayne syndrome cells. Dianov G. L., Houle J. F., Iyer N., Bohr V. A. Friedberg E. C. Nucleic Acids Res 1997; 25: 3636-42. Medline 9278484

Sequence-specific and domain-specific DNA repair in xeroderma pigmentosum and Cockayne syndrome cells. Tu Y., Bates S. Pfeifer G. P. J Biol Chem 1997; 272: 20747-55. Medline 9252397

A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Weeda G., Eveno E., Donker I., Vermeulen W., Chevallier-Lagente O., Taieb A., Stary A., Hoeijmakers J. H., Mezzina M. Sarasin A. Am J Hum Genet 1997; 60: 320-9. Medline 9012405

The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor. Weeda G., Rossignol M., Fraser R. A., Winkler G. S., Vermeulen W., van't Veer L. J.,

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -211- Ma L., Hoeijmakers J. H. Egly J. M. Nucleic Acids Res 1997; 25: 2274-83. Medline 9173976

Retrovirus-mediated gene transfer corrects DNA repair defect of xeroderma pigmentosum cells of complementation groups A, B and C. Zeng L., Quilliet X., Chevallier-Lagente O., Eveno E., Sarasin A. Mezzina M. Gene Ther 1997; 4: 1077-84. Medline 9415314

A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. de Boer J., de Wit J., van Steeg H., Berg R. J., Morreau H., Visser P., Lehmann A. R., Duran M., Hoeijmakers J. H. Weeda G. Mol Cell 1998; 1: 981-90. Medline 9651581

Cloning of a cDNA from Arabidopsis thaliana homologous to the human XPB gene. Ribeiro D. T., Machado C. R., Costa R. M., Praekelt U. M., Van Sluys M. A. Menck C. F. Gene 1998; 208: 207-13. Medline 9524267

RNA polymerase II elongation complexes containing the Cockayne syndrome group B protein interact with a molecular complex containing the transcription factor IIH components xeroderma pigmentosum B and p62. Tantin D. J Biol Chem 1998; 273: 27794-9.

Mutations in XPB and XPD helicases found in xeroderma pigmentosum patients impair the transcription function of TFIIH. Coin F., Bergmann E., Tremeau-Bravard A. Egly J. M. Embo J 1999; 18: 1357-66. Medline 10064601

BCR binds to the xeroderma pigmentosum group B protein. Maru Y., Kobayashi T., Tanaka K. Shibuya M. Biochem Biophys Res Commun 1999; 260: 309-12. Medline 10403766

A role for the TFIIH XPB DNA helicase in promoter escape by RNA polymerase II. Moreland R. J., Tirode F., Yan Q., Conaway J. W., Egly J. M. Conaway R. C. J Biol Chem 1999; 274: 22127-30. Medline 10428772

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -212-

Molecular characterization of mutant alleles of the DNA repair/basal transcription factor haywire/ERCC3 in Drosophila. Mounkes L. C. Fuller M. T. Genetics 1999; 152: 291-7. Medline 10224261

The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes. Riou L., Zeng L., Chevallier-Lagente O., Stary A., Nikaido O., Taieb A., Weeda G., Mezzina M. Sarasin A. Hum Mol Genet 1999; 8: 1125-33. Medline 10332046

The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein. Takeda N., Shibuya M. Maru Y. Proc Natl Acad Sci U S A 1999; 96: 203-7. Medline 9874796

Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7. Tirode F., Busso D., Coin F. Egly J. M. Mol Cell 1999; 3: 87-95. Medline 10024882

Identification of four single nucleotide polymorphisms in DNA repair genes: XPA and XPB (ERCC3) in Polish population. Butkiewicz D., Rusin M., Harris C. C. Chorazy M. Hum Mutat 2000; 15: 577-8. Medline 10862089

Mechanism of promoter melting by the xeroderma pigmentosum complementation group B helicase of transcription factor IIH revealed by protein-DNA photo-cross-linking. Douziech M., Coin F., Chipoulet J. M., Arai Y., Ohkuma Y., Egly J. M. Coulombe B. Mol Cell Biol 2000; 20: 8168-77. Medline 10862089

Molecular structure of human TFIIH. Schultz P., Fribourg S., Poterszman A., Mallouh V., Moras D. Egly J. M. Cell 2000; 102: 599-607. Medline 11007478

REVIEW articles automatic search in PubMed

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -213- Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Anne Stary and Alain Sarasin 2001 Citation This paper should be referenced as such : Stary A, Sarasin A . ERCC-3 (Excision repair cross-complementing rodent repair deficiency, complementation group 3). Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/XPBID296.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -214- Atlas of Genetics and Cytogenetics in Oncology and Haematology

XPC

Identity Other XPCC xeroderma pigmentosum, complementation group C names Hugo XPC Location 3p25.1 DNA/RNA Description 17703 bp; 16 exons Transcription 3558 b mRNA Protein

Description 939 amino acids Expression ubiquitous Localisation nuclear Function Involved in the early recognition of DNA damage present in chromatine. Two proteins have been identified and implicated in (one of) the first steps of NER, i.e. the recognition of lesions in the DNA: the XPA gene product and the XPC gene product in complex with HR23B. This XPC- HR23B complex has been implicated in DNA damage recognition, especially the cyclobutane pyrimidine dimers induced by UV-light. XPC cells have low Nucleotide Excision Repair (NER) repair capacity, but the residual repair has been shown to occur specifically in transcribed genes. It is very likely that the XPC-HR23B complex is the principal damage recognition complex i.e. essential for the recognition of DNA lesions in the genome. Binding of XPC-HR23B to a DNA lesion causes local unwinding, so that the XPA protein can bind and the whole repair machinery can be loaded onto the damaged site. The XPC-HR23B complex is only required for global genome repair. In case of transcription coupled repair when an RNA polymerase is stalled at a lesion, the DNA is unwound by the transcription complex and XPA can bind independently of XPC-HR23B complex. Homology MGI : Xpc (Nb 103557) Mutations Germinal 19 mutated sites involved in the XP group C syndrome ( XPC), 95% of these mutations (non sense, frameshift, deletion or splice site mutations) give rise to truncated proteins indicating that the XPC gene is not essential for viability

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -215- Implicated in Entity Xeroderma pigmentosum XPC Disease predisposition to skin cancer: early skin tumours

External links Nomenclature Hugo XPC GDB XPC Entrez_Gene XPC 7508 xeroderma pigmentosum, complementation group C Cards Atlas XPCID122 GeneCards XPC Ensembl XPC CancerGene XPC Genatlas XPC GeneLynx XPC eGenome XPC euGene 7508 Genomic and cartography XPC - 3p25.1 chr3:14161651-14195143 - 3p25.1 (hg17- GoldenPath May_2004) Ensembl XPC - 3p25.1 [CytoView]

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

Genbank AF261901 [ SRS ] AF261901 [ ENTREZ ]

Genbank AY131066 [ SRS ] AY131066 [ ENTREZ ]

Genbank BC016620 [ SRS ] BC016620 [ ENTREZ ]

Genbank D21089 [ SRS ] D21089 [ ENTREZ ]

Genbank X65024 [ SRS ] X65024 [ ENTREZ ]

RefSeq NM_004628 [ SRS ] NM_004628 [ ENTREZ ]

RefSeq NT_086636 [ SRS ] NT_086636 [ ENTREZ ] AceView XPC AceView - NCBI TRASER XPC Traser - Stanford

Unigene Hs.475538 [ SRS ] Hs.475538 [ NCBI ] HS475538 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q01831 [ SRS] Q01831 [ EXPASY ] Q01831 [ INTERPRO ]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -216- Interpro IPR004583 Rad4 [ SRS ] IPR004583 Rad4 [ EBI ] CluSTr Q01831

Pfam PF03835 Rad4 [ SRS ] PF03835 Rad4 [ Sanger ] pfam03835 [ NCBI-CDD ] Blocks Q01831 Polymorphism : SNP, mutations, diseases OMIM 278720 [ map ] GENECLINICS 278720

SNP XPC [dbSNP-NCBI]

SNP NM_004628 [SNP-NCI]

SNP XPC [GeneSNPs - Utah] XPC [SNP - CSHL] XPC] [HGBASE - SRS] General knowledge Family XPC [UCSC Family Browser] Browser SOURCE NM_004628 SMD Hs.475538 SAGE Hs.475538 Amigo function|damaged DNA binding Amigo process|nucleotide-excision repair Amigo component|nucleus Amigo function|single-stranded DNA binding PubGene XPC Other databases Probes Probe XPC Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography Survival of UV-irradiated mammalian cells correlates with efficient DNA repair in an essential gene. Bohr V. A., Okumoto D. S. Hanawalt P. C. Proc Natl Acad Sci U S A 1986; 83: 3830-3. Medline 3459159

Deficiency in the catalase activity of xeroderma pigmentosum cell and simian virus 40-transformed human cell extracts. Vuillaume M., Calvayrac R., Best-Belpomme M., Tarroux P., Hubert M., Decroix Y. Sarasin A. Cancer Res 1986; 46: 538-44. Medline 3000576

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -217- The localization of ultraviolet-induced excision repair in the nucleus and the distribution of repair events in higher order chromatin loops in mammalian cells. Mullenders L. H., van Zeeland A. A. Natarajan A. T. J Cell Sci Suppl 1987; 6: 243-62. Medline 3477564

Chromatin and nucleolar changes in Xeroderma pigmentosum cells resemble aging-related nuclear events. Puvion-Dutilleul F. Sarasin A. Mutat Res 1989; 219: 57-70.

Selective repair of specific chromatin domains in UV-irradiated cells from xeroderma pigmentosum complementation group C. Kantor G. J., Barsalou L. S. Hanawalt P. C. Mutat Res 1990; 235: 171-80. Medline 2342504

The residual repair capacity of xeroderma pigmentosum complementation group C fibroblasts is highly specific for transcriptionally active DNA. Venema J., van Hoffen A., Natarajan A. T., van Zeeland A. A. Mullenders L. H. Nucleic Acids Res 1990; 18: 443-8. Medline 2308842

A re-examination of the intragenome distribution of repaired sites in proliferating xeroderma pigmentosum complementation group C fibroblasts. Kantor G. J. Shanower G. A. Mutat Res 1992; 293: 55-64. Medline 1383811

Expression cloning of a human DNA repair gene involved in xeroderma pigmentosum group C [published erratum appears in Nature 1992 Dec 10;360(6404):610] [see comments]. Legerski R. Peterson C. Nature 1992; 359: 70-3. Medline 1522891

UV-induced base substitution mutations in a shuttle vector plasmid propagated in group C xeroderma pigmentosum cells. Yagi T., Sato M., Tatsumi-Miyajima J. Takebe H. Mutat Res 1992; 273: 213-20. Medline 1372104

Characterization of molecular defects in xeroderma pigmentosum group C. Li L., Bales E. S., Peterson C. A. Legerski R. J. Nat Genet 1993; 5: 413-7.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -218- Medline 8298653

DNA strand bias in the repair of the p53 gene in normal human and xeroderma pigmentosum group C fibroblasts. Evans M. K., Taffe B. G., Harris C. C. Bohr V. A. Cancer Res 1993; 53: 5377-81. Medline 8221675

U.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle. Yamaizumi M. Sugano T. Oncogene 1994; 9: 2775-84. Medline 8084582

Chromosomal localization of three repair genes: the xeroderma pigmentosum group C gene and two human homologs of yeast RAD23. van der Spek P. J., Smit E. M., Beverloo H. B., Sugasawa K., Masutani C., Hanaoka F., Hoeijmakers J. H. Hagemeijer A. Genomics 1994; 23: 651-8. Medline 7851894

Assignment of xeroderma pigmentosum group C (XPC) gene to chromosome 3p25. Legerski R. J., Liu P., Li L., Peterson C. A., Zhao Y., Leach R. J., Naylor S. L. Siciliano M. J. Genomics 1994; 21: 266-9. Medline 8088800

Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosum group C protein and a human homologue of yeast RAD23. Masutani C., Sugasawa K., Yanagisawa J., Sonoyama T., Ui M., Enomoto T., Takio K., Tanaka K., van der Spek P. J., Bootsma D. et al. Embo J 1994; 13: 1831-43. Medline 8168482

Development of a new easy complementation assay for DNA repair deficient human syndromes using cloned repair genes. Carreau M., Eveno E., Quilliet X., Chevalier-Lagente O., Benoit A., Tanganelli B., Stefanini M., Vermeulen W., Hoeijmakers J. H., Sarasin A. et al. Carcinogenesis 1995; 16: 1003-9. Medline 7767957

Transcription-coupled repair removes both cyclobutane pyrimidine dimers and 6-4 photoproducts with equal efficiency and in a sequential way from transcribed DNA in xeroderma pigmentosum group C fibroblasts. van Hoffen A., Venema J., Meschini R., van Zeeland A. A. Mullenders L. H.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -219- Embo J 1995; 14: 360-7. Medline 7835346

Overproduction, purification, and characterization of the XPC subunit of the human DNA repair excision nuclease. Reardon J. T., Mu D. Sancar A. J Biol Chem 1996; 271: 19451-6. Medline 8702634

XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes. van der Spek P. J., Eker A., Rademakers S., Visser C., Sugasawa K., Masutani C., Hanaoka F., Bootsma D. Hoeijmakers J. H. Nucleic Acids Res 1996; 24: 2551-9. Medline 8692695

Sequence of the mouse XPC cDNA and genomic structure of the human XPC gene. Li L., Peterson C. Legerski R. Nucleic Acids Res 1996; 24: 1026-8. Medline 8604333

Retroviral-mediated correction of DNA repair defect in xeroderma pigmentosum cells is associated with recovery of catalase activity. Quilliet X., Chevallier-Lagente O., Zeng L., Calvayrac R., Mezzina M., Sarasin A. Vuillaume M. Mutat Res 1997; 385: 235-42. Medline 9506892

Prolonged p53 protein accumulation in trichothiodystrophy fibroblasts dependent on unrepaired pyrimidine dimers on the transcribed strands of cellular genes. Dumaz N., Duthu A., Ehrhart J. C., Drougard C., Appella E., Anderson C. W., May P.,

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -220- Sarasin A. Daya-Grosjean L. Mol Carcinog 1997; 20: 340-7. Medline 9433478

Identification and characterization of XPC-binding domain of hHR23B. Masutani C., Araki M., Sugasawa K., van der Spek P. J., Yamada A., Uchida A., Maekawa T., Bootsma D., Hoeijmakers J. H. Hanaoka F. Mol Cell Biol 1997; 17: 6915-23. Medline 9372923

Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. Evans E., Moggs J. G., Hwang J. R., Egly J. M. Wood R. D. Embo J 1997; 16: 6559-73. Medline 9351836

Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals. Ahrens C., Grewe M., Berneburg M., Grether-Beck S., Quilliet X., Mezzina M., Sarasin A., Lehmann A. R., Arlett C. F. Krutmann J. Proc Natl Acad Sci U S A 1997; 94: 6837-41. Medline 9192652

Characterization of defective nucleotide excision repair in XPC mutant mice. Cheo D. L., Ruven H. J., Meira L. B., Hammer R. E., Burns D. K., Tappe N. J., van Zeeland A. A., Mullenders L. H. Friedberg E. C. Mutat Res 1997; 374: 1-9. Medline 9067411 p53 mutations in skin and internal tumors of xeroderma pigmentosum patients belonging to the complementation group C. Giglia G., Dumaz N., Drougard C., Avril M. F., Daya-Grosjean L. Sarasin A. Cancer Res 1998; 58: 4402-9. Medline 9766670

Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Sugasawa K., Ng J. M., Masutani C., Iwai S., van der Spek P. J., Eker A. P., Hanaoka F., Bootsma D. Hoeijmakers J. H. Mol Cell 1998; 2: 223-32. Medline 9734359

Interactions of the transcription/DNA repair factor TFIIH and XP repair proteins with DNA lesions in a cell-free repair assay. Li R. Y., Calsou P., Jones C. J. Salles B. J Mol Biol 1998; 281: 211-8.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -221- Medline 9698541

Nucleosome unfolding during DNA repair in normal and xeroderma pigmentosum (group C) human cells. Baxter B. K. Smerdon M. J. J Biol Chem 1998; 273: 17517-24. Medline 9651343

Defective global genome repair in XPC mice is associated with skin cancer susceptibility but not with sensitivity to UVB induced erythema and edema. Berg R. J., Ruven H. J., Sands A. T., de Gruijl F. R. Mullenders L. H. J Invest Dermatol 1998; 110: 405-9. Medline 9540983

Persistence of p53 mutations and resistance of keratinocytes to apoptosis are associated with the increased susceptibility of mice lacking the XPC gene to UV carcinogenesis. Ananthaswamy H. N., Ouhtit A., Evans R. L., Gorny A., Khaskina P., Sands A. T. Conti C. J. Oncogene 1999; 18: 7395-8. Medline 10602497

Order of assembly of human DNA repair excision nuclease. Wakasugi M. Sancar A. J Biol Chem 1999; 274: 18759-68.

Molecular mechanism of nucleotide excision repair. de Laat W. L., Jaspers N. G. Hoeijmakers J. H. Genes Dev 1999; 13: 768-85. Medline 10197977

Differential behaviors toward ultraviolet A and B radiation of fibroblasts and keratinocytes from normal and DNA-repair-deficient patients. Otto A. I., Riou L., Marionnet C., Mori T., Sarasin A. Magnaldo T. Cancer Res 1999; 59: 1212-8. Medline 10096550

Mutational inactivation of the xeroderma pigmentosum group C gene confers predisposition to 2-acetylaminofluorene-induced liver and lung cancer and to spontaneous testicular cancer in Trp53-/- mice. Cheo D. L., Burns D. K., Meira L. B., Houle J. F. Friedberg E. C. Cancer Res 1999; 59: 771-5. Medline 10029060

Clinical, Cellular, and Molecular Features of an Israeli Xeroderma Pigmentosum Family with a Frameshift Mutation in the XPC Gene: Sun Protection Prolongs

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -222- Life. Slor H., Batko S., Khan S. G., Sobe T., Emmert S., Khadavi A., Frumkin A., Busch D. B., Albert R. B. Kraemer K. H. J Invest Dermatol 2000; 115: 974-980. Medline 11121128

Age-dependent spontaneous mutagenesis in xpc mice defective in nucleotide excision repair [In Process Citation]. Wijnhoven S. W., Kool H. J., Mullenders L. H., van Zeeland A. A., Friedberg E. C., van Der Horst G. T., Steeg H. Vrieling H. Oncogene 2000; 19: 5034-7. Medline 11042691

A new xeroderma pigmentosum group C poly(AT) insertion/deletion polymorphism [In Process Citation]. Khan S. G., Metter E. J., Tarone R. E., Bohr V. A., Grossman L., Hedayati M., Bale S. J., Emmert S. Kraemer K. H. Carcinogenesis 2000; 21: 1821-5. Medline 11023539

Differential role of transcription-coupled repair in UVB-induced G2 arrest and apoptosis in mouse epidermis [In Process Citation]. van Oosten M., Rebel H., Friedberg E. C., van Steeg H., van Der Horst G. T., van Kranen H. J., Westerman A., van Zeeland A. A., Mullenders L. H. de Gruijl F. R. Proc Natl Acad Sci U S A 2000; 97: 11268-73. Medline 11005836

Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites [In Process Citation]. Batty D., Rapic'-Otrin V., Levine A. S. Wood R. D. J Mol Biol 2000; 300: 275-90. Medline 10873465

Impact of global genome repair versus transcription-coupled repair on ultraviolet carcinogenesis in hairless mice. Berg R. J., Rebel H., van der Horst G. T., van Kranen H. J., Mullenders L. H., van Vloten W. A. de Gruijl F. R. Cancer Res 2000; 60: 2858-63. Medline 10850428

Transcription-coupled and global genome repair differentially influence UV-B- induced acute skin effects and systemic immunosuppression. Garssen J., van Steeg H., de Gruijl F., de Boer J., van der Horst G. T., van Kranen H., van Loveren H., van Dijk M., Fluitman A., Weeda G. Hoeijmakers J. H. J Immunol 2000; 164: 6199-205. Medline 10843671

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -223-

Mutations in the XPC gene in families with xeroderma pigmentosum and consequences at the cell, protein, and transcript levels. Chavanne F., Broughton B. C., Pietra D., Nardo T., Browitt A., Lehmann A. R. Stefanini M. Cancer Res 2000; 60: 1974-82. Medline 10766188

Genotype-specific Trp53 mutational analysis in ultraviolet B radiation- induced skin cancers in Xpc and Xpc Trp53 mutant mice. Reis A. M., Cheo D. L., Meira L. B., Greenblatt M. S., Bond J. P., Nahari D. Friedberg E. C. Cancer Res 2000; 60: 1571-9. Medline 10749125

The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA. Yokoi M., Masutani C., Maekawa T., Sugasawa K., Ohkuma Y. Hanaoka F. J Biol Chem 2000; 275: 9870-5. Medline 10734143

Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition. Friedberg E. C., Bond J. P., Burns D. K., Cheo D. L., Greenblatt M. S., Meira L. B., Nahari D. Reis A. M. Mutat Res 2000; 459: 99-108. Medline 10725660

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Anne Stary and Alain Sarasin 2001 Citation This paper should be referenced as such : Stary A, Sarasin A . XPC. Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/XPCID122.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -224- Atlas of Genetics and Cytogenetics in Oncology and Haematology

ERCC2 (Excision repair cross-complementing rodent repair deficiency, complementation group 2)

Identity Other XPD names Hugo ERCC2 Location 19q13.2

XPD (19q13) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNA Description 54336 bp; 23 exons Transcription 2400b mRNA Protein

Description 760 amino acids Expression ubiquitous Localisation nuclear Function 5Õ-3Õ ATP-dependent helicase activity involved in DNA excision repair (NER) and as a subunit of the basal transcription factor TFIIH The XPD gene product displayed 5'-3' helicase activity. The XPD as the XPB protein are also found in the transcription factor TFIIH, a large complex involved in the initiation of transcription The striking discovery that subunits of basal transcription factor TFIIH were involved in Nucleotide Excision Repair (NER) sheds light on a new aspect of NER : a close coupling to transcription via common use of essential factors. TFIIH fulfills a dual role in transcription initiation and NER and the role of TFIIH in NER might closely mimic its role in the transcription initiation process. In transcription initiation TFIIH is thought to be involved in unwinding of the promoter site and to allow promoter clearance. In the NER process TFIIH causes unwinding of the damage containing region

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -225- that has been localized by XPC-HR23B and XPA-RPA, enabling the accumulation of NER proteins around the damaged site. Contrarely to the XPB helicase, the helicase activity of XPD is indispensable for NER but not for transcription initiation. So, there is much more XPD patients, and only two patients have been described as XP and CS. Homology FLYBASE :Xpd ; MGI : Ercc2 (Nb 95413) Mutations Germinal 17 mutated sites associated with the xeroderma pigmentosum group D syndrome (among them 3 are also associated with the CockayneÕsyndrome) and 15 mutated sites associated with the trichothiodystrophy syndrome Implicated in Entity xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (CS), and trichothiodystrophy (TTD) Disease predisposition to skin cancer: early skin cancers (XPD). Mental and stature abnormalities (XP/CS, and TTD)

External links Nomenclature Hugo ERCC2 GDB ERCC2 ERCC2 2068 excision repair cross-complementing rodent repair Entrez_Gene deficiency, complementation group 2 (xeroderma pigmentosum D) Cards Atlas XPDID297 GeneCards ERCC2 Ensembl ERCC2 CancerGene XPD Genatlas ERCC2 GeneLynx ERCC2 eGenome ERCC2 euGene 2068 Genomic and cartography ERCC2 - 19q13.2 chr19:50546686-50565669 - 19q13.32 (hg17- GoldenPath May_2004) Ensembl ERCC2 - 19q13.32 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ERCC2 Gene and transcription

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -226- Genbank AY092780 [ SRS ] AY092780 [ ENTREZ ]

Genbank L47234 [ SRS ] L47234 [ ENTREZ ]

Genbank AK092872 [ SRS ] AK092872 [ ENTREZ ]

Genbank BC008346 [ SRS ] BC008346 [ ENTREZ ]

Genbank BM769772 [ SRS ] BM769772 [ ENTREZ ]

RefSeq NM_000400 [ SRS ] NM_000400 [ ENTREZ ]

RefSeq NT_086903 [ SRS ] NT_086903 [ ENTREZ ] AceView ERCC2 AceView - NCBI TRASER ERCC2 Traser - Stanford

Unigene Hs.487294 [ SRS ] Hs.487294 [ NCBI ] HS487294 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt P18074 [ SRS] P18074 [ EXPASY ] P18074 [ INTERPRO ]

PS00690 DEAH_ATP_HELICASE [ SRS ] PS00690 Prosite DEAH_ATP_HELICASE [ Expasy ]

Interpro IPR010614 DEAD_2 [ SRS ] IPR010614 DEAD_2 [ EBI ]

Interpro IPR002464 DEAH_box [ SRS ] IPR002464 DEAH_box [ EBI ]

Interpro IPR010643 DUF1227 [ SRS ] IPR010643 DUF1227 [ EBI ] Interpro IPR001945 XPD_DNA_repair [ SRS ] IPR001945 XPD_DNA_repair [ EBI ] CluSTr P18074 Pfam PF06733 DEAD_2 [ SRS ] PF06733 DEAD_2 [ Sanger ] pfam06733 [ NCBI-CDD ] Pfam PF06777 DUF1227 [ SRS ] PF06777 DUF1227 [ Sanger ] pfam06777 [ NCBI-CDD ] Blocks P18074 Polymorphism : SNP, mutations, diseases OMIM 126340 [ map ] GENECLINICS 126340

SNP ERCC2 [dbSNP-NCBI]

SNP NM_000400 [SNP-NCI]

SNP ERCC2 [GeneSNPs - Utah] ERCC2 [SNP - CSHL] ERCC2] [HGBASE - SRS] General knowledge Family ERCC2 [UCSC Family Browser] Browser SOURCE NM_000400 SMD Hs.487294 SAGE Hs.487294

Enzyme 3.6.1.- [ Enzyme-SRS ] 3.6.1.- [ Brenda-SRS ] 3.6.1.- [ KEGG ] 3.6.1.- [ WIT ] Amigo function|5' to 3' DNA helicase activity Amigo function|ATP binding

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -227- Amigo function|ATP-dependent DNA helicase activity Amigo function|DNA binding Amigo function|hydrolase activity function|hydrolase activity, acting on acid anhydrides, in phosphorus- Amigo containing anhydrides Amigo process|induction of apoptosis Amigo function|magnesium ion binding Amigo component|nucleus Amigo process|perception of sound Amigo function|protein binding Amigo process|regulation of transcription, DNA-dependent Amigo component|transcription factor TFIIH complex Amigo process|transcription from Pol II promoter Amigo process|transcription-coupled nucleotide-excision repair PubGene ERCC2 Other databases Probes Probe Cancer Cytogenetics (Bari) Probe ERCC2 Related clones (RZPD - Berlin) PubMed PubMed 48 Pubmed reference(s) in LocusLink Bibliography The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Lehmann A. R. Genes Dev 2001; 15: 15-23. Medline 11156600

XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case- control analysis. Sturgis E. M., Zheng R., Li L., Castillo E. J., Eicher S. A., Chen M., Strom S. S., Spitz M. R. Wei Q. Carcinogenesis 2000; 21: 2219-2223. Medline 11133811

Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD- A trichothiodystrophy disorder [In Process Citation]. Vermeulen W., Bergmann E., Auriol J., Rademakers S., Frit P., Appeldoorn E., Hoeijmakers J. H. Egly J. M. Nat Genet 2000; 26: 307-13. Medline 11062469

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -228-

DNA repair capacity: inconsistency between effect of over-expression of five NER genes and the correlation to mRNA levels in primary lymphocytes [In Process Citation]. Vogel U., Dybdahl M., Frentz G. Nexo B. A. Mutat Res 2000; 461: 197-210. Medline 11056291

Molecular structure of human TFIIH. Schultz P., Fribourg S., Poterszman A., Mallouh V., Moras D. Egly J. M. Cell 2000; 102: 599-607. Medline 11007478

Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7. Chen D., Riedl T., Washbrook E., Pace P. E., Coombes R. C., Egly J. M. Ali S. Mol Cell 2000; 6: 127-37. Medline 10949034 p44/SSL1, the regulatory subunit of the XPD/RAD3 helicase, plays a crucial role in the transcriptional activity of TFIIH [In Process Citation]. Seroz T., Perez C., Bergmann E., Bradsher J. Egly J. M. J Biol Chem 2000; 275: 33260-6. Medline 10924514

Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome. Le Page F., Kwoh E. E., Avrutskaya A., Gentil A., Leadon S. A., Sarasin A. Cooper P. K. Cell 2000; 101: 159-71. Medline 10786832

UV damage causes uncontrolled DNA breakage in cells from patients with combined features of XP-D and Cockayne syndrome. Berneburg M., Lowe J. E., Nardo T., Araujo S., Fousteri M. I., Green M. H., Krutmann J., Wood R. D., Stefanini M. Lehmann A. R. Embo J 2000; 19: 1157-66. Medline 10698956

Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. Araujo S. J., Tirode F., Coin F., Pospiech H., Syvaoja J. E., Stucki M., Hubscher U., Egly J. M. Wood R. D. Genes Dev 2000; 14: 349-59. Medline 10673506

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -229- The cancer-free phenotype in trichothiodystrophy is unrelated to its repair defect. Berneburg M., Clingen P. H., Harcourt S. A., Lowe J. E., Taylor E. M., Green M. H., Krutmann J., Arlett C. F. Lehmann A. R. Cancer Res 2000; 60: 431-8. Medline 10667598

TFIIH with inactive XPD helicase functions in transcription initiation but is defective in DNA repair. Winkler G. S., Araujo S. J., Fiedler U., Vermeulen W., Coin F., Egly J. M., Hoeijmakers J. H., Wood R. D., Timmers H. T. Weeda G. J Biol Chem 2000; 275: 4258-66. Medline 10660593

Distinct roles for the helicases of TFIIH in transcript initiation and promoter escape. Bradsher J., Coin F. Egly J. M. J Biol Chem 2000; 275: 2532-8. Medline 10644710

[Trichothiodystrophy: progresssive manifestations]. Foulc P., Jumbou O., David A., Sarasin A. Stalder J. F. Ann Dermatol Venereol 1999; 126: 703-7. Medline 10604009

[Trichothiodystrophies: anomalies of the repair and transcription of genes (editorial)]. Robert C. Sarasin A. Ann Dermatol Venereol 1999; 126: 669-71. Medline 10604001

Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition. de Boer J., van Steeg H., Berg R. J., Garssen J., de Wit J., van Oostrum C. T., Beems R. B., van der Horst G. T., van Kreijl C. F., de Gruijl F. R., Bootsma D., Hoeijmakers J. H. Weeda G. Cancer Res 1999; 59: 3489-94.

Cells from XP-D and XP-D-CS patients exhibit equally inefficient repair of UV- induced damage in transcribed genes but different capacity to recover UV-

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -230- inhibited transcription. van Hoffen A., Kalle W. H., de Jong-Versteeg A., Lehmann A. R., van Zeeland A. A. Mullenders L. H. Nucleic Acids Res 1999; 27: 2898-904. Medline 10390531

Recovery of the normal p53 response after UV treatment in DNA repair- deficient fibroblasts by retroviral-mediated correction with the XPD gene. Dumaz N., Drougard C., Quilliet X., Mezzina M., Sarasin A. Daya-Grosjean L. Carcinogenesis 1998; 19: 1701-4. Medline 9771945

Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH [see comments]. Coin F., Marinoni J. C., Rodolfo C., Fribourg S., Pedrini A. M. Egly J. M. Nat Genet 1998; 20: 184-8. Medline 9771713

From a DNA helicase to brittle hair [news; comment]. Winkler G. S. Hoeijmakers J. H. Nat Genet 1998; 20: 106-7. Medline 9771695

Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity. Botta E., Nardo T., Broughton B. C., Marinoni S., Lehmann A. R. Stefanini M.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -231- Am J Hum Genet 1998; 63: 1036-48. Medline 9758621

Expression of DNA excision-repair-cross-complementing proteins p80 and p89 in brain of patients with Down Syndrome and Alzheimer's disease. Hermon M., Cairns N., Egly J. M., Fery A., Labudova O. Lubec G. Neurosci Lett 1998; 251: 45-8. Medline 9714461

Hair today, gone tomorrow: transgenic mice with human repair deficient hair disease. Cleaver J. E. Cell 1998; 93: 1099-102. Medline 9657142

Cyclobutane pyrimidine dimers are the main mutagenic DNA photoproducts in DNA repair-deficient trichothiodystrophy cells. Marionnet C., Armier J., Sarasin A. Stary A. Cancer Res 1998; 58: 102-8. Medline 9426065

Disruption of the mouse xeroderma pigmentosum group D DNA repair/basal transcription gene results in preimplantation lethality. de Boer J., Donker I., de Wit J., Hoeijmakers J. H. Weeda G. Cancer Res 1998; 58: 89-94. Medline 9426063

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Competent transcription initiation by RNA polymerase II in cell-free extracts from xeroderma pigmentosum groups B and D in an optimized RNA transcription assay. Satoh M. S. Hanawalt P. C. Biochim Biophys Acta 1997; 1354: 241-51. Medline 9427533

Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. Evans E., Moggs J. G., Hwang J. R., Egly J. M. Wood R. D. Embo J 1997; 16: 6559-73. Medline 9351836

Sequence-specific and domain-specific DNA repair in xeroderma pigmentosum and Cockayne syndrome cells. Tu Y., Bates S. Pfeifer G. P. J Biol Chem 1997; 272: 20747-55. Medline 9252397

Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. Taylor E. M., Broughton B. C., Botta E., Stefanini M., Sarasin A., Jaspers N. G., Fawcett H., Harcourt S. A., Arlett C. F. Lehmann A. R. Proc Natl Acad Sci U S A 1997; 94: 8658-63. Medline 9238033

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -233- Medline 9192652

DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a trichothiodystrophy patient. Takayama K., Danks D. M., Salazar E. P., Cleaver J. E. Weber C. A. Hum Mutat 1997; 9: 519-25. Medline 9195225

Mutations in the XPD gene leading to xeroderma pigmentosum symptoms. Kobayashi T., Kuraoka I., Saijo M., Nakatsu Y., Tanaka A., Someda Y., Fukuro S. Tanaka K. Hum Mutat 1997; 9: 322-31. Medline 9101292

Quantitation of ERCC-2 gene expression in human tumor cell lines by reverse transcription-polymerase chain reaction in comparison to northern blot analysis. Chen Z. P., Malapetsa A., Mohr G., Brien S. Panasci L. C. Anal Biochem 1997; 244: 50-4. Medline 9025907

Long-term complementation of DNA repair deficient human primary fibroblasts by retroviral transduction of the XPD gene. Quilliet X., Chevallier-Lagente O., Eveno E., Stojkovic T., Destee A., Sarasin A. Mezzina M. Mutat Res 1996; 364: 161-9. Medline 8960128

Recovery of normal DNA repair and mutagenesis in trichothiodystrophy cells after transduction of the XPD human gene. Marionnet C., Quilliet X., Benoit A., Armier J., Sarasin A. Stary A. Cancer Res 1996; 56: 5450-6. Medline 8968100

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Human cyclin-dependent kinase-activating kinase exists in three distinct complexes. Drapkin R., Le Roy G., Cho H., Akoulitchev S. Reinberg D. Proc Natl Acad Sci U S A 1996; 93: 6488-93. Medline 8692842

Isolation and characterization of two human transcription factor IIH (TFIIH)- related complexes: ERCC2/CAK and TFIIH [published erratum appears in Proc Natl Acad Sci U S A 1996 Sep 17;93(19):10538]. Reardon J. T., Ge H., Gibbs E., Sancar A., Hurwitz J. Pan Z. Q. Proc Natl Acad Sci U S A 1996; 93: 6482-7. Medline 8692841

Sequence analysis of the ERCC2 gene regions in human, mouse, and hamster reveals three linked genes. Lamerdin J. E., Stilwagen S. A., Ramirez M. H., Stubbs L. Carrano A. V. Genomics 1996; 34: 399-409. Medline 8786141

Functional interactions between p53 and the TFIIH complex are affected by tumour-associated mutations. Leveillard T., Andera L., Bissonnette N., Schaeffer L., Bracco L., Egly J. M. Wasylyk B. Embo J 1996; 15: 1615-24. Medline 8612585

Five polymorphisms in the coding sequence of the xeroderma pigmentosum group D gene. Broughton B. C., Steingrimsdottir H. Lehmann A. R. Mutat Res 1996; 362: 209-11. Medline 8596540

Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. Takayama K., Salazar E. P., Broughton B. C., Lehmann A. R., Sarasin A., Thompson L. H. Weber C. A. Am J Hum Genet 1996; 58: 263-70. Medline 8571952

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Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Wang X. W., Gibson M. K., Vermeulen W., Yeh H., Forrester K., Sturzbecher H. W., Hoeijmakers J. H. Harris C. C. Cancer Res 1995; 55: 6012-6. Medline 8521383

Defects in the DNA repair and transcription gene ERCC2 in the cancer- prone disorder xeroderma pigmentosum group D. Takayama K., Salazar E. P., Lehmann A., Stefanini M., Thompson L. H. Weber C. A. Cancer Res 1995; 55: 5656-63. Medline 7585650

Detection of nucleotide excision repair incisions in human fibroblasts by immunostaining for PCNA. Aboussekhra A. Wood R. D. Exp Cell Res 1995; 221: 326-32. Medline 7493631

Characteristics of UV-induced mutation spectra in human XP-D/ERCC2 gene- mutated xeroderma pigmentosum and trichothiodystrophy cells. Marionnet C., Benoit A., Benhamou S., Sarasin A. Stary A. J Mol Biol 1995; 252: 550-62. Medline 7563073

Functional retroviral vector for gene therapy of xeroderma pigmentosum group D patients. Carreau M., Quilliet X., Eveno E., Salvetti A., Danos O., Heard J. M., Mezzina M. Sarasin A. Hum Gene Ther 1995; 6: 1307-15. Medline 8590735

Lethality in yeast of trichothiodystrophy (TTD) mutations in the human xeroderma pigmentosum group D gene. Implications for transcriptional defect in TTD. Guzder S. N., Sung P., Prakash S. Prakash L. J Biol Chem 1995; 270: 17660-3. Medline 7629061 p53 modulation of TFIIH-associated nucleotide excision repair activity. Wang X. W., Yeh H., Schaeffer L., Roy R., Moncollin V., Egly J. M., Wang Z., Freidberg E. C., Evans M. K., Taffe B. G. et al. Nat Genet 1995; 10: 188-95. Medline 8580493

TFIIH: a link between transcription, DNA repair and cell cycle regulation.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -236- Seroz T., Hwang J. R., Moncollin V. Egly J. M. Curr Opin Genet Dev 1995; 5: 217-21. Medline 7613092

Mammalian DNA nucleotide excision repair reconstituted with purified protein components. Aboussekhra A., Biggerstaff M., Shivji M. K., Vilpo J. A., Moncollin V., Podust V. N., Protic M., Hubscher U., Egly J. M. Wood R. D. Cell 1995; 80: 859-68. Medline 7697716

Stable SV40-transformation and characterisation of some DNA repair properties of fibroblasts from a trichothiodystrophy patient. Eveno E., Quilliet X., Chevallier-Lagente O., Daya-Grosjean L., Stary A., Zeng L., Benoit A., Savini E., Ciarrocchi G., Kannouche P. et al. Biochimie 1995; 77: 906-12. Medline 8824772

Molecular and cellular analysis of the DNA repair defect in a patient in xeroderma pigmentosum complementation group D who has the clinical features of xeroderma pigmentosum and Cockayne syndrome. Broughton B. C., Thompson A. F., Harcourt S. A., Vermeulen W., Hoeijmakers J. H., Botta E., Stefanini M., King M. D., Weber C. A., Cole J. et al. Am J Hum Genet 1995; 56: 167-74. Medline 7825573

Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene. Frederick G. D., Amirkhan R. H., Schultz R. A. Friedberg E. C. Hum Mol Genet 1994; 3: 1783-8. Medline 7849702

Correction by the ERCC2 gene of UV sensitivity and repair deficiency phenotype in a subset of trichothiodystrophy cells. Mezzina M., Eveno E., Chevallier-Lagente O., Benoit A., Carreau M., Vermeulen W., Hoeijmakers J. H., Stefanini M., Lehmann A. R., Weber C. A. et al. Carcinogenesis 1994; 15: 1493-8. Medline 8055625

Molecular analysis of CXPD mutations in the repair-deficient hamster mutants UV5 and UVL-13 [published erratum appears in Mutat Res 1995 Jun;347(1):53]. Weber C. A., Kirchner J. M., Salazar E. P. Takayama K. Mutat Res 1994; 324: 147-52. Medline 8052270

The human DNA repair gene, ERCC2 (XPD), corrects ultraviolet

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -237- hypersensitivity and ultraviolet hypermutability of a shuttle vector replicated in xeroderma pigmentosum group D cells. Gozukara E. M., Parris C. N., Weber C. A., Salazar E. P., Seidman M. M., Watkins J. F., Prakash L. Kraemer K. H. Cancer Res 1994; 54: 3837-44. Medline 8033104

Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy. Broughton B. C., Steingrimsdottir H., Weber C. A. Lehmann A. R. Nat Genet 1994; 7: 189-94. Medline 7920640

Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II. Drapkin R., Reardon J. T., Ansari A., Huang J. C., Zawel L., Ahn K., Sancar A. Reinberg D. Nature 1994; 368: 769-72.

Transcription factor b (TFIIH) is required during nucleotide-excision repair in yeast. Wang Z., Svejstrup J. Q., Feaver W. J., Wu X., Kornberg R. D. Friedberg E. C. Nature 1994; 368: 74-6. Medline 8107888

Molecular analysis of the XP-D gene in Italian families with patients affected by trichothiodystrophy and xeroderma pigmentosum group D. Mondello C., Nardo T., Giliani S., Arrand J. E., Weber C. A., Lehmann A. R., Nuzzo F. Stefanini M. Mutat Res 1994; 314: 159-65. Medline 7510365

DNA repair gene RAD3 of S. cerevisiae is essential for transcription by RNA polymerase II. Guzder S. N., Qiu H., Sommers C. H., Sung P., Prakash L. Prakash S. Nature 1994; 367: 91-4. Medline 8107780

Human xeroderma pigmentosum group D gene encodes a DNA helicase.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -238- Sung P., Bailly V., Weber C., Thompson L. H., Prakash L. Prakash S. Nature 1993; 365: 852-5. Medline 8413672

A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy. Stefanini M., Vermeulen W., Weeda G., Giliani S., Nardo T., Mezzina M., Sarasin A., Harper J. I., Arlett C. F., Hoeijmakers J. H. et al. Am J Hum Genet 1993; 53: 817-21. Medline 8213812

UV-induced mutations in a shuttle vector replicated in repair deficient trichothiodystrophy cells differ with those in genetically-related cancer prone xeroderma pigmentosum. Madzak C., Armier J., Stary A., Daya-Grosjean L. Sarasin A. Carcinogenesis 1993; 14: 1255-60. Medline 8392442

Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy. Stefanini M., Lagomarsini P., Giliani S., Nardo T., Botta E., Peserico A., Kleijer W. J., Lehmann A. R. Sarasin A. Carcinogenesis 1993; 14: 1101-5. Medline 8508495

Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy. Mariani E., Facchini A., Honorati M. C., Lalli E., Berardesca E., Ghetti P., Marinoni S., Nuzzo F., Astaldi Ricotti G. C. Stefanini M. Clin Exp Immunol 1992; 88: 376-82. Medline 1535035

DNA repair investigations in nine Italian patients affected by trichothiodystrophy. Stefanini M., Giliani S., Nardo T., Marinoni S., Nazzaro V., Rizzo R. Trevisan G. Mutat Res 1992; 273: 119-25.

Correction of xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: involvement of the human ERCC2 DNA repair gene. Flejter W. L., McDaniel L. D., Johns D., Friedberg E. C. Schultz R. A. Proc Natl Acad Sci U S A 1992; 89: 261-5. Medline 1729695

ERCC2: cDNA cloning and molecular characterization of a human nucleotide excision repair gene with high homology to yeast RAD3.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -239- Weber C. A., Salazar E. P., Stewart S. A. Thompson L. H. Embo J 1990; 9: 1437-47. Medline 2184031

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 02- Anne Stary and Alain Sarasin 2001 Citation This paper should be referenced as such : Stary A, Sarasin A . ERCC2 (Excision repair cross-complementing rodent repair deficiency, complementation group 2). Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/XPDID297.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -240- Atlas of Genetics and Cytogenetics in Oncology and Haematology

POLH (polymerase (DNA direct), eta)

Identity Note see also the deep insight on: END_IDENTITY_GENE Other XP-V names RAD30A Hugo POLH Location 6p21.1 DNA/RNA Description 11 exons. Of the 11 splice donor/acceptor sites, 10 contained consensus GT/AG dinucleotides; only the splice donor site in exon 11 (sequence CT) varied from the consensus pattern. The POLH gene lacked a TATA sequence in the region upstream of the transcription-initiation site and the upstream region was GC rich (76% in the sequence between +1 and Ð270). The first ATG codon for initiation of translation was included in the second exon. Exon 11 contained the termination codon followed by 661 bp of 3Õ-untranslated sequence Protein

Description 713 amino acids Function The POLH gene encodes DNA polymerase h, which catalyzes the translesion synthesis past a cis-syn T-T pyrimidine dimer, one of the major DNA photoproducts induced by UV light Homology mXPV: 80.3% amino acids identity and 86.9% similarity Mutations Germinal 12 mutated sites involved in the XP variant syndrome Implicated in Entity xeroderma pigmentosum, XP group V Disease predisposition to skin cancer

External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -241- Hugo POLH GDB POLH Entrez_Gene POLH 5429 polymerase (DNA directed), eta Cards Atlas XPVID303 GeneCards POLH Ensembl POLH CancerGene POLH Genatlas POLH GeneLynx POLH eGenome POLH euGene 5429 Genomic and cartography POLH - 6p21.1 chr6:43651923-43691357 + 6p21.1 (hg17- GoldenPath May_2004) Ensembl POLH - 6p21.1 [CytoView]

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

Genbank AB038008 [ SRS ] AB038008 [ ENTREZ ]

Genbank AL353602 [ SRS ] AL353602 [ ENTREZ ]

Genbank AY388614 [ SRS ] AY388614 [ ENTREZ ]

Genbank AB024313 [ SRS ] AB024313 [ ENTREZ ]

Genbank AF158185 [ SRS ] AF158185 [ ENTREZ ]

RefSeq NM_006502 [ SRS ] NM_006502 [ ENTREZ ]

RefSeq NT_086693 [ SRS ] NT_086693 [ ENTREZ ] AceView POLH AceView - NCBI TRASER POLH Traser - Stanford

Unigene Hs.439153 [ SRS ] Hs.439153 [ NCBI ] HS439153 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9Y253 [ SRS] Q9Y253 [ EXPASY ] Q9Y253 [ INTERPRO ]

Prosite PS50173 UMUC [ SRS ] PS50173 UMUC [ Expasy ]

Interpro IPR001126 UMUC_like [ SRS ] IPR001126 UMUC_like [ EBI ] CluSTr Q9Y253

Pfam PF00817 IMS [ SRS ] PF00817 IMS [ Sanger ] pfam00817 [ NCBI-CDD ] Blocks Q9Y253 Polymorphism : SNP, mutations, diseases

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -242- OMIM 603968 [ map ] GENECLINICS 603968

SNP POLH [dbSNP-NCBI]

SNP NM_006502 [SNP-NCI]

SNP POLH [GeneSNPs - Utah] POLH [SNP - CSHL] POLH] [HGBASE - SRS] General knowledge Family POLH [UCSC Family Browser] Browser SOURCE NM_006502 SMD Hs.439153 SAGE Hs.439153 Amigo process|DNA replication Amigo function|damaged DNA binding Amigo function|eta DNA polymerase activity Amigo function|magnesium ion binding Amigo component|nucleoplasm Amigo process|regulation of DNA repair Amigo function|transferase activity KEGG Purine Metabolism KEGG Pyrimidine Metabolism KEGG DNA Polymerase PubGene POLH Other databases Probes Probe POLH Related clones (RZPD - Berlin) PubMed PubMed 23 Pubmed reference(s) in LocusLink Bibliography Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene [In Process Citation]. Yuasa M., Masutani C., Eki T. Hanaoka F. Oncogene 2000; 19: 4721-8.

Efficient and accurate replication in the presence of 7,8-dihydro-8- oxoguanine by DNA polymerase eta. Haracska L., Yu S. L., Johnson R. E., Prakash L. Prakash S. Nat Genet 2000; 25: 458-61.

Complementation of defective translesion synthesis and UV light sensitivity in xeroderma pigmentosum variant cells by human and mouse DNA polymerase

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -243- eta. Yamada A., Masutani C., Iwai S. Hanaoka F. Nucleic Acids Res 2000; 28: 2473-80.

Fidelity of human DNA polymerase eta. Johnson R. E., Washington M. T., Prakash S. Prakash L. J Biol Chem 2000; 275: 7447-50.

Sloppier copier DNA polymerases involved in genome repair. Goodman M. F. Tippin B. Curr Opin Genet Dev 2000; 10: 162-8.

Inaugural article: polymerase eta deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double- strand break repair. Limoli C. L., Giedzinski E., Morgan W. F. Cleaver J. E. Proc Natl Acad Sci U S A 2000; 97: 7939-46.

Mechanisms of accurate translesion synthesis by human DNA polymerase eta. Masutani C., Kusumoto R., Iwai S. Hanaoka F. Embo J 2000; 19: 3100-9.

Low fidelity DNA synthesis by human DNA polymerase-eta. Matsuda T., Bebenek K., Masutani C., Hanaoka F. Kunkel T. A. Nature 2000; 404: 1011-3.

Proofreading of DNA polymerase {eta}-dependent replication errors. Bebenek K., Matsuda T., Masutani C., Hanaoka F. Kunkel T. A. J Biol Chem 2000;

Inefficient bypass of an abasic site by DNA polymerase eta. Haracska L., Washington M. T., Prakash S. Prakash L. J Biol Chem 2000;

Error-prone lesion bypass by human DNA polymerase eta. Zhang Y., Yuan F., Wu X., Rechkoblit O., Taylor J. S., Geacintov N. E. Wang Z. Nucleic Acids Res 2000; 28: 4717-4724.

Replication of damaged DNA: molecular defect in xeroderma pigmentosum variant cells. Cordonnier A. M. Fuchs R. P. Mutat Res 1999; 435: 111-9. hRAD30 mutations in the variant form of xeroderma pigmentosum [see comments]. Johnson R. E., Kondratick C. M., Prakash S. Prakash L.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -244- Science 1999; 285: 263-5.

The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta [see comments]. Masutani C., Kusumoto R., Yamada A., Dohmae N., Yokoi M., Yuasa M., Araki M., Iwai S., Takio K. Hanaoka F. Nature 1999; 399: 700-4.

Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. Masutani C., Araki M., Yamada A., Kusumoto R., Nogimori T., Maekawa T., Iwai S. Hanaoka F. Embo J 1999; 18: 3491-501.

Abnormal, error-prone bypass of photoproducts by xeroderma pigmentosum variant cell extracts results in extreme strand bias for the kinds of mutations induced by UV light. McGregor W. G., Wei D., Maher V. M. McCormick J. J. Mol Cell Biol 1999; 19: 147-54.

Increased ultraviolet sensitivity and chromosomal instability related to P53 function in the xeroderma pigmentosum variant. Cleaver J. E., Afzal V., Feeney L., McDowell M., Sadinski W., Volpe J. P., Busch D. B., Coleman D. M., Ziffer D. W., Yu Y., Nagasawa H. Little J. B. Cancer Res 1999; 59: 1102-8.

Impaired translesion synthesis in xeroderma pigmentosum variant extracts. Cordonnier A. M., Lehmann A. R. Fuchs R. P. Mol Cell Biol 1999; 19: 2206-11.

Defective bypass replication of a leading strand cyclobutane thymine dimer in xeroderma pigmentosum variant cell extracts. Svoboda D. L., Briley L. P. Vos J. M. Cancer Res 1998; 58: 2445-8.

Bypass of a site-specific cis-Syn thymine dimer in an SV40 vector during in vitro replication by HeLa and XPV cell-free extracts. Ensch-Simon I., Burgers P. M. Taylor J. S. Biochemistry 1998; 37: 8218-26.

Comparison of the rate of excision of major UV photoproducts in the strands of the human HPRT gene of normal and xeroderma pigmentosum variant cells. Tung B. S., McGregor W. G., Wang Y. C., Maher V. M. McCormick J. J. Mutat Res 1996; 362: 65-74.

Induction and repair of (6-4) photoproducts in normal human and xeroderma

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -245- pigmentosum variant cells during the cell cycle. Mitchell D. L., Cleaver J. E., Lowery M. P. Hewitt R. R. Mutat Res 1995; 337: 161-7.

Xeroderma pigmentosum variant: generation and characterization of fibroblastic cell lines transformed with SV40 large T antigen. King S. A., Wilson S. J., Farber R. A., Kaufmann W. K. Cordeiro-Stone M. Exp Cell Res 1995; 217: 100-8.

Assignment of six patients with xeroderma pigmentosum in Hokkaido area to a variant form. Fujikawa K., Ayaki H., Ishizaki K., Takatera H., Matsuo S., Iizuka H., Koizumi H. Ikenaga M. J Radiat Res (Tokyo) 1994; 35: 168-78.

Ultraviolet hypermutability of a shuttle vector propagated in xeroderma pigmentosum variant cells. Waters H. L., Seetharam S., Seidman M. M. Kraemer K. H. J Invest Dermatol 1993; 101: 744-8.

Evidence from mutation spectra that the UV hypermutability of xeroderma pigmentosum variant cells reflects abnormal, error-prone replication on a template containing photoproducts. Wang Y. C., Maher V. M., Mitchell D. L. McCormick J. J. Mol Cell Biol 1993; 13: 4276-83.

Defective replication of psoralen adducts detected at the gene-specific level in xeroderma pigmentosum variant cells. Misra R. R. Vos J. M. Mol Cell Biol 1993; 13: 1002-12.

Xeroderma pigmentosum variant cells are less likely than normal cells to incorporate dAMP opposite photoproducts during replication of UV- irradiated plasmids. Wang Y. C., Maher V. M. McCormick J. J. Proc Natl Acad Sci U S A 1991; 88: 7810-4.

Effect of UV light on DNA chain growth and replicon initiation in xeroderma pigmentosum variant cells. Griffiths T. D. Ling S. Y. Mutagenesis 1991; 6: 247-51.

Defective postreplication repair in xeroderma pigmentosum variant fibroblasts. Boyer J. C., Kaufmann W. K., Brylawski B. P. Cordeiro-Stone M. Cancer Res 1990; 50: 2593-8.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -246- Xeroderma pigmentosum variant and normal fibroblasts show the same response to the inhibition of DNA replication by benzo[a]pyrene-diol- epoxide-I. Cordeiro-Stone M., Boyer J. C., Smith B. A. Kaufmann W. K. Carcinogenesis 1986; 7: 1783-6.

Abnormal sensitivity of human fibroblasts from xeroderma pigmentosum variants to transformation to anchorage independence by ultraviolet radiation. McCormick J. J., Kateley-Kohler S., Watanabe M. Maher V. M. Cancer Res 1986; 46: 489-92.

Cytological evidence for DNA chain elongation after UV irradiation in the S phase. Minka D. F. Nath J. Biochem Genet 1981; 19: 199-210.

The relationship between pyrimidine dimers and replicating DNA in UV- irradiated human fibroblasts. Lehmann A. R. Nucleic Acids Res 1979; 7: 1901-12.

Defective and enhanced postreplication repair in classical and variant xeroderma pigmentosum cells treated with N-acetoxy-2- acetylaminofluorene. D'Ambrosio S. M. Setlow R. B. Cancer Res 1978; 38: 1147-53.

Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation. Lehman A. R., Kirk-Bell S., Arlett C. F., Paterson M. C., Lohman P. H., de Weerd- Kastelein E. A. Bootsma D. Proc Natl Acad Sci U S A 1975; 72: 219-23.

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

BiblioGene - INIST

Contributor(s) Written 02- Anne Stary and Alain Sarasin 2001

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -247- Citation This paper should be referenced as such : Stary A, Sarasin A . POLH (polymerase (DNA direct), eta). Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/XPVID303.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -248- Atlas of Genetics and Cytogenetics in Oncology and Haematology

FBP17 (Formin Binding Protein 17)

Identity Other KIAA0554 names Hugo KIAA0554 Location 9q34 centromeric of ABL DNA/RNA Description at least 2042 bp Transcription open reading frame of 679 amino acids Protein

FCH-domain: amino terminus; cdc15 homology region: aa 96-290; Rho-binding domain: aa 475-537; SH3-domain: aa 612-669

Description 679 amino acids, 75 kDa Expression strong expression in epithelial cells from the respiratory system, gastrointestinal tract, urinary, and reproductive system Localisation exclusively cytoplasmatic Function interacts with Sorting nexin 2 (SNX2) in vivo and in vitro Mutations Germinal unknown Somatic unknown Implicated in Entity t(9;11)(q34;q23) acute non lymphocytic leukemia --> FBP17 - MLL Prognosis poor

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -249-

Hybrid/Mutated 5' MLL - 3' FBP17 Gene Abnormal MLL/FBP17 Protein

External links Nomenclature Hugo KIAA0554 GDB FNBP1 Entrez_Gene FNBP1 23048 formin binding protein 1 Cards Atlas FBP17ID353 GeneCards FNBP1 Ensembl FNBP1 CancerGene FBP17 Genatlas FNBP1 GeneLynx FNBP1 eGenome FNBP1 euGene 23048 Genomic and cartography FNBP1 - 9q34 chr9:129729020-129884981 - 9q34.11 (hg17- GoldenPath May_2004) Ensembl FNBP1 - 9q34.11 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene FNBP1 Gene and transcription

Genbank AL136141 [ SRS ] AL136141 [ ENTREZ ]

Genbank AL158207 [ SRS ] AL158207 [ ENTREZ ]

Genbank AB011126 [ SRS ] AB011126 [ ENTREZ ]

Genbank AF265550 [ SRS ] AF265550 [ ENTREZ ]

Genbank AK000975 [ SRS ] AK000975 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -250- RefSeq NM_015033 [ SRS ] NM_015033 [ ENTREZ ]

RefSeq NT_086756 [ SRS ] NT_086756 [ ENTREZ ] AceView FNBP1 AceView - NCBI TRASER FNBP1 Traser - Stanford

Unigene Hs.189409 [ SRS ] Hs.189409 [ NCBI ] HS189409 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q96RU3 [ SRS] Q96RU3 [ EXPASY ] Q96RU3 [ INTERPRO ]

Prosite PS50133 FCH [ SRS ] PS50133 FCH [ Expasy ]

Prosite PS50002 SH3 [ SRS ] PS50002 SH3 [ Expasy ] Interpro IPR001060 Cdc15_Fes_CIP4 [ SRS ] IPR001060 Cdc15_Fes_CIP4 [ EBI ]

Interpro IPR001452 SH3 [ SRS ] IPR001452 SH3 [ EBI ] CluSTr Q96RU3

Pfam PF00611 FCH [ SRS ] PF00611 FCH [ Sanger ] pfam00611 [ NCBI-CDD ] Pfam PF00018 SH3_1 [ SRS ] PF00018 SH3_1 [ Sanger ] pfam00018 [ NCBI- CDD ]

Smart SM00055 FCH [EMBL]

Smart SM00326 SH3 [EMBL]

Prodom PD000066 SH3[INRA-Toulouse] Prodom Q96RU3 Q96RU3 [ Domain structure ] Q96RU3 Q96RU3 [ sequences sharing at least 1 domain ] Blocks Q96RU3 Polymorphism : SNP, mutations, diseases OMIM 606191 [ map ] GENECLINICS 606191

SNP FNBP1 [dbSNP-NCBI]

SNP NM_015033 [SNP-NCI]

SNP FNBP1 [GeneSNPs - Utah] FNBP1 [SNP - CSHL] FNBP1] [HGBASE - SRS] General knowledge Family FNBP1 [UCSC Family Browser] Browser SOURCE NM_015033 SMD Hs.189409 SAGE Hs.189409 PubGene FNBP1 Other databases Other HUGE database Probes Probe KIAA0554 Related clones (RZPD - Berlin)

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -251- PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography The human formin binding protein 17 (FBP17) interacts with sorting nexin SNX2, and is a MLL-fusion partner in acute myelogenous leukemia Fuchs U, Rehkamp G, Haas OA, Slany R, König M, Bojesen S, Bohle RM, Damm- Welk C, Ludwig WD, Harbott J, Borkhardt A PNAS, 2001, in press

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Uta Fuchs, Arndt Borkhardt 2001 Citation This paper should be referenced as such : Fuchs U, Borkhardt A . FBP17 (Formin Binding Protein 17). Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FBP17ID353.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -252- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Ghrelin/MTLRP

Identity Other Motilin-related peptide (MTLRP) names GHRL Hugo LOC51738 Location 3p26-p25 DNA/RNA Transcription 600 bp, two mRNAs are encoded by the same genes, they are identical except for the lack of one codon (CAG) located at an exon intron boundary. Protein

Description two precursor s of 117 and 116 amino acids encoding preproGhrelin/MTLRP and prepro-des-Gln14-Ghrelin/ delta Gln14 MTLRP, respectively. The 28 amino-acids Ghrelin/MTLRP and the 27 amino-acids des-Gln14-Ghrelin/delta Gln14 MTLRP are modified post- translationally by the addition of a n-octanoic acid on Serine 3. The 28 amino acids Ghrelin/MTLRP is produced from a protein precursor of 117 residues that contains a signal peptide from residues 1to 23, the ghrelin/MTLRP moity from residues 24 to 51, the MTLRP- associated peptide moity from residues 52 to 117. The 27 amino acids des-Gln14-Ghrelin/delta Gln 14 MTLRP is produced from a protein precursor of 116 residues identical to the 117 aa precursor excep that the des-Gln14-Ghrelin/delta Gln14 MTLRP moity corresponds to residues 24 to 50 and accordingly the MTLRP- associated peptide moity from resisues 51 to 116. Expression Ghrelin/MTLRP is mainly expressed by the enteroendocrine cells of the stomach; its expression decreased gradually along the gastro-intestinal tract and a faint expression was also detected in testis. By Immnunochemistry Ghrelin-immuno reactive neurons were found in the hypothalamic arcuate nucleus. Localisation As a peptide hormone Ghrelin/MTLRP is secreted in the blood. Function As the endogenous ligand of the growth hormone secretagogues (GHS) receptor, Ghrelin/MTLRP is involved in the pulsatile secretion of Growth hormone. In addition to this role Ghrelin/MTLRP is in the regulation of feeding. In rodent In contrast to leptin, Ghrelin/MTLRP promotes food intake and obesity. In addition Ghrelin/MTLRP stimulates motricity of the

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -253- gastrointestinal tract and acid secretion. Homology ppGhrelin/MTLRP share 47% of similarity with the precursor of Motilin. In addition Ghrelin receptor (GHS-R) and Motilin receptor (GPR38) share 52% identity. External links Nomenclature Hugo LOC51738 GDB GHRL Entrez_Gene GHRL 51738 ghrelin precursor Cards Atlas GhrelinID327 GeneCards GHRL Ensembl GHRL CancerGene GHRL Genatlas GHRL GeneLynx GHRL eGenome GHRL euGene 51738 Genomic and cartography GoldenPath GHRL - chr3:10302434-10307409 - 3p25.3 (hg17-May_2004) Ensembl GHRL - 3p25.3 [CytoView]

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

Genbank AF296558 [ SRS ] AF296558 [ ENTREZ ]

Genbank AY701846 [ SRS ] AY701846 [ ENTREZ ]

Genbank AB029434 [ SRS ] AB029434 [ ENTREZ ]

Genbank AB035700 [ SRS ] AB035700 [ ENTREZ ]

Genbank AJ252278 [ SRS ] AJ252278 [ ENTREZ ]

RefSeq NM_016362 [ SRS ] NM_016362 [ ENTREZ ]

RefSeq NT_086636 [ SRS ] NT_086636 [ ENTREZ ] AceView GHRL AceView - NCBI TRASER GHRL Traser - Stanford

Unigene Hs.302131 [ SRS ] Hs.302131 [ NCBI ] HS302131 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q9UBU3 [ SRS] Q9UBU3 [ EXPASY ] Q9UBU3 [ INTERPRO ] CluSTr Q9UBU3

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -254- Blocks Q9UBU3 Polymorphism : SNP, mutations, diseases OMIM 605353 [ map ] GENECLINICS 605353

SNP GHRL [dbSNP-NCBI]

SNP NM_016362 [SNP-NCI]

SNP GHRL [GeneSNPs - Utah] GHRL [SNP - CSHL] GHRL] [HGBASE - SRS] General knowledge Family GHRL [UCSC Family Browser] Browser SOURCE NM_016362 SMD Hs.302131 SAGE Hs.302131 Amigo process|G-protein coupled receptor protein signaling pathway Amigo process|cell-cell signaling Amigo component|extracellular region Amigo component|extracellular space Amigo function|growth hormone receptor binding Amigo function|growth hormone-releasing hormone activity Amigo process|regulation of physiological process Amigo component|soluble fraction BIOCARTA Ghrelin: Regulation of Food Intake and Energy Homeostasis PubGene GHRL Other databases Probes Probe Cancer Cytogenetics (Bari) Probe LOC51738 Related clones (RZPD - Berlin) PubMed PubMed 84 Pubmed reference(s) in LocusLink Bibliography Ghrelin is a growth-hormone-releasing acylated peptide from stomach Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., and Kangawa, K. Nature 1999; 402: 656-60 . Medline 10604470

Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor Hosoda, H., Kojima, M., Matsuo, H., and Kangawa, K J Biol Chem 2000; 275: 21995-2000 . Medline 10801861

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -255-

Ghrelin stimulates gastric acid secretion and motility in rats Masuda, Y., Tanaka, T., Inomata, N., Ohnuma, N., Tanaka, S., Itoh, Z., Hosoda, H., Kojima, M., and Kangawa, K. Biochem Biophys Res Commun 2000; 276: 905-8 . Medline 11027567

Identification and characterization of a novel gastric peptide hormone: the motilin-related peptide Tomasetto, C., Karam, S. M., Ribieras, S., Masson, R., Lefebvre, O., Staub, A., Alexander, G., Chenard, M. P., and Rio, M. C. Gastroenterology 2000; 119: 395-405 . Medline 10930375

Ghrelin induces adiposity in rodents Tschop, M., Smiley, D. L., and Heiman, M. L. Nature 2000; 407: 908-13 . Medline 11057670

The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion Wren, A. M., Small, C. J., Ward, H. L., Murphy, K. G., Dakin, C. L., Taheri, S., Kennedy, A. R., Roberts, G. H., Morgan, D. G., Ghatei, M. A., and Bloom, S. R. Endocrinology 2000; 141: 4325-8. Medline 11089570

A role for ghrelin in the central regulation of feeding Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., and Matsukura, S. Nature 2001; 409: 194-8. Medline 11196643

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Contributor(s) Written 03- Catherine Tomasetto 2001

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -256- Citation This paper should be referenced as such : Tomasetto C . Ghrelin/MTLRP. Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/GhrelinID327.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -257- Atlas of Genetics and Cytogenetics in Oncology and Haematology

MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1)

Identity Note MAD2L1 was intially (and errounously) mapped by fluorescence in situ hybridization (FISH) to 5q23-q31. Subsequent comprehensive mapping studies using somatic cell hybrid analysis, radiation hybrid (RH) mapping, and FISH localized it to 4q27. This location was susequently confrimed by RH analysis and through the Human Genome Project Draft sequence assembly. A related gene, MAD2L2, maps to to 1p36, and a MAD2 pseudogene maps to to 14q21-q23. Other related family members exist with similar names (eg. MAD2L2, MAD1L1) highlighting the need for using the MAD2L1 nomenclature to avoid confusion (A MAD2L1 pseudogene maps to chromosome 14) Other HsMAD2 names MAD2 MAD2A Hugo MAD2L1 Location 4q27 As noted on the GM99-GB4 Chromosome 4 map: Position: 548.24 (cR3000) Lod score: 1.16 Reference Interval: D4S2945-D4S430 (115.1- 125.1 cM) It is located within the NCBI BAC genomic contig: NT_006302.2 which is part of the homo sapiens chromosome 4 sequence segment DNA/RNA

Shadded boxes (1-5) depict the 5 exons of MAD2L1. The black triangle indicates a del A mutation that was found in the CAL51 breast cancer cell line. Open triangkes depict the locations of identified sequence variants. Figure is not drawn to scale.

Description the human MAD2L1 DNA sequence had an open reading frame that was 60% identical to the yeast MAD2 gene.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -258- Transcription MAD2L1 has 5 coding exons. No alternative splicing has been described. Regulation of its transcription in human cells is currently poorly understood. Protein

Description called MAD2A (aliases MAD2-LIKE 1, MD2l, HSMAD2); 205 amino acids; molecular weight: 23,509.95; theoretical pI: 5.02 Expression The MAD2L1 protein is widely expressed in all fetal and adult and fetal tissues studied to date. Localisation Localizes to the nucleus and associates with unattached kinetochores during after chromosome condensation. Function Much of what we currently understand about MAD2L1 and its role in the mitotic spindle checkpoint stems from early studies in non- mammalian cells. Several genes have demonstrated critically important, interrelated roles in appropriately responding to aberrant spindle integrity or kinetochore damage by arresting cell cycle progression including BUB (budding uninhibited by benomyl), MAD (mitotic arrest- deficient) genes, additional protein kinase genes, and other cyclin related genes. In budding yeast the mitotic arrest-deficient-2 (MAD2) gene was shown to encode a protein that monitored accurate chromosome segregation via the mitotic spindle checkpoint. The mitotic spindle checkpoint helps regulate cell division to ensure the creation of euploid daughter cells following anaphase and cytokinesis. The checkpoint acts to block cell cycle progression when the mitotic spindle apparatus is not properly assembled or when the kinetochore is not properly attached to the mitotic spindle. The amphibian (Xenopus) homolog of MAD2 was identified and it was demonstrated that the MAD2 protein played a critical role in the normal spindle checkpoint assembly as it associated only with unattached kinetochores in prometaphase and in those cells treated with a microtubule inhibitor, nocodazole. MAD2 was absent from kinetochores in normal cells at metaphase The human homolog of MAD2, MAD2L1, has been isolated through identification of genes that reduced sensitivity to a chemical mitotic spindle assembly inhibiotor, thiabendazole, in yeast that were deficient for a particular kinetochore element , CBF1. The protein encoded by MAD2L1 monitors kinetochore attachments to the mitotic spindle in human cells. Interaction of MAD2L1 and additional checkpoint components with kinetochores unattached to chromosomes blocks the onset of anaphase, preventing missegregation of chromosomes and aneuploidy in resulting daughter cells The nuclear protein encoded by MAD2L1, MAD2A, is a member of the MAD family of proteins that is a critical component of the mitotic checkpoint. MAD2A is required for proper execution of the mitotic checkpoint. When kinetochore-spindle attachment is not completed properly, anaphase is delayed via activation of the mitotic spindle checkpoint. Anaphase is prevented until all chromosomes are properly aligned at the metaphase plate. Normally, the human MAD2A protein localizes as part of a protein complex at unattached kinetochores after

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -259- chromosome condensation but not after metaphase. Similarly, MAD2A localizes at the kinetochore upon activation of the mitotic spindle checkpoint and mediates cell cycle arrest by associating with CDC20/p55CDC and the anaphase promoting complex (APC) when chromosomes are not properly attached at the kinetochore. Therefore, MAD2A may regulate the activities of the WD40 protein CDC20 that is necessary for progression through anaphase and exit from mitosis. MAD2A reportedly exist in two states, a monomer and a tetramer, both which are capable of binding CDC20. In vitro studies have suggested, but not conclusively established, that only the tetrameric form of MAD2A is capable of inhibiting CDC20 activation of the APC. A yeast 2-hybrid assay using cytoplasmic tails of several a disintegrin and metalloproteinase domain (ADAM) bait proteins, demonstrated that MAD2A interacts strongly with TACE (ADAM17) but not with other ADAMs tested, including ADAM9 which interacts with another MAD family member, the MAD2L2 encoded protein MAD2B. A 35-amino acid stretch of TACE that contains a proline-rich SH3-ligand domain (PXPXXP) has been demonstrated as the interaction site with MAD2A. As noted above, MAD2A is a key protein that functions as part of a larger protein complex that regulates the highly conserved mitotic spindle checkpoint. Appropriate chromosome segregation at anaphase is regulated at least in part by this spindle assembly checkpoint that monitors completion of chromosome-microtubule attachment during metaphase. To further determine the function of Mad2 during normal cell division, Mad2 knockout mice were created and analyzed; day 5.5 embryonic cells lacking Mad2, like mad2 deficient budding yeast cells, grew normally but did not arrest in response to spindle disruption. By d 6.5, the epiblast cells began rapid division associated with widespread chromosome missegregation and subsequent apoptosis. Interestingly, postmitotic trophoblast giant cells survived, however, without Mad2. It was concluded that Mad2 is critical for the spindle assembly checkpoint and accurate chromosome segregation in mitotic mouse cells as well as for embryonic viability, even in the absence of any mitotic spindle damage. Mad2 and the spindle checkpoint in meiosis of S. cerevisiae were further characterized by comparing wildtype and mad2 -/- yeast that lacked normal checkpoint function. In the mad2 deficient yeast cells, meiosis I missegregation was noted to be significantly increased. These studies suggested that mad2 and the spindle checkpoint in budding yeast are critically important for normal meiotic chromosome segregation, despite the fact that normal mad2 function is largely dispensable in wildtype mitosis of budding yeast. Homology Homologous sequences: Mouse: Mm.43444 Mad2l1; Mm.9648 ESTs, Highly similar to AF072933_1 Mad2-like protein [H.sapiens]; Mm.28402 ESTs, Moderately similar to KIAA0280 [H.sapiens]; Rat: Rn.27237 ESTs, Highly similar to AF072933_1 Mad2-like protein; Rn.34733 ESTs, Weakly similar to mitotic checkpoint component Mad2; Drosophila: Dm.LL.40677 CG2948 CG2948 gene product; Dm.LL.38656 CG17498 CG17498 gene product; Human: Hs.19400 MAD2L2 Related Proteins: H. sapiens: MAD2L2 (27%); M. musculus: MAD2L1

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -260- (95%); D. melanogaster: CG17498 (46%); C. elegans: MDF-2 (53%); S. pombe: Mad2p (48%); Spac12d12.09p (26%); S. cerevisiae: Mad2p (43%) [details] Mutations Note No proven germline or somatic disease causing mutations; one somatic frameshift mutation has been identified , due to a 1 bp deletion, in one breast cancer cell line, CAL51, that caused truncation of the resulting protein product as assessed by in vitro transcription and translation assays. The functional significance of this alteration in relationship to cancer needs to be determined Implicated in Disease Like other solid tumors, ovarian cancers, especially those at later stages, demonstrate significant aneuploidy and multiple regions of chromosome loss and amplification. MAD2L1 maps to 4q27, an area that is unstable in several cancers as revealed by loss of heterozygosity and comparative genomic hybridization studies. Interestingly, some of the malignant tumors in individuals with BRCA1 germline mutations have somatic loss of chromosome 4q, suggesting that alterations of genes in this region may be associated with breast cancer Cytogenetics No cytogenetic translocations involving this gene, however, have been reported or have been associated with any disease, including cancer Hybrid/Mutated None described Gene Oncogenesis Work by several groups have now suggested that dysfunction of MAD2A may lead to malignancy or degeneration of normal cells, but compelling evidence that supports a role for MAD2L1 alterations in human cancers are still lacking. Despite this lack of solid data, there is increasing suggestive evidence to implicate MAD2L1 alterations in association with the development and/or progression of human cancer. First, aneuploidy is a commonly observed phenotype in many solid tumor malignancies, especially in later stage tumors. Chromosomal instability (CIN) correlates with aneuploidy and is thought to contribute to genetic instability. Thus, it is widely hypothesized that genomic instability which leads to aneuploidy may accelerate malignant progression in many solid tumor malignancies. Mutations in the genes controlling the mitotic checkpoint, including MAD2L1, have therefore been implicated to contribute to CIN in the pathogenesis of solid tumor malignancies. By monitoring proper microtubule assembly and attachment at the kinetochore, the mitotic checkpoint genes regulate the cell cycle to ensure accurate chromosome alignment and segregation at anaphase to generate euploid daughter cells. Loss of appropriate chromosome attachments at the kinetochore or defects in the mitotic spindle lead to cell cycle arrest and a block in the initiation of anaphase. Mad2 is just one member of a handful of yeast genes, the budding uninhibited by

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -261- benomyl BUB and mitotic arrest deficient (MAD) families of genes, that are important regulators of this mitotic spindle checkpoint. Studies in colorectal cell lines suggest that dominant negative mutations in the human ortholog BUB1 may have a role in CIN and aneuploidy led to speculation about the potential role of MAD2L1 in human cancers. However, no MAD2L1 mutations were identified in colon cancer cells. Human breast tumor cell line T47D has reduced MAD2 expression and it fails to arrest in mitosis after nocodazole treatment. That loss of MAD2 function might also lead to aberrant chromosome segregation in mammalian cells was suggested. A truncation mutation in MAD2L1 in breast cancer with altered protein expression was subsequently reported but no functional studies have yet demonstrated a functional role in oncogenesis has been demonstrated. Studies of Brca2 deficient murine cells further supported a putative role for these genes in cancer as Bub1 mutations were demonstrated to potentiate growth and cellular transformation (Lee et al., 1999). Secondly, the studies of Mad2 knockout mice have demonstrated that embryonic cells lacking Mad2 fail to arrest in response to microtubule inhibitors and that loss of the checkpoint results in chromosome missegregation and apoptosis. It has subsequently been reported that deletion of one allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome missegregation events in the absence of these agents. Furthermore, Mad2 +/- mice develop lung tumors at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.

External links Nomenclature Hugo MAD2L1 GDB MAD2L1 Entrez_Gene MAD2L1 4085 MAD2 mitotic arrest deficient-like 1 (yeast) Cards Atlas MAD2L1ID304 GeneCards MAD2L1 Ensembl MAD2L1 CancerGene MAD2L1 Genatlas MAD2L1 GeneLynx MAD2L1 eGenome MAD2L1 euGene 4085 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -262- MAD2L1 - 4q27 chr4:121338195-121345566 - 4q27 (hg17- GoldenPath May_2004) Ensembl MAD2L1 - 4q27 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MAD2L1 Gene and transcription

Genbank AB056160 [ SRS ] AB056160 [ ENTREZ ]

Genbank AF202273 [ SRS ] AF202273 [ ENTREZ ]

Genbank AF394735 [ SRS ] AF394735 [ ENTREZ ]

Genbank AJ000186 [ SRS ] AJ000186 [ ENTREZ ]

Genbank BC000356 [ SRS ] BC000356 [ ENTREZ ]

RefSeq NM_002358 [ SRS ] NM_002358 [ ENTREZ ]

RefSeq NT_086653 [ SRS ] NT_086653 [ ENTREZ ] AceView MAD2L1 AceView - NCBI TRASER MAD2L1 Traser - Stanford

Unigene Hs.533185 [ SRS ] Hs.533185 [ NCBI ] HS533185 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q13257 [ SRS] Q13257 [ EXPASY ] Q13257 [ INTERPRO ]

Prosite PS50815 HORMA [ SRS ] PS50815 HORMA [ Expasy ] Interpro IPR003511 DNAbind_HORMA [ SRS ] IPR003511 DNAbind_HORMA [ EBI ] CluSTr Q13257 Pfam PF02301 HORMA [ SRS ] PF02301 HORMA [ Sanger ] pfam02301 [ NCBI-CDD ] Blocks Q13257

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

PDB 1KLQ [ SRS ] 1KLQ [ PdbSum ], 1KLQ [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 601467 [ map ] GENECLINICS 601467

SNP MAD2L1 [dbSNP-NCBI]

SNP NM_002358 [SNP-NCI]

SNP MAD2L1 [GeneSNPs - Utah] MAD2L1 [SNP - CSHL] MAD2L1] [HGBASE - SRS] General knowledge Family MAD2L1 [UCSC Family Browser] Browser SOURCE NM_002358 SMD Hs.533185

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -263- SAGE Hs.533185 Amigo process|cell cycle Amigo component|kinetochore Amigo process|mitosis Amigo process|mitotic checkpoint Amigo component|nucleus PubGene MAD2L1 Other databases Probes Probe MAD2L1 Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Hoyt MA, Totis L, Roberts BT. Cell 1991; 66: 507-17. Medline 1651171

Feedback control of mitosis in budding yeast. Li R, Murray AW. Cell 1991; 66: 519-31. Medline 1651172

Mitotic forces control a cell-cycle checkpoint. Li X and Nicklas RB. Nature 1995; 373: 630-632. Medline 7854422

Association of spindle assembly checkpoint component XMAD2 with unattached kinetochores. Chen RH, Waters JC, Salmon ED, Murray AW. Science 1996; 274: 242-246. Medline 8824188

Identification of a human mitotic checkpoint gene: hsMAD2. Li Y and Benezra R. Science 1996; 274: 246-248. Medline 8824189

Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R,

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -264- Tanner M, Isola J, Barkardottir RB, Borg A, Kallioniemi OP. Cancer Res 1997; 57: 1222-7. Medline 9102202

Assignment of mitotic arrest deficient protein 2 (MAD2L1) to human chromosome band 5q23.3 by in situ hybridization. Xu L, Deng HX, Yang Y, Xia JH, Hung WY, Siddque T. Cytogenet Cell Genet 1997; 78: 63-4. Medline 9345911

Mutations of mitotic checkpoint genes in human cancers. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B. Nature 1998; 392: 300-303. Medline 9521327

The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Fang G, Yu H, Kirschner MW. Genes Dev 1998; 12, 1871-83. Medline 9637688

Fang G, Yu H, Kirschner MW. Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Mol Cell 1998; 2: 163-71. Medline 9734353

Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Jin DY, Spencer F, Jeang KT. Cell 1998; 3, 93: 81-91. Medline 9546394

Map location and gene structure of the Homo sapiens mitotic arrest deficient 2 (MAD2L1) gene at 4q27. Krishnan R, Goodman B, Jin DY, Jeang KT, Collins C, Stetten G, Spencer F. Genomics 1998; 49: 475-478. Medline 9615237

Characterization of MAD2B and other mitotic spindle checkpoint genes. Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C. Genomics 1999; 58: 181-187. Medline 10366450

Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -265- Lee H, Trainer HA, Friedman LS, Thistlethwaite FC, Evans MJ, Ponder BAJ, Venkitaraman AR. Mol Cell 1999; 4: 1-10. Medline 10445022

Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2-beta. Nelson KK. Schlondorff J, Blobel CP. Biochem J 1999; 343: 673-680. Medline 10527948

Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK. Cell 2000; 101: 635-45. Medline 10892650

Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Myrie KA, Percy MJ, Azim JN, Neeley CK, Petty EM. Cancer Lett 2000; 152: 193-9. Medline 10773412

Expression and mutational analyses of the human MAD2L1 gene in breast cancer cell. Percy MJ, Myrie KA, Neeley CK, Azim JN, Ethier SP, Petty EM. (2000). Genes Chromosomes Cancer 2000; 29: 356-62. Medline 11066082

Requirement of the spindle checkpoint for proper chromosome segregation in budding yeast meiosis. Shonn, M. A.; McCarroll, R.; Murray, A. W. Science 2000; 289: 300-303. Medline 10894778

MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, Dobles M, Sorger PK, Murty V VVS, Benezra R. Nature 2001; 409: 355-359. Medline 11201745

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Atlas Genet Cytogenet Oncol Haematol 2001; 2 -266- publications

BiblioGene - INIST

Contributor(s) Written 03- Elizabeth M. Petty, Kenute Myrie 2001

Citation This paper should be referenced as such : Petty EM, Myrie K . MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like- 1). Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MAD2L1ID304.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -267- Atlas of Genetics and Cytogenetics in Oncology and Haematology

TFF3

Identity Other ITF (Intestinal Trefoil Factor) names Hugo TFF3 Location 21q22.3 Belongs to the TFF cluster DNA/RNA Description 3.3 kb gene, 3 exons Transcription 600 bp Protein

Description precursor 74 amino acids, mature peptide 51 aminoacids, trefoil domain from aminoacids residues 24 to 67. The 74 aminoacids TFF3 protein precusor contains a signal peptide. The mature secreted peptide of 51 aminoacids contains one TFF (TreFoil Factor) domain and one acidic C- terminal domain. The acidic C-terminal domain contains a free cystein residue that promotes homodimerization and heterodimerization. Expression Under normal conditions TFF3 is expressed by gobblet cell of the intesine and the colon. TFF3 expression was found in human respiratory tract, human conjunctival goblet cells and in human salivarygland. In addition TFF3 peptive was found in human hypothalamus. Localisation In secreterory epithelia TFF3 is expressed by mucin-producing cells. In the brain TFF3 is expressed by a population of neurons of the human hypothamic paraventricular and supraoptic nuclei. Function TFF3 promotes migration of epithelial cells in vitro and enhance mucosal healing and epithelial restitutions in vivo in the gastrointestinal mucosa. TFF3 deficient mice aresuceptible to colonic injury induced by standard agents and restitution is impaired. In addition TFF3 deficient mice have an increase in colonocyte apoptosis. The protective action of TFF3 involves activation of both EGF-R and PI3K-Akt pathways. The role of TFF3 in the brain is not clear yet. Homology TFF3 belongs to the Trefoil peptide family (TFF) and possesse one TFF1 motif homologous to the TFF motif of TFF1 and TFF2. The TFF motif spans about 40 amino acids and is formed by 6 conserved cysteines residues involved in specific disulfites bridges.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -268- Implicated in Entity Inflamatory bowel diseases, TFF3 is expressed in cancer cells derived from the gastrointestinal tract, in hepatocellular carcinoma cells and in small cell lung carcinoma cells. Like TFF1, TFF3 is expressed in oestrogen-responsive breast cancer cell line and is expressed in breast cancer.

External links Nomenclature Hugo TFF3 GDB TFF3 Entrez_Gene TFF3 7033 trefoil factor 3 (intestinal) Cards Atlas TFF3ID265 GeneCards TFF3 Ensembl TFF3 CancerGene TFF3 Genatlas TFF3 GeneLynx TFF3 eGenome TFF3 euGene 7033 Genomic and cartography TFF3 - 21q22.3 chr21:42605233-42608775 - 21q22.3 (hg17- GoldenPath May_2004) Ensembl TFF3 - 21q22.3 [CytoView]

NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TFF3 Gene and transcription

Genbank AB038162 [ SRS ] AB038162 [ ENTREZ ]

Genbank AP001746 [ SRS ] AP001746 [ ENTREZ ]

Genbank U25657 [ SRS ] U25657 [ ENTREZ ]

Genbank AF432265 [ SRS ] AF432265 [ ENTREZ ]

Genbank BC017859 [ SRS ] BC017859 [ ENTREZ ]

RefSeq NM_003226 [ SRS ] NM_003226 [ ENTREZ ]

RefSeq NT_086913 [ SRS ] NT_086913 [ ENTREZ ] AceView TFF3 AceView - NCBI TRASER TFF3 Traser - Stanford

Unigene Hs.82961 [ SRS ] Hs.82961 [ NCBI ] HS82961 [ spliceNest ]

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -269- Protein : pattern, domain, 3D structure

SwissProt Q07654 [ SRS] Q07654 [ EXPASY ] Q07654 [ INTERPRO ]

Prosite PS00025 P_TREFOIL [ SRS ] PS00025 P_TREFOIL [ Expasy ]

Interpro IPR000519 P_trefoil [ SRS ] IPR000519 P_trefoil [ EBI ] CluSTr Q07654 Pfam PF00088 Trefoil [ SRS ] PF00088 Trefoil [ Sanger ] pfam00088 [ NCBI-CDD ]

Smart SM00018 PD [EMBL] Blocks Q07654

PDB 1E9T [ SRS ] 1E9T [ PdbSum ], 1E9T [ IMB ] Polymorphism : SNP, mutations, diseases OMIM 600633 [ map ] GENECLINICS 600633

SNP TFF3 [dbSNP-NCBI]

SNP NM_003226 [SNP-NCI]

SNP TFF3 [GeneSNPs - Utah] TFF3 [SNP - CSHL] TFF3] [HGBASE - SRS] General knowledge Family TFF3 [UCSC Family Browser] Browser SOURCE NM_003226 SMD Hs.82961 SAGE Hs.82961 Amigo process|defense response Amigo process|digestion Amigo component|extracellular region BIOCARTA Trefoil Factors Initiate Mucosal Healing PubGene TFF3 Other databases Probes Probe TFF3 Related clones (RZPD - Berlin) PubMed PubMed 17 Pubmed reference(s) in LocusLink Bibliography hP1.B, a human P-domain peptide homologous with rat intestinal trefoil factor, is expressed also in the ulcer-associated cell lineage and the uterus. Hauser, F., R. Poulsom, R. Chinery, L. A. Rogers, A. M. Hanby, N. A. Wright and W. Hoffmann . Proc Natl Acad Sci U S A 1993; 90(15): 6961-5. Medline 8346203

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -270- Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. Podolsky, D. K., K. Lynch-Devaney, J. L. Stow, P. Oates, B. Murgue, M. De- Beaumont, B. E. Sands and Y. R. Mahida . J Biol Chem 1993; 268(16): 12230. Medline 8505343

Characterisation of the single copy trefoil peptides intestinal trefoil factor and pS2 and their ability to form covalent dimers. Chinery, R., P. A. Bates, A. De and P. S. Freemont. FEBS Lett 1995; 357(1): 50-4.

Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein. Kindon, H., C. Pothoulakis, L. Thim, K. Lynch-Devaney and D. K. Podolsky . Gastroenterology 1995; 109(2): 516-23. Medline 7615201

Oral trefoil peptides protect against ethanol- and indomethacin-induced gastric injury in rats. Babyatsky, M. W., M. deBeaumont, L. Thim and D. K. Podolsky. Gastroenterology 1996; 110(2): 489-97. Medline 8566596

Mashimo, H., D. C. Wu, D. K. Podolsky and M. C. Fishman . Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 1996; 274(5285): 262-5. Medline 8824194

The trefoil peptide family. Sands, B. E. and D. K. Podolsky . Annu Rev Physiol 1996; 58: 253-73. Medline 8815795

Expression of human intestinal trefoil factor in malignant cells and its regulation by oestrogen in breast cancer cells. May, F. E. and B. R. Westley . J Pathol 1997; 182(4): 404-13.

Intestinal trefoil factor (TFF 3) and pS2 (TFF 1), but not spasmolytic polypeptide (TFF 2) mRNAs are co-expressed in normal, hyperplastic, and neoplastic human breast epithelium. Poulsom, R., A. M. Hanby, E. N. Lalani, F. Hauser, W. Hoffmann and G. W. Stamp . J Pathol 1997; 183(1): 30-8. Medline 9370944

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -271- The three human trefoil genes TFF1, TFF2, and TFF3 are located within a region of 55 kb on chromosome 21q22.3. Seib, T., N. Blin, K. Hilgert, M. Seifert, B. Theisinger, M. Engel, S. Dooley, K. D. Zang and C. Welter . Genomics 1997; 40(1): 200-2. Medline 9070946

Trefoil peptides: from structure to function. Thim, L. Cell Mol Life Sci 1997; 53(11-12): 888-903. Medline 9447240

Intestinal trefoil factor controls the expression of the adenomatous polyposis coli-catenin and the E-cadherin-catenin complexes in human colon carcinoma cells. Efstathiou, J. A., M. Noda, A. Rowan, C. Dixon, R. Chinery, A. Jawhari, T. Hattori, N. A. Wright, W. F. Bodmer and M. Pignatelli . Proc Natl Acad Sci U S A 1998; 95(6): 3122-7. Medline 9501226

Intestinal trefoil factor induces inactivation of extracellular signal- regulated protein kinase in intestinal epithelial cells. Kanai, M., C. Mullen and D. K. Podolsky. Proc Natl Acad Sci U S A 1998; 95(1): 178-82. Medline 9419349

Secretory peptides TFF1 and TFF3 synthesized in human conjunctival goblet cells. Langer, G., W. Jagla, W. Behrens-Baumann, S. Walter and W. Hoffmann . Invest Ophthalmol Vis Sci 1999; 40(10): 2220-4. Medline 10476786

Localization of TFF3, a new mucus-associated peptide of the human respiratory tract. Wiede, A., W. Jagla, T. Welte, T. Kohnlein, H. Busk and W. Hoffmann . Am J Respir Crit Care Med 1999; 159(4 Pt 1): 1330-5. Medline 10194185

Co-localization of TFF3 peptide and oxytocin in the human hypothalamus. Jagla, W., A. Wiede, K. Dietzmann, K. Rutkowski and W. Hoffmann. Faseb J 2000; 14(9): 1126-31. Medline 10834934

Distinct pathways of cell migration and antiapoptotic response to epithelial injury: structure-function analysis of human intestinal trefoil factor. Kinoshita, K., D. R. Taupin, H. Itoh and D. K. Podolsky .

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -272- Mol Cell Biol 2000; 20(13): 4680-90. Medline 10848594

Mechanisms of regulatory peptide action in the gastrointestinal tract: trefoil peptides. Podolsky, D. K. . J Gastroenterol 2000; 35(Suppl 12): 69-74. Medline 10779222

Intestinal trefoil factor confers colonic epithelial resistance to apoptosis. Taupin, D. R., K. Kinoshita and D. K. Podolsky . Proc Natl Acad Sci U S A 2000; 97(2): 799-804. Medline 10639160

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Catherine Tomasetto 2001 Citation This paper should be referenced as such : Tomasetto C . TFF3. Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFF3ID265.html

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WRN

Identity Hugo WRN Location 8p12 DNA/RNA Transcription 4.4 kb mRNA Protein

Description 1432 amino acids; contains one ATP binding site, one DExH helicase box, one exonuclease domain unique among known RecQ helicases in the N-terminal region, a nuclear localization signal in the C-terminus and a direct repeat of 27 amino acids between the exonuclease and helicase domains. Localisation nuclear, predominant nucleolar localization. Function 3-5 DNA helicase; 3-5 exonuclease; functionally interacts with DNA polymerase delta (POLD1) and RPA which are required for DNA replication and DNA repair, with Ku which is involved in double strand DNA break repair by non-homologous DNA end joining, and with p53. Homology Homologous to RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. In particular, similarities with the four known human members in the RecQ subfamily, human RecQL, human BLM, the product of the Bloom syndrome gene, and the recently identified human RecQL4, involved in the Rothmund-Thomson syndrome, and RecQL5 proteins Mutations Germinal WRN mutations are located over the entire gene and include stop codons, insertions/deletions and exon deletions: not a single missense mutation has been identified so far. Implicated in Entity Werner syndrome Disease Uncommon autosomal recessive disorder characterized by early onset of geriatric diseases, including atherosclerosis, osteoporosis, diabetes mellitus, juvenile cataract, graying of the hair and neoplasia, in particular soft-tissue sarcomas, in approximately 10% of WS patients. Prognosis WS patients die at mean age 46 +/- 11,6 years due to malignant tumors or cardiovascular infarctions.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -274- Cytogenetics Reciprocal chromosomal translocations and extensive genomic deletions.

External links Nomenclature Hugo WRN GDB WRN Entrez_Gene WRN 7486 Werner syndrome Cards Atlas WRNID284 GeneCards WRN Ensembl WRN CancerGene WRN Genatlas WRN GeneLynx WRN eGenome WRN euGene 7486 Genomic and cartography WRN - 8p12 chr8:31010320-31150818 + 8p12 (hg17- GoldenPath May_2004) Ensembl WRN - 8p12 [CytoView]

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

Genbank AB003173 [ SRS ] AB003173 [ ENTREZ ]

Genbank AF032113 [ SRS ] AF032113 [ ENTREZ ]

Genbank AF181896 [ SRS ] AF181896 [ ENTREZ ]

Genbank AF181897 [ SRS ] AF181897 [ ENTREZ ]

Genbank AY442327 [ SRS ] AY442327 [ ENTREZ ]

RefSeq NM_000553 [ SRS ] NM_000553 [ ENTREZ ]

RefSeq NT_086740 [ SRS ] NT_086740 [ ENTREZ ] AceView WRN AceView - NCBI TRASER WRN Traser - Stanford

Unigene Hs.512715 [ SRS ] Hs.512715 [ NCBI ] HS512715 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q14191 [ SRS] Q14191 [ EXPASY ] Q14191 [ INTERPRO ]

Prosite PS00690 DEAH ATP HELICASE [ SRS ] PS00690

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -275- DEAH_ATP_HELICASE [ Expasy ]

Prosite PS50967 HRDC [ SRS ] PS50967 HRDC [ Expasy ] Interpro IPR002562 3_5_exonuclease [ SRS ] IPR002562 3_5_exonuclease [ EBI ]

Interpro IPR001410 DEAD [ SRS ] IPR001410 DEAD [ EBI ]

Interpro IPR002464 DEAH_box [ SRS ] IPR002464 DEAH_box [ EBI ]

Interpro IPR001650 Helicase_C [ SRS ] IPR001650 Helicase_C [ EBI ]

Interpro IPR002121 HRDC [ SRS ] IPR002121 HRDC [ EBI ]

Interpro IPR004589 RecQ [ SRS ] IPR004589 RecQ [ EBI ] CluSTr Q14191

PF01612 3_5_exonuc [ SRS ] PF01612 3_5_exonuc [ Sanger Pfam ] pfam01612 [ NCBI-CDD ] Pfam PF00270 DEAD [ SRS ] PF00270 DEAD [ Sanger ] pfam00270 [ NCBI-CDD ]

PF00271 Helicase_C [ SRS ] PF00271 Helicase_C [ Sanger Pfam ] pfam00271 [ NCBI-CDD ] Pfam PF00570 HRDC [ SRS ] PF00570 HRDC [ Sanger ] pfam00570 [ NCBI-CDD ] Blocks Q14191 Polymorphism : SNP, mutations, diseases OMIM 604611 [ map ] GENECLINICS 604611

SNP WRN [dbSNP-NCBI]

SNP NM_000553 [SNP-NCI]

SNP WRN [GeneSNPs - Utah] WRN [SNP - CSHL] WRN] [HGBASE - SRS] Orphanet Werner syndrome General knowledge Family WRN [UCSC Family Browser] Browser SOURCE NM_000553 SMD Hs.512715 SAGE Hs.512715 Amigo function|3'-5' exonuclease activity Amigo function|ATP binding Amigo function|ATP-dependent helicase activity Amigo function|DNA binding Amigo function|DNA helicase activity Amigo process|DNA metabolism Amigo process|aging Amigo function|hydrolase activity

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -276- Amigo component|nucleus PubGene WRN Other databases Other http://www.ncbi.nlm.nih.gov/cgi-bin/SCIENCE96/gene?WRN database Probe WRN Related clones (RZPD - Berlin) PubMed PubMed 45 Pubmed reference(s) in LocusLink Bibliography Variegated translocation mosaicism in human skin fibroblast cultures. Hoehn, H.; Bryant, E. M.; Au, K.; Norwood, T. H.; Boman, H.; Martin, G. M. : Cytogenet. Cell Genet 1975; 15: 282-298. Medline 1222585

Mutator phenotype of Werner syndrome is characterized by extensive deletions. Fukuchi, K.; Martin, G. M.; Monnat, R. J., Jr. Proc. Nat. Acad. Sci. 1989, 86: 5893-5897. Medline 2762303

Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients. Fukuchi, K.; Tanaka, K.; Kumahara, Y.; Marumo, K.; Pride, M. B.; Martin, G. M.; Monnat, R. J., Jr. Hum. Genet 1990, 84: 249-252. Medline 2303247

The gene responsible for Werner syndrome may be a cell division 'counting' gene. Faragher, R. G. A.; Kill, I. R.; Hunter, J. A. A.; Pope, F. M.; Tannock, C.; Shall, S. Proc. Nat. Acad. Sci 1993, 90:12030-12034. Medline 8265666

Werner syndrome and biological ageing: a molecular genetic hypothesis. Thweatt, R.; Goldstein, S. BioEssays 1993, 15: 421-426. Medline 8357345

Homozygous and compound heterozygous mutations at the Werner syndrome locus. Oshima, J.; Yu, C.-E.; Piussan, C.; Klein, G.; Jabkowski, J.; Balci, S.; Miki, T.; Nakura, J.; Ogihara, T.; Ells, J.; Smith, M. A. C.; Melaragno, M. I.; Fraccaro, M.; Scappaticci, S.; Matthews, J.; Ouais, S.; Jarzebowicz, A.; Schellenberg, G. D.; Martin, G. M.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -277- Hum. Molec. Genet. 1996, 5:1909-1913. Medline 8968742

Positional cloning of the Werner's syndrome gene. Yu, C.-E.; Oshima, J.; Fu, Y.-H.; Wijsman, E. M.; Hisama, F.; Alisch, R.; Matthews, S.; Nakura, J.; Miki, T.; Quais, S.; Martin,G. M.; Mulligan, J.; Schellenberg, G. D. Science 1996, 272: 258-262. Medline 8602509

An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants. Ogburn, C. E.; Oshima, J.; Poot, M.; Chen, R.; Hunt, K. E.; Gollahon, K. A.; Rabinovitch, P. S.; Martin, G. M. : Hum. Genet 1997, 101: 121-125. Medline 9402954

Nucleolar localization of the Werner syndrome protein in human cells. Marciniak, R. A.; Lombard, D. B.; Johnson, F. B.; Guarente, L. : Proc. Nat. Acad. Sci 1998, 95: 6887-6892. Medline 9618508

WRN mutations in Werner syndrome. Moser, M. J.; Oshima, J.; Monnat, R. J., Jr. : Hum. Mutat 1999, 13: 271-279. Medline 10220139

Replication focus-forming activity 1 and the Werner syndrome gene product. Yan H, Chen CY, Kobayashi R, Newport J. Nat Genet. 1998, 4:375-378. Medline 9697700

Physical and functional interaction between p53 and the Werner's syndrome protein. Blander G, Kipnis J, Leal JF, Yu CE, Schellenberg GD, Oren M. J Biol Chem 1999, 274: 29463-29469. Medline 10506209

Functional interaction between the Werner syndrome protein and DNA polymerase delta. Kamath-Loeb, A. S.; Johansson, E.; Burgers, P. M. J.; Loeb, L. A. : Proc. Nat. Acad. Sci 2000, 97: 4603-4608. Medline 10781066

Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Wyllie, F. S.; Jones, C. J.; Skinner, J. W.; Haughton, M. F.; Wallis, C.; Wynford-

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -278- Thomas, D.; Faragher, R. G. A.; Kipling, D. (Letter) Nature Genet 2000, 24: 16-17. Medline 10615119

Ku complex interacts with and stimulates the Werner protein. Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D, Bohr VA. Genes Dev. 2000 Apr 15;14(8):907-12. Medline 20245490

Functional interaction between Ku and the Werner syndrome protein in DNA end processing. Li B, Comai L. J Biol Chem. 2000 Sep 15;275(37):28349-52. Medline 20435782

The Werner syndrome protein contributes to induction of p53 by DNA damage. Blander G, Zalle N, Leal JF, Bar-Or RL, Yu CE, Oren M. FASEB J. 2000 14:2138-2140. Medline 11023999

Werner protein recruits DNA polymerase delta to the nucleolus. Szekely AM, Chen YH, Zhang C, Oshima J, Weissman SM. Proc Natl Acad Sci U S A. 2000, 97:11365-11370. Medline 11027336

Telomere repeat DNA forms a large non-covalent complex with unique cohesive properties which is dissociated by Werner syndrome DNA helicase in the presence of replication protein A. Ohsugi I, Tokutake Y, Suzuki N, Ide T, Sugimoto M, Furuichi Y. Nucleic Acids Res. 2000, 28:3642-3648. Medline 10982887

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications BiblioGene - INIST Contributor(s) Written 03- Mounira Amor-Guéret 2001 Citation This paper should be referenced as such : Amor-Guéret M . WRN. Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/WRNID284.html

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Burkitt's lymphoma (BL)

Clinics and Pathology Phenotype / Pan-B antigens positive; TdT-, CD10+; CD5-; sIgM+. The cell of origin cell stem is a peripheral IgM+ memory B-cell (presence of somatic origin hypermutation of the Ig gene) Epidemiology Most common in children (1/3 of lymphomas). In adult it accounts for 3-4% of all lymphomas in western countries and it is frequently associated with immunodeficiency Clinics There is an endemic variant, affecting africans, which primarily involves the jaws and other facial bones. The non-endemic variant may be associated with immunodeficiency states and usually presents with abdominal involvement (distal ileum, ciecum, mesentery). The disease is very aggressive and requires prompt treatment with appropriate regimens. Cytology The blast cells in the peripheral blood and bone marrow display a basophilic cytoplasm with characteristic vacuolization, a picture indisinguishable from acute lymphoblastic leukemia (ALL) L3 of the FAB classification, which represents the leukemic counterpart of BL. Pathology The lymphoma consists of a monomorphic infiltrate of the lymph node by medium-sized cells showing round nuclei with several nucleoli and basophilic cytoplasm. Numerous benign macrophages confer a histologic pattern referred to as ³starry sky². Involvement of the peripheral blood and bone marrow may occur. The related form ³Burkitt-like² lymphoma shows intermediate features between diffuse large cell lymphoma and BL and probably includes different disease entities. It was suggested by the WHO panel that only those cases with c-MYC rearrangement and/or a >99% proliferation fraction as demonstrated by Ki-67 positivity should be classified as Burkitt-like lymphoma Treatment Aggressive regimens specifically designed for this lymphoma must be used Evolution Very rapid if untreated. Patients with limited disease and favourable prognostic features at presentation may rapidly show disease dissemination Prognosis If treated promptly with appropriate regimens the majority of patients can be cured Cytogenetics

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -281- Cytogenetics The primary chromosome anomaly is the translocation Morphological t(8;14)(q24;q32), found in 60-70% of the cases. Variant translocations having in common an 8q24 break, i.e the t(8;22)(q24;q11) and t(2;8)(p11;q24) occur in approximately 10-15% and 2-5% of the cases, respectively. A minority of cases may carry a duplication of chromosome 1, involving the 1q21-25 segment as the only detectable chromosome lesion In the Burkitt-like form there are at least 3 cytogenetic categories: one with an 8q24/c-MYC translocation, one with an 8q24 and 18q21/ BCL2 translocation and another with ³miscellaneous² rearrangements, frequently including an 18q21 break Probes Conventional karyotyping is the method of choice for the detection of the 8q24 translocations occurring in BL. There is variability in the location of the breakpoint at band 8q24, making the detection of c-MYC rearrangement (see below) difficult by molecular genetics. Southern blotting is the preferred method. In the endemic form the breakpoint in the Ig locus is usually located in the Ig heavy chain variable region, whereas in the nonendemic form the breakpoint falls in the Ig switch region. Fluorescence in situ hybridization is of value in detecting the the t(8;14) in interphase cells. Dual color FISH detection of the t(8;14) in interphase cells is possible by using cosmid clones spanning the c- MYC locus at 8q24 and a differently labelled IgH probe Additional Recurrent chromosome aberrations associated with the 8q24 anomalies translocations include 1q21‹25 duplications, deletions of 6q11-14, 17p deletions and trisomy 12, +7, +8 and +18. Genes involved and Proteins Note The t(8,14) and the variant t(8;22) and t(2;8) juxtapose IgH sequences and the c-MYC oncogene, bringing about its constitutional expression. The 17p deletion may have a correlation with p53 loss of function, determined by deletion of one allele and inactivating mutation of the remaining allele

Result of the chromosomal anomaly Fusion Constitutive expression of c-MYC is crucial for the pathogenesis of BL, Protein this protein being a key transcriptional regulator, controlling cell Oncogenesis proliferation, differentiation and death. The deregulated expression of c-MYC, caused by the 8q24 translocations, is achieved through multiple mechanisms: a) juxtaposition to regulatory elements of the Ig loci, b) mutations in the c-MYC 5' regulatory regions and, c) aminoacid substitutions occurring in exon 2, making the c-MYC transactivation domain less susceptible to modulation

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -282-

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 1869243

A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, De Wolf- Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink HK, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA. Blood 1994; 84: 1361. Medline 8068936

Catalogue of chromosome aberrations in cancer (5th edition). Mitelmam F (ed). Wiley Liss, New York 1994.

High frequency of EBV association with non-random abnormalities of the chromosome region 1q21-25 in AIDS-related Burkitt's lymphoma-derived cell lines. Polito P, Cilia AM, Gloghini A, Cozzi M, Perin T, De Paoli P, Gaidano G, Carbone A. Int J Cancer. 1995; 61: 370-4. Medline 7729949

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

Small noncleaved cell lymphomas (Burkitt's and Burkitt-like lymphomas). Magrath I. In: Magrath I (ed): The non Hodgkin's lymphomas. Pp781-811. Arnold, London 1997.

Application of interphase fluorescence in situ Hybridization for the detection of the Burkitt translocation t(8;14)(q24;q32) in B-cell lymphomas. Siebert R, Matthiesen P, Harder S, Zhang Y, Borowski A, Zuhlke-Jenisch R, Metzke S, Joos S, Weber-Matthiesen K, Grote W, Schlegelberger B. Blood. 1998; 91:984-90. Medline 9446660

World Health Organization classification of neoplastic diseases of hematopoietic and lymphoid tissues: Report of the clinical advisory committee - Airlie House, Virginia, Novembre 1997.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -283- Harris NNL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. J Clin Oncol 1999; 17: 3835-3849 Medline 10577857

Small noncleaved, non Burkitt's (Burkitt-like) lymphoma: Cytogenetics predict outcome and reflect clinical presentation. Macpherson N, Lesak D, Klasa R, Horsman D, Connors JM, Barnett M, Gascoyne RD. J Clin Oncol 1999; 17: 1558-1567. Medline 10334544

Clinicopthogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma. Schlegelberger B, Zwingers T, Harder T, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Muller-Hermelink K, Feller A, Heinz R, for the Kiel-Wien-Lymphoma Study Group. Blood 1999; 94: 3114-3120. Medline 10556197

Contributor(s) Written 03- Antonio Cuneo and Gianluigi Castoldi 2001 Citation This paper should be referenced as such : Cuneo A, Castoldi G . Burkitt's lymphoma (BL). Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/BurkittID2077.html

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del(13q) in multiple myeloma

Clinics and Pathology Disease Multiple myeloma (MM) is a monoclonal B-cell malignancy, which originates theoretically in lymph node germinal centers but locates and expands in bone marrow. It represents 10% of all the hematopoietic cancers, with a great variability in clinical presentation, response to therapy and survival duration. In more than 1/3 of cases, MM can be preceded by a phase of monoclonal gammopathy of uncertain significance (MGUS). At the extreme it can evolve in plasma blast acute leukemia. Phenotype / malignant myeloma cells are long-lived cells with morphological cell stem features varying from normal to dystrophic considering size of the origin cells, presence of nucleolar structures and aspect of the chromatin. Immunophenotype includes inconstant expression of CD56, CD38, CD40 and CD138. Epidemiology del(13q) is detected in 15-20% of MM patients by conventional karyotype and in 33-52% of cases by FISH analysis Prognosis -13/del(13q) appears as one of the main prognostic factors with ?2- microglobulin serum level and the percentage of bone marrow plasma cells. Patients with del(13q) have a significantly lower event-free survival, overall survival and complete remission duration, either in standard-dose or in high dose therapy protocols. Cytogenetics Cytogenetics del(13q) is a frequent occurrence in chronic lymphoproliferative Morphological diseases and in non Hodgkin lymphoma. del(13q) in MM is rarely observed as a sole anomaly; detected both in hyperdiploid and hypodiploid karyotypes, but with a higher incidence in hypodiploi forms; consequently, according to some authors, the prognostic value of del(13q) should have to be related to the ploidy. it is considered as a secondary event, however occurring early in the evolution of MM because it is observed in patients with MGUS. The minimal common region of deletion is in band 13q14.3, the same as in chronic lymphocytic leukemia. Del(13q) is clearly underscored by karyotyping because a number of deletions are submicroscopic or only detected in interphase nuclei. It involves rb-1, and loci D13S319 and D13S272 which are approximately 100kb distal from rb-1. rb-1 deletion / mutation would be a key event in MM evolution;

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -285- however other gene(s) would be involved at 13q14.3 because rb-1 and D13S319 deletions are dissociated in some cases. External links Other del(13q) in multiple myeloma Mitelman database (CGAP - NCBI) database Bibliography 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Avet-Loiseau H, Facon T, Daviet A, Godon C, Rapp MJ, Harousseau JL, Grosbois B, Bataille R Cancer Res 1999 Sep 15;59(18):4546-50 Medline 99421247

Frequent monoallelic loss of D13S319 in multiple myeloma patients shown by interphase fluorescence in situ hybridization. Chang H, Bouman D, Boerkoel CF, Stewart AK, Squire JA Leukemia 1999 Jan;13(1):105-9 Medline 99139899

Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization. Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease. Zojer N, Konigsberg R, Ackermann J, Fritz E, Dallinger S, Kromer E, Kaufmann H, Riedl L, Gisslinger H, Schreiber S, Heinz R, Ludwig H, Huber H, Drach J Blood 2000 Mar 15;95(6):1925-30 Medline 20173555

Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Desikan R, Barlogie B, Sawyer J, Ayers D, Tricot G, Badros A, Zangari M, Munshi NC, Anaissie E, Spoon D, Siegel D, Jagannath S, Vesole D, Epstein J, Shaughnessy J, Fassas A, Lim S, Roberson P, Crowley J Blood 2000 Jun 15;95(12):4008-4010 Medline 10845942

High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. Shaughnessy J, Tian E, Sawyer J, Bumm K, Landes R, Badros A, Morris C, Tricot G, Epstein J, Barlogie B Blood 2000 Aug 15;96(4):1505-11

Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -286- Konigsberg R, Ackermann J, Kaufmann H, Zojer N, Urbauer E, Kromer E, Jager U, Gisslinger H, Schreiber S, Heinz R, Ludwig H, Huber H, Drach J Leukemia 2000 Nov;14(11):1975-9

Contributor(s) Written 03- Franck Viguié 2001 Citation This paper should be referenced as such : Viguié F . del(13q) in multiple myeloma. Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/del13qMMyeloID2094.html

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Follicular lymphoma (FL)

Clinics and Pathology Phenotype / Pan-B antigens test positive. The immunophenotypic profile is CD10+, cell stem CD5-, sIg+ and the cell of origin is a germinal centre B-cell that has origin encountered the antigen Epidemiology This lymphoma accounts for 30-40% of all lymphomas occurring in the adult population in western countries. Its peak incidence is in the fifth and sixth decade Clinics The patients most often present widespead disease at diagnosis, with nodal and extranodal (bone marrow) involvement. Peripheral blood involvement is detectable by light microscopy in approximately 10% of the cases, but the majority of cases can be shown to have circulating malignant cells by sensitive molecular genetic methods. The disease usually runs an indolent course. Grade 3 FL may be characterized by earlier relapse, especially if treated with regimens not including an anthracycline drug Pathology The lymphoma is composed of a mixture of centrocytes and centroblasts with a follicular and diffuse pattern. Lymphoma grading by the number of large cells/centroblasts is recommended: three grades are recognized with incresing number of centroblasts Treatment Depending on age and stage at presentation it may vary from a ³watch and wait² policy in initial stages to multiagent chemotherapy in advanced stages. Immunotherapy using chimeric anti-CD20 monoclonal antibody has an important role in combination with chemotherapy Evolution The majority of patients cannot be cured by chemotherapy and eventually relapse. Histologic switch into high grade lymphoma may occur Prognosis Approximately 60% of the patients presenting with limited disease are alive at 10 years. Patients in stages III and IV were reported to have a median survival in the 8-12 years range Cytogenetics Cytogenetics Seventy-80% of the cases carry the t(14;18)(q32;q21) as the primary Morphological chromosome anomaly. Rare variant translocation t(2;18)(p11;q21) and t(18;22)(q21;q11) were described. Approximately 15% of the cases show a 3q27 break, half of which include the t(3;14)(q27;q32) and the variant translocations t(3;22)(q27;q11) and t(2;3)(p11;q27)

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -288- Cytogenetics The incidence of 6q21 deletion and 17p13/p53 deletion (see below) by Molecular interphase FISH analysis may be around 60% and 20%, respectively Additional Secondary chromosome changes are both numerical and anomalies structural. Trisomy 7, +8; +12, +3, +18, +X each occur in 10-20% of the cases. There is an association between +7 and the presence of a large cell component, but no numerical anomaly has an independent impact on prognosis. Deletions of 6q23-26 occur at a 25-30% incidence; 17p anomalies are present in approximately 10% of the cases. The presence of these anomalies may have a correlation with disease transfornation and it was associated with an inferior prognosis. Rarely, histologic switch into a high grade lymphoma may be associated with the development of an additional t(8;14)(q24;q32). Other anomalies include 1p36 deletion in 10-12% of the cases, probably centered around the p73 gene; 10q22-24 deletions in 10- 13% of the cases and 9p21 deletions/ p16 deletions, associated with histologic transformation Result of the chromosomal anomaly Fusion No fusion protein. The t(14;18) brings about the juxtaposition of BCL-2 Protein with the Ig heavy chain joining segment, with consequent marked Description overexpression of the BCL2 protein product. The majority of breakpoints on 18q22 fall into two regions: the major breakpoint region (60-70% of the cases) and the minor cluster region (20-25% of the cases) Oncogenesis BCL-2 overexpression prevents cell to die by apoptosis (Gaidano, 1997). BCL-2 forms heterodimers with BAX and the relative proportion of BCL-2 to BAX determines the functional activity of BCL-2. In vitro, BCL-2 constitutive expression has a definite role in sustaining cell growth, whereas in vivo, BCL-2 transgenes induce a pattern of polyclonal proliferation of mature B-cells.

Bibliography LAZ3 rearrangements in Non-Hodgkin's lymphoma: correlation with histoogy, immunophenotype, karyotype and clinical outcome in 217 patients. Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F, Fruchart C, Duval C, Monconduit M, Tilly H. Blood 1994; 83:2423-2427. Medline 8167331

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -289- Blood 1994; 84: 1361. Medline 8068936

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

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

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

Frequent deletions of 6q23-24 in B-cell non-Hodgkin's lymphomas detected by fluorescence in situ hybridization. Zhang Y, Weber-Matthiesen K, Siebert R, Matthiesen P, Schlegelberger B. Genes Chromosomes Cancer. 1997;18:310-3. Medline 9087572

Gain of chromosome 7 marks the progression from indolent to aggressive follicle centre lymphoma and is a common finding in patients with diffuse large B-cell lymphoma: a study by FISH. Bernell P, Jacobsson B, Liliemark J, Hjalmar V, Arvidsson I, Hast R. Br J Haematol. 1998;101:487-91. Medline 9633892

Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma. Elenitoba-Johnson KS, Gascoyne RD, Lim MS, Chhanabai M, Jaffe ES, Raffeld M. Blood. 1998;91:4677-85. Medline 9616165

Analysis of PTEN mutations and deletions in B-cell non-Hodgkin's lymphomas. Butler MP, Wang SI, Chaganti RS, Parsons R, Dalla-Favera R. Genes Chromosomes Cancer. 1999;24:322-7. Medline 10092130

Rearrangements of chromosome band 1p36 in non-Hodgkin's lymphoma. Dave BJ, Hess MM, Pickering DL, Zaleski DH, Pfeifer AL, Weisenburger DD, Armitage JO, Sanger WG. Clin Cancer Res. 1999 5:1401-9.

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

Contributor(s) Written 03- Antonio Cuneo and Gianluigi Castoldi 2001 Citation This paper should be referenced as such : Cuneo A, Castoldi G . Follicular lymphoma (FL). Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/FollLymphomID2075.html

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t(5;11)(q31;q23)

Clinics and Pathology Phenotype / 1 case of chronic myelogenous leukemia (CML), one JMML evolving cell stem towards a M4-M5 type acute non lymphocytic leukemia (ANLL), two origin M5-ANLL, one treatment related ANLL (t-ANLL), and one L2 acute lymphoblastic leukemia (ALL) Epidemiology 6 cases known in the litterature; two infants, one 18 months old baby, and three adults (?, 55, 60 yrs); sex ration 4M/1F Clinics WBC: 20-420 X 109 /l Pathology In at least 2 infant cases, cutane infiltrations were noticed Prognosis survival (mths) was: 8+, 17, 17+, 48+ and 65+ Cytogenetics Probes YAC, 13HH4 Additional sole anomaly in 5 of 6 cases; acompanied with +8 in one case anomalies Genes involved and Proteins Gene GRAF (GTPase regulator associated with FAK) Name Location 5q31 Gene MLL (Mixed Lineage Leukemia) Name Location 11q23 Result of the chromosomal anomaly Hybrid gene 5' MLL-Inverted MLL-GRAF 3' Description

Fusion Hybrid transcript MLL-GRAF contains the code for the following Protein domains: AT-hook+DNA methyltransferase (from MLL) + SH3 (from Description GRAF)

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External links Other t(5;11)(q31;q23) Mitelman database (CGAP - NCBI) database Other t(5;11)(q31;q23) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC's 9th AML trial. Hoyle CF et al. Br J Haematol 1989; 72: 45-53. Medline 2736242

Chromosome 11q23 translocations in both infant and adult acute leukemias are detected by in situ hybridization with a yeast artificial chromosome. Kearney L et al. Blood 1992; 80: 1659-1665. Medline 1391936

The isolation of a yeast artificial chromosome which spans the chromosome 11q23 region involved in a number of translocations in acute leukaemias. Bower M et al. Leukemia, 1993; 7: S34-S39. Medline 8361230

Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants. Harrison CJ et al. Leukemia 1998; 12: 811-822. Medline 9593286

Congenital leukemia: successful treatment of a newborn with t(5;11)(q31;q23). Fernandez MC et al. J Ped Hematol Oncol 1999; 21: 152-157. Medline 10206463

Acute myeloid leukemia with t(5;11): two case reports. Itoh M et al. Leuk Res, 1999; 23: 677-680.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -293- Medline 10400190

The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q. Borkhardt A et al. Proc Natl Acad Sci USA 2000; 97: 9168-9173. Medline 10908648

Contributor(s) Written 03- Stig E Bojesen 2001 Citation This paper should be referenced as such : Bojesen SE . t(5;11)(q31;q23). Atlas Genet Cytogenet Oncol Haematol. March 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0511ID1192.html

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Classification of T-Cell disorders

Identity Note T-cell lymphoid disorders include a variety of disease entities which result from the clonal neoplastic expansion of an uncommitted (thymic) or a committed (post thymic) T-cell. Some of these diseases have distinct cytogenetic/molecular genetic features which allow to better define the various entities and understand their pathogenesis. Clinics and Pathology Disease T-prolymphocytic leukemia (T-PLL) Variants:small cell and cerebriform cell Phenotype / TdT-, CD1a-, cell stem CD4+ CD8- origin CD4 - CD8+ CD4+ CD8+ Clinics Aggressive course splenomegaly, high WBC with prolymphocytes Cytogenetics Inv(14)(q11q32), t(14;14)(q11;q32) Xq28 abnormalities idic(8)(p11), t(8; 8)(p11;q1-2) 11q22-23 abnormalities 12p abnormalities 13q14.3 deletions Genes ATM gene (11q22-23) mutated. TCL1 (14q32.1) or MTCP1 (Xq28) activated

Disease Large granular lymphocyte leukemia (LGL) - T-cell Type Phenotype / TdT-,CD1a cell stem CD3+,CD2+,CD8+ CD4 -,CD57+, CD16+/-Cytotoxic or suppressor origin activity Clinics Indolent cytopenias, splenomegaly, lymphocytosis with granular lymphocytes. Cytogenetics Clonal abnormalities.in some cases, but no consistent specific abnormalities Genes Clonality established by TCR rearrangements

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -295- Disease Large granular lymphocyte leukemia (LGL) - NK type Phenotype / TdT-,CD1a cell stem CD2+,CD56+, CD16+ ,CD7+/-CD3-, CD5-,TCR-Natural killer origin Activity. Clinics Aggressive or indolent lymphocytosis, splenomegaly, hepatomegaly Cytogenetics del(6)(q21-25) Genes TCR chain genes in germ line.

Disease Sezary syndrome (SS) Phenotype / cell stem TdT-, CD1a-, CD3+,CD4+,CD8-, Helper or no functional activity. origin Clinics Variable clinical course with skin involvement and cells with cerebriform nuclei Cytogenetics Complex, clonal, oligoclonal or nonclonal with variable ploidy Abnormal.2p, Abnormal.6q i(17q), del (13)(q14) Genes P53 gene deletion and protein expression in the absence of gene mutation. Few cases express MDM2

Disease Adult T-cell leukemia lymphoma (ATLL) Phenotype / cell stem TdT-, CD1a- CD7- CD4+ CD8- CD25+, Suppressor activity origin Clinics Aggressive , hypercalcaemia, lymphadenopathy, Œflower cells', HTLV-1 Positive. Cytogenetics Complex and often oligoclonal. Numerical abnormalities: 3, 7, X Structural abnormalities: 1q, 3q, 6q, 14q. Genes Oligoclonal/mono clonal integration of HTLV-1in host DNA Abnormalities of p53, p16 and p15 genes.

Disease a/d T-NHL hepatosplenic lymphoma Phenotype / cell stem TdT- CD1a- CD3+/- CD56+, CD7+, granzymeA+, TCR g/d+ origin Clinics Aggressive, Hepato splenomegaly Cytogenetics Abnormal.7q, i (7p)

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -296- Genes TCR genes gamma/delta rearranged but alpha/beta not rearranged

Disease Peripheral/post-thymic T cell lymphoma (pleomorphic and immunoblastic subtypes) Phenotype / cell stem TdT-, CD1a-, Variable expression of CD4 or CD8 origin Clinics Aggressive; advanced stages. Cytogenetics variable

Disease Angio immunoblastic T-cell lymphoma Phenotype / cell stem TdT-, CD1a-, CD2+, CD5+, CD3+ CD4+ CD8- origin Clinics Disproteinemia, lymphadenopathy,immune abnormalities Cytogenetics Complex with multiple related or unrelated clones. +3 or i(3q), +5, del(6q). Progression from normal karyotype to abnormal clone observed during transition from hyperplasia to neoplasia. Genes Integrated EBV sequences present in both B-and T-cells and is unlikely to be the etiological agent.

Disease Angiocentric (nasal) T-cell lymphoma Phenotype / cell stem TdT-, CD1a-, T-cell or NK phenotype. origin Clinics Prevalent in Asia and south America; extra nodal involvement. Cytogenetics i(1q), del(6q), i(6p) Genes Majority have no TCR rearrangement; EBV clonally integrated and plays a role in the etiology of the disease

Disease Anaplastic (Ki 1+) large cell lymphoma Phenotype / cell stem TdT-, CD1a-, CD3+/- CD30+ (Ki 1+), CD15-, CD25+, HLA-Dr+, CD71+. origin Clinics Aggressive with skin nodes and extranodal involvement. Cytogenetics t(2;5)(p23;q35) Genes Fusion gene NPM-ALK; 2p23 -Nucleolar phosphoprotein- NPM; 5q35 - Anaplastic lymphoma kinase- ALK

Disease Intestinal T-cell lymphoma Phenotype / TdT CD1a -, CD3+, CD8+, CD103+, CD4-, CD8- cell stem

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -297- origin Clinics Bone pain, coeliac disease, mesenteric nodes. Genes EBV genome present in mexican population but not in the europeans.

Disease T-lymphoblastic Lymphoma/leukaemia (T-Lbly/T-ALL) Phenotype / TDT+, CD1a+, CD7+, cytCD3+ or +/-, other T-cell antigens.Thymic cell stem uncommitted T-cell. origin Clinics Aggressive; course similar to ALL mediastinal mass, high WBC Cytogenetics del(6)(q21-q22) t(11;14)(p13;q11) t(1;14)(p34;q11); 1p34: tal-1gene; 14q11: TCR alpha Genes TCR chain genes rearranged. Bibliography CD30-positive large cell lymphomas (Ki-1 lymphoma) are associated with chromosomal translocation involving 5q35. Mason DY, Bastard C, Rimokh R, Dastugue N,Huret JL, Kristoffersson U, Magaud J- P et al. Br J Haematol 1990; 74: 161-168. Medline 2156548

Chromosome abnormalities in adult T-cell Leukemia/Lymphoma : A karyotype review committee report. Kamada N, Sakurai M, Miyamoto K, Sanada I, Sadamori N, Fukuhara S,Abe S, Shiraishi Y, and Shimoyama M. Cancer Res 1992; 52:1481-1493. Medline 1540956

Clonal diseases of large granular lymphocytes. Loughran TP. Blood 1993; 82:1-14. Medline 8324214

Cytogenetic findings in peripheral T-cell lymphomas as a basis for distinguishing low- grade and high-grade lymphomas. Schlegelberger B, Himmler A, Godde E, Grote W, Feller AC, and Lennert K. Blood 1994; 83: 505-511. Medline 8286748

Detection of aberrant clones in nearly all cases of angioimmunoblastic lymphadenopathy with dysproteinemia type T-cell lymphoma by combined interphase and metaphase cytogenetics. Schlegelberger B, Zhang Y, Weber-Natthiesen K, Grote W.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -298- Blood 1994; 84:2640-2648. Medline 7919378

Consistent presence of isochromosome 7p in Hepatosplenic T-gamma/delta lymphoma: a new cytogenetic-clinicopathologic entity. Wang CC,Tien HF, Lin MT, Su IJ, Wang CH, Chuang SM, Shen MC,Liu CH. Genes Chromosom Cancer 1995;.12:161-164. Medline 7536454

Response to : "presence of t(2;5) in primary CD30+ cutaneous lymphoproliferative disorders". DeCocteau JF, Lowsky R, Kinney MC, Kadin ME.. Blood 1996; 88:3251

Classification of natural killer(NK) cell and NK- like T-cell malignancies. Jaffe E. . Blood 1996; 87: 1207-1210. Medline 8608206

Relationship of T- cell leukaemias with cerebriform nuclei to T-Prolymphocytic leukaemia: A cytogenetic analysis with in situ hybridisation. Brito-Babapulle V, Maljaie SH, Matutes E, Hedges M, Yuille M, Catovsky D. Br J Haematol 1997; 96 : 724-732. Medline 9074412

Identification of del(6)(q21q25)as a recurring chromosomal abnormality in putative NK cell lymphoma /leukaemia. Wong KF, Chan JKC, Kwong YL.. Br J Haematol 1997; 98:922-926. Medline 9326190 p53 allele deletion and protein expression occurs in the absence of p53 gene mutation in T-Prolymphocytic leukaemia and Sezary syndrome. Brito-Babapulle V, Hamoudi R, Matutes E, Watson S, Kaczmarek P, H.Maljaie, and Catovsky. Br J Haematol 2000; 110:180-187. Medline 10930996

The D13S25 locus mapping to 13q14.3 locus is deleted in T-Prolymphocytic leukemia. Brito-Babapulle V, Baou M, Atkinson S, Catovsky D. Int.Natl.J Hematol.2000; Suppl1. 72:167 (abstract 15780).

T-Cell Lymphoproliferative Disorders. Classification, Clinical and Laboratory Aspects.. Matutes E.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -299- Advances in Blood Disorders 2000. Ed:.A.Polliak. Harwood Academic Publishers

Contributor(s) Written 02- Vasantha Brito-Babapulle, Estella Matutes, Daniel Catovsky 2001 Citation This paper should be referenced as such : Brito-Babapulle V, Matutes E, Catovsky D . Classification of T-Cell disorders. Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/TcellClassifID2079.html

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Testis: Germ cell tumors (updated: old version not available)

Identity Other Testicular cancer names Classification

Germ cell tumours comprise a heterogeneous group of neoplasms, which can be found at different, although restricted anatomical locations. In the testis three groups of germ cell-derived tumours are distinguished:

• I- teratomas and yolk sac tumours of infants; • II- seminomas and nonseminomas of adolescents and adults; • III- spermatocytic seminomas of the elderly.

These groups are defined by epidemiological characteristics, histological composition and chromosomal constitution (Table 1). Designation of tumours to these groups is clinically relevant because they require different strategies for treatment Clinics and Pathology Disease Testicular germ cell tumours, teratomas and yolk sac tumours, seminomas and nonseminomas, carcinoma in situ (CIS), intratubular germ cell neoplasia undifferentiated (IGCNU) , testicular intratubular neoplasia (TIN) , spermatocytic seminomas Embryonic That the different types of germ cell tumours of the testis are derived origin from cells belonging to the germ cell lineage, is established, although

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -301- the actual non-malignant counterparts are still a matter of debate. It is likely that the teratomas and yolk sac tumours of infants originate from an embryonic germ cell, while this is a spermatogonial/spermatocyte- type of cell for spermatocytic seminomas. In contrast, it is established that the precursor of seminomas and nonseminomas is carcinoma in situ (CIS), also referred to as intratubular germ cell neoplasia undifferentiated (IGCNU) or testicular intratubular neoplasia (TIN). CIS is composed of tumour cells located on the basal membrane at the inner side of the seminiferous tubules, under the tight junction, where normally the spermatogonia reside. It has been suggested that the normal counterpart of CIS, i.e., a primordial germ cell/gonocyte is present within the gonad around the 7th to 10th week gestational age. This is supported by the epidemiological finding that the incidence of seminomas and nonseminomas show a lower incidence in cohorts of men born during the period of the second word war in Denmark, Norway and Sweden. An alternative model has been proposed, in which the cell of origin is a pachytene spermatocyte. Epidemiology During the first few years of life, the only types of germ cell tumours diagnosed in the testis are teratomas and yolk sac tumours. They are evidently unrelated to puberty. In contrast, the seminomas, nonseminomas, and spermatocytic seminomas are clinically manifest during or after puberty, therefore likely related to sexual maturation. Spermatocytic seminomas are predominantly found in patients of 50 years and older. While most patients with a seminoma present in their 4th decade of life, this is in the 3rd decade for patients with a nonseminoma. An increasing incidence (in between 6-11/100.000) has been reported both for seminomas and nonseminomas during the last decades in white populations throughout the world, with an annual increase of 3-6%. Although in general rare, accounting for 1-2% of all malignancies in males, seminomas and nonseminomas are the most common cancer in young Caucasian males. In some European countries, i.e., Denmark and Switzerland, the life time risk for seminoma or nonseminoma is up to 1%. However, the increase seems to stabilise to date. In contrast to whites, blacks have a significantly lower, not increasing, incidence for seminomas/nonseminomas, although histology and age-distribution are the same. No significantly increasing incidence has been reported for teratomas and yolk sac tumours of infants and spermatocytic seminomas. The incidence of CIS, the precursor of both seminomas and nonseminomas, in the general population is similar to the life time risk to develop a seminoma/nonseminoma. This indicates that CIS will always progress to invasiveness. About 5% of patients with a unilateral seminoma or nonseminoma have contralateral CIS.

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Figure 1. Representative example of the precursor cells of both seminoma and nonseminoma of the adult testis, known as carcinoma in situ (CIS), intratubular germ cell neoplasia undifferentiated (IGCNU), and testicular intratubular neoplasia (TIN).

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -303- The cells are identified by detection of alkaline phosphatase reactivity on a frozen tissue section of testicular parenchyma adjacent to an invasive seminoma. Note the presence of the alkaline phosphatase positive IGCNU cells at the inner basal membrane of the seminiferous tubules (indicted by an arrow), under the tight junctions present between the Sertoli cells (indicated by 'S'). Micro-invasive seminoma cells (indicated by an arrow-head) are also detectable, as well as IGCNU cells in the lumen of the seminiferous tubules (within the squares). Figure 2. Representative example of a seminoma, stained for placental/germ cell specific alkaline phosphatase. Note the presence of lymphocytic infiltrations. Figure 3. Representative example of an embryonal carcinoma, stained for CD30. Figure 4. Representative example of a teratoma, stained for cytokeratin. Figure 5. Representative example of a yolk sac tumor, stained for AFP. Figure 6. Representative example of a choriocarcinona, stained for hCG. Figure 7. Representative example of a spermatocytic seminoma, stained with hematoxylin and eosin.

Pathology CIS cells show similarities to embryonic germ cells, like their positivity for alkaline phosphatase, the stem cell factor receptor (c-KIT), and their glycogen content. These cells are frequently found in the adjacent parenchyma of an invasive seminoma and nonseminoma, of which a representative example is given in Figure 1. Histologically and immunohistochemically, seminoma cells mimick CIS. Lymphocytic infiltrations in the supportive stroma are a consistent feature of these tumors (Figure 2). So far, no differences have been found between CIS and seminoma cell, except the invasive growth of the latter. In contrast to the homogeneity of CIS and seminomas, nonseminomas can be composed of different elements, including embryonal carcinoma (the undifferentiated, stem cell, component), teratoma (the somatically differentiated component), yolk sac tumour and choriocarcinoma (the components of extra-embryonal differentiation) (see Figure 3-6). These different histological elements can be identified using immunohistochemistry for different markers, like CD30 for embryonal carcinoma, alpha fetoprotein (AFP) for yolk sac tumour, and human chorionic gonadotropin (hCG) for choriocarcinoma (see illustrations). Most nonseminomas are mixtures of these different elements. About 50% of germ cell tumors of adolescents and adults are pure seminomas, and 40% pure or mixed nonseminomas. Tumours containing both a seminoma and a nonseminoma component are classified as combined tumours according to the British Classification system, and as nonseminomas according to the World Health Organisation (WHO) classification. These tumours present at an age in between that of pure seminoma and nonseminoma. The spermatocytic seminomas are histologically uniform and composed of three cell types, small, intermediate and large cells, that are evenly distributed (Figure 7). The immunohistochemical markers for CIS/seminoma are overall negative in spermatocytic seminomas. So far, no specific markers have been reported for spermatocytic seminomas, Histologically and immunohistochemically, the teratoma and yolk sac tumour components found in the infantile testis are indistinguishable from those elements found in nonseminomas of the adult testis. However, they differ in chromosomal constitution (see Table 1 and below), and the first lack CIS in the adjacent parenchyma.

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Evolution In spite of the fact that it is generally accepted that CIS is the precursor for seminoma and nonseminoma, the relationship(s) between these histological elements is still a matter of debate. It has been shown, especially using cell lines derived from nonseminomas, that embryonal carcinoma is the undifferentiated stem cell of all differentiated nonseminomatous components. So far, no cell lines for seminoma or CIS are available. Nonseminomas mimick embryonal development to a certain level. However, it is unproven so far whether seminomas may also progress into nonseminoma, although various observations, both biological and clinical, may support this model. It has been suggested that CIS present in the adjacent parenchyma of an invasive seminoma or nonseminoma is only one step behind in the progression of the cancer, which is supported by molecular findings. Prognosis The teratomas of infants, and the spermatocytic seminomas are generally benign. Therefore, orchidectomy alone is mostly curative. However, spermatocytic seminomas may progress to sarcoma, a highly malignant tumour. When the yolk sac tumour component of infants is metastatic, it can be cured in the majority of patients using chemotherapy. Seminomas are highly sensitive to irradiation, while nonseminomas are overall highly sensitive to cisplatin-based chemotherapy, with cure rates of up to 90%. Criteria have been developed to distinguish nonseminoma patients with a good, intermediate and poor response (Table 2). Although these parameters are not informative on an individual basis, they separate the three groups as a whole. Seminoma patients always fall in the good and intermediate prognostic group. Stage I disease might be treated by orchidectomy followed by a "wait and see" strategy. Alternatively, retroperitoneal lymph node dissection (nerve sparing) and/or irradiation (in case of pure seminoma) can be performed. Moreover, a single dose cisplatin-based chemotherapy is tested in an experimental set up. These issues are of interest, because the risk of occult metastases in clinically stage I nonseminomas is about 30%. Established factors predicting metastastic disease are lymphovascular space invasion and percentage of embryonal carcinoma. For nonseminomas there is no consensus on the best method to define the risk of occult metastases and on how the information can be used for the clinical management of patients. In clinically stage I seminoma patients occult metastases are predicted by vascular invasion and tumor size. More recently, the mean nuclear

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -305- volume has been reported to be an informative parameter. Obviously these parameters could serve to define a group of patients that could benefit from surveillance. Patients with refractory disease might benefit from high-dose chemotherapy. Because CIS is formed during intra-uterine growth, and the treatable cancer in most cases becomes clinically manifest after puberty, methods for early diagnosis and treatment might prevent progression of CIS to an invasive seminoma or nonseminoma, thereby preventing possible progression to refractory disease. A number of putative parameters have been reported, although none of them have been tested in a clinical setting thus far. Moreover, it has been shown that CIS can be effectively eradicated using local irradiation, with limited side effects. The presence of CIS in the contralateral testis in 5% of patients with a seminoma or nonseminomas has led to the routine of a contralateral biopsy in some countries. However, in most countries the clinicians prefer a closely "wait and see" strategy. Patients with cryptorchidism, atrophic testis, or prior infertility have a higher risk of CIS in the contralateral testis. The exact numbers are unknown, but it is estimated that high-risk patients comprise 40-50% of the population with CIS. Altogether about 50-60% of patients with a unilateral testis tumor will have no other risk factors for CIS. Genetics Note Familial predisposition About 2% of the patients with a seminoma or nonseminoma have an affected family member, indicating a genetic component in the development of this cancer. So far, two genome-wide linkage analyses have been performed. The first showed linkage to regions of chromosome 1, 4, 5, 14 and 18, while the second found no evidence for linkage to chromosome 1, and a weaker indication for involvement of region 2 of chromosome 4 (4cen-q13). For the other region on chromosome 4 (p14-p13), and for chromosome 5, similar results were obtained. Both studies indicated linkage to chromosome 18. The latter study found linkage to the short arm of chromosome 2, and the telomeric region of 3q. A telomeric region of the long arm of chromosome 12 showed linkage when the results of both studies were combined, while no linkage was found in the separate studies. An other finding of interest is the fact that bilateral occurrence of the tumor is more frequent in familial than in sporadic cases (15 versus 5%). Indeed, most recently linkage to Xq27 has been found for cryptorchidism and bilateral germ cell tumors, although the gene involved is still unknown. Cytogenetics Cytogenetics The three groups of germ cell tumours of the testis show Morphological characteristic chromosomal anomalies, which favor the model of separate pathogeneses. The chromosomal data on germ cell tumors of the infantile testis and spermatocytic seminomas are scarse. While no aberrations are found so far in teratomas of the infantile testis, the yolk sac tumours show recurrent loss of part of 6q, and gain of parts of 1q, 20q, and 22. In addition, these yolk sac tumours are all

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -306- found to be aneuploid. One study reports the analysis of spermatocytic seminomas by karyotyping and comparative genomic hybridization, showing gain of chromosome 9 as the only recurrent and characteristic chromosomal abnormality. Seminomas, nonseminomas as well as CIS are consistently aneuploid with a characteristic pattern of chromosomal gains and losses. The cells of seminoma and CIS are hypertriploid, while those of nonseminoma, irrespective of histological composition, are hypotriploid. Using karyotyping, more recently supported by in situ and comparative genomic hybridization, a complex, but similar pattern of over- and underrepresentation of (parts of) chromosomes has been identified in seminomas and nonseminomas. Overall, the chromosomes 4, 5, 11, 13, 18 and Y are underrepresented, while the chromosomes 7, 8, 12 and X are overrepresented. In spite of the highly similar pattern of gains and losses in seminomas and nonseminomas, some differences were observed, like overrepresentation of chromosome 15 in seminomas compared to nonseminomas, which might explain the ploidy difference between these two histological groups. The recurrent pattern of chromosomal gains and losses suggests that both activation of proto-oncogenes, and inactivation of tumor suppressor genes is involved in the development of this cancer. Gain of 12p The isochromosome 12p can be used as a diagnostic molecular marker for seminomas and nonseminomas: the most consistent chromosomal anomaly in seminomas and nonseminomas, besides their aneuploidy, is gain of the short arm of chromosome 12. In fact, about 80% of the invasive tumors have extra copies of 12p due to the formation of an isochromosome (i(12p)) (Figure). The 20% i((12p) negative tumors also show gain of 12p, due to other chromosomal changes. These data strongly indicate that the short arm of chromosome 12 contains a gene or genes of which extra copies are required for the development of the invasive tumor. Analysis of LOH on the long arm of chromosome 12 showed that polyploidisation occurs prior to i(12p) formation. In addition, it was demonstrated that i(12p) results from sister chromatin exchange. In contrast, non-sister cromatin exchange has also been suggested. Most recently, it was shown that the presence of extra copies of the short arm of chromosome 12 is related to invasive growth of the tumor, i.e., no gain of 12p is observed in CIS. This suggests that addition copies of one or more genes on 12p is relevant for the progression of CIS to an invasive tumor. Analysis of seminomas and nonseminomas containing a high level amplification of a restricted region of 12p, i.e., band p11.2-12.1, cyclin D2 being outside this region, might be a tool to identify the gene(s) on 12p. So far, these data suggest that is relates to a gene that suppresses induction of apoptosis upon invasive growth of the tumour cells. Proto-oncogenes Several studies deal with the possible role of activation of proto-oncogenes in the development of seminomas and nonseminomas. RAS genes are rarely found to be mutated One study reported the presence of mutations in c-KIT in some cases. Overexpression of c-MYC has been found in less than 10% of

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -307- nonseminomas, and amplification of MDM2 in also less than 10% of the tumors. Cyclin D2 has been suggested as the candidate gene on 12p. However, this gene maps outside the amplified region found in some seminomas and nonseminomas. In conclusion, the role of activation of proto-oncogenes in the genesis of seminomas and nonseminomas is not illucidated so far. Tumor suppressor genes Studies of loss of heterozygosity (LOH), a hallmark of the involvement of tumor suppressor genes, have given rather inconsistent results in seminomas and nonseminomas, which might be related to their aneuploidy. Several studies have been performed on chromosomes 1, 5, 11, 12 and 18. Recurrent loss has been observed on 1p, in particular bands p13, p22, p31.3-p32, and 1q; in particular bands q32. Several regions on chromosome 5 show LOH, including p15.1-p15.2, q11, q14, q21, and q34-qter. Chromosome 12 contains two regions of interest, i.e., q13 and q22. In spite of the identification of homozygous deletions at 12q22, no candidate genes have been identified so far. Homozygous deletions have also been identified on the long arm of chromosome 18. Although DCC (deleted in colorectal cancer) might be a candidate, it has been indicated that loss of this gene is likely progression-related. More recently, inactivating mutations of SMAD4, also mapped to 18q, have been reported in a limited number of seminomas. LOH analysis on microdissected tumor cells of different histologies, including CIS, revealed recurrent LOH at 3q27-q28, 5q31, 5q34-q35, 9p21-p22 and 12q22. These anomalies were also found in the adjacent CIS cells. Interestingly, loss of 3q27-q28 was only but consistently detected in the embryonal carcinoma components. The other targets investigated with overall negative findings are: NME1 and 2, APC, MCC, RB, WT1, and P53. However, hypermethylation of exon 1 of p16 was found in about 50% of the tumors, which was related to no, or a low level of expression. In summary, although interesting observations have been made, no convincing data based on studies on LOH, mutations and expression so far, indicate a significant involvement of one of the studied tumor suppressor genes in the development of testicular seminomas and nonseminomas. Moreover, no candidate genes have been identified for the teratomas and yolk sac tumors of the infantile testis, as well as for spermatocytic seminomas.

Representative example of: actual G-banding and schematic of a normal chromosome

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -308- 12 (left within panel) and an isochromosome 12p (i(12p)) (right within panel); the fluorescent in situ hybridization pattern with a probe specific for the centromeric region of chromosome 12 (red) and the p-arm (green). Note the presence of three normal chromosomes 12 (paired green and red signal), and two isochromosomes (one red and two green signals).

Cytogenetics The isochromosome 12p can be identified on interphase nuclei by Molecular fluorescent in situ hybridization, using simultaneously a probe specific for the centromeric region and the short am of chromosome 12. The use of the centromeric probe only was not found to be informative. Genes involved and Proteins Note In spite of several suggestions about a possible role of a number of genes in the development of teratomas and yolk sac tumours of the infantile testis, the seminomas and nonseminomas and the spermatocytic seminomas, actual prove for their involvement is missing so far.

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A novel SMAD4 gene mutation in seminoma germ cell tumors. Bouras M, Tabone E, Bertholon J, Sommer P, Bouvier R, Droz JP , Benahmed M. Cancer Res 2000; 60: 922-8. Medline 10706106

Frequent p16INK4 (MTS1) gene inactivation in testicular germ cell tumors. Chaubert P, Guillou L, Kurt A-M, Bertholet M-M, Metthez G, Leisinger H-J, Bosman F , Shaw P. Am J Pathol 1997; 151: 859-865. Medline 9284835

No recurrent structural abnormalities in germ cell tumors of the adult testis apart from i(12p). Van Echten-Arends J, Oosterhuis JW, Looijenga LHJ, Wiersma J, Te Meerman G, Schraffordt Koops H, Sleijfer DT , De Jong B. Genes Chromosom Cancer 1995; 14: 133-144. Medline 8527395

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Atlas Genet Cytogenet Oncol Haematol 2001; 2 -318- Detection and analysis of origin of i(12p), a diagnostic marker of human male germ cell tumors by fluorescent in situ hybridization. Mukherjee AB, Murty VVVS, Rodriquez E, Reuter VE, Bosl GJ , Chaganti RSK. Genes Chromosom Cancer 1991; 3: 300-307. Medline 1683567

Overrepresentation of the short arm of chromosome 12 is related to invasive growth of human testicular seminomas and nonseminomas. Rosenberg C, Van Gurp RJHLM, Geelen E, Oosterhuis JW , Looijenga LHJ. Oncogene 2000; 19: 5858-5862. Medline 11127816

Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults. Mostert MC, Verkerk AJ, van de Pol M, Heighway J, Marynen P, Rosenberg C, van Kessel AG, van Echten J, de Jong B, Oosterhuis JW , Looijenga LH. Oncogene 1998; 16: 2617-27. Medline 9632138

Restricted 12p-amplification and RAS mutation in human germ cell tumors of the adult testis. Roelofs H, Mostert MC, pompe K, Zafarana G, Van Oosrschot M, Van Gurp RHJLM, Gillis AJM, Stoop H, Beverloo B, J.W. o, Bokemeyer C , Looijenga LHJ. Am J Pathol 2000; 157: 1155-1166. Medline 11021820

Origin and Biology of a Testicular Wilms' Tumor. Gillis AJM, Oosterhuis JW, Schipper MEI, Barten EJ, Van Berlo R, Van Gurp RJHLM, Abraham M, Saunders GF , Looijenga LHJ. Genes Chromosom Cancer 1994; 11: 126-135. Medline 7529549

Fluorescence in situ hybridization-based approaches for the detection of 12p- overrepresentation, in particular i(12p), in cell lines of human testicular germ cell tumors of adults. Mostert MC, Van de Pol M, Van Echten-Arends J, Olde Weghuis D, Geurts van Kessel A, Oosterhuis JW , Looijenga LHJ. Cancer Genet Cytogenet 1996; 87: 95-102. Medline 8625271

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 08- François Desangles, Philippe Camparo 1998

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -319- Updated 02- Leendert H.J. Looijenga 2001 Citation This paper should be referenced as such : Desangles F, Camparo P . Testis: Germ cell tumors. Atlas Genet Cytogenet Oncol Haematol. August 1998 . URL : http://AtlasGeneticsOncology.org/Tumors/malegermID5005.html Looijenga LHJ . Testis: Germ cell tumors. Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://AtlasGeneticsOncology.org/Tumors/malegermID5005.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -320- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Bruton's agammaglobulinemia Identity Other X-linked agammaglobulinemia (XLA) names Inheritance X-linked disorder occurring in males; frequency of XLA is about 0.3- 0.6/105. Clinics Phenotype immunological deficiency, first described in 1952, manifest from late and clinics infancy and typically resulting in frequent bacterial infections commencing in the second half of the first year of life: tonsils and lymph nodes are very small; marked decrease of serum immunoglobulins of all isotypes (maternal IgG gives some protection in early infancy) Neoplastic probably slight; in a 1963 paper, two patients with lymphoma were risk reported and reference was made to two adults with hypoglobulinemia who also had lymphomas; recent surveys of XLA patients do not reveal any cases of lymphoma; however, long-term vigilance needs to be maintained; at least seven cases of adenocarcinoma of the gastrointestinal tract in young adults with XLA have been reported; other malignancies have also been reported, but it is not clear whether they occur with an increased frequency Treatment vigorous antibiotic therapy and regular injections of immunoglobulin Prognosis good, on survival into early adulthood Other findings Note absence of plasma cells in bone marrow and lymph nodes (the latter lack germinal centres) resulting in an almost complete lack of humoral immunity due to a failure of early B-lymphocyte development; normal myeloid and T-cell function: extremely deficient production of antibodies to all antigens Genes involved and Proteins Gene BTK (Bruton's tyrosine kinase) Name Location Xq21.3-Xq22 DNA/RNA Description encoded in 19 exons spanning 37 kb Protein Description Btk is a 659 amino-acid cytoplasmic tyrosine kinase

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -321- Expression is expressed at all except the terminally differentiated plasma cell stage of B-cell development Function it is a member of a small family of src-related hematopoietic kinases and, like them, has several interaction domains that allow it to bind to other components of signal-transduction pathways; unlike other src family members, Btk family members have a pleckstrin homology (PH) domain which is followed by a proline rich region that binds to the SH3 region of several src family members Mutations Germinal over 300 different mutations in Btk have been identified; only about 50% of patients with the clinical and laboratory findings of XLA have a family history of immunodeficiency; most of the remaining patients are the first manifestation of a new mutation in Btk; most mutations are single base- pair substitutions that result in premature stop codons, splice defects, or amino-acid substitutions. 5-10% of patients with XLA have gross alterations in the BTK gene (usually deletions) detectable by Southern- blot analysis; most amino-acid substitutions in Btk render the protein unstable and markedly reduced or absent

External links OMIM 300310 Orphanet gammaglobulinemia X-linked Bibliography Agamaglobulinemia. Bruton OC. Pediatrics 1952; 9:722-728.

Occurrence of leukemia and lymphoma in patients with agammaglobulinemia. Page AR, Hansen AE, Good RA. Blood 1963; 21:197-206.

The immunological deficiency diseases of man: consideration of some questions asked by these patients with an attempt at classification. Good RA, Peterson RDA, Perey DY, Finstad J, Cooper MD. Birth Defects Original Article Series 1968; 4:17-39.

Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: A nationwide study of Btk deficiency in Japan. Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, Kobayashi S, Iwata T, Hayakawa H, Matsuoka H, Tsuge I, Yamadori T, Kunikata T, Arai S, Yoshizaki K, Taniguchi N, Kishimoto T. Blood 1996; 88:561-573.

Activation of BTK by a phosphorylation mechanism initiated by SRC family

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -322- kinases. Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP. Science 1996; 271: 822-825.

Symposium on gene abnormalities in medical diseases. 1. Immunological diseases: Bruton's agammglobulinemia. Tsukada S. Internal Medicine 1997; 36:148-150.

X-Linked agammaglobulinemia. Conley ME, Rohrer J, Minegishi Y. Clinical Reviews in Allergy and Immunology 2000; 19:183-204.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Niels B Atkin 2001 Citation This paper should be referenced as such : Atkin NB . Bruton's agammaglobulinemia. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/BrutonAgammaID10023.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -323- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Familial nervous system tumour syndromes Identity Inheritance eight genetic syndromes are associated with nervous system tumours; these are: Neufibromatosis 1 (NF1) Neufibromatosis 2 (NF2) Tuberous sclerosis Turcot syndrome Von Hippel-Lindau syndrome Li-Fraumeni syndrome Gorlin syndrome Cowden syndrome Clinics Neoplastic Neufibromatosis 1 (NF1): risk • Nervous System Tumors Neurofibromas, Astrocytomas, Optic nerve gliomas • Other tumors Pheochromocytoma , Osseous lesions, Iris hamartomas • Genes NF1 located in 17q11

Neufibromatosis 2 (NF2):

• Nervous System Tumors Schwanomas, Meningiomas, Spinal ependymomas, Astrocytomas • Other tumors Retinal hamartoma • Genes NF2 located in 22q12

Tuberous sclerosis:

• Nervous System Tumors Astrocytomas, Subependymal giant cell tumors • Other tumors Cutaneous angio-fibroma, Cardiac rhabdomyomas, Adenomatous polyps of duodenum, Renal hamartomatous tumors, Cysts of the lung and kidney.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -324- • Genes TSC1 and TSC2 located in 9q34 and 16p13 respectively

Turcot syndrome:

• Nervous System Tumors Medulloblastomas, Glioblastomas • Other tumors Colorectal polyps • Genes APC, hMLh1 and hPMS2 located in 5q21, 3p21, and 7p22 respectively

Von Hippel-Lindau syndrome:

• Nervous System Tumors Hemangioblastomas • Other tumors Retinal hemangioblastomas, Renal cell carcinoma, Pheochromocytoma • Genes VHL located in 3p25

Li-Fraumeni syndrome:

• Nervous System Tumors Astrocytomas, PNET • Other tumors Breast carcinoma, Bone and soft tissues sarcomas, Adenocortical carcinoma, leukaemia • Genes TP53 located in 17p13

Gorlin syndrome:

• Nervous System Tumors Medulloblastomas • Other tumors Multiple basal cell carcinomas, Ovarian fibromas. • Genes PTCH located in 9q31

Cowden syndrome:

• Nervous System Tumors Dysplastic gangliocytoma of the cerebellum • Other tumors Hamartomatous polyps of the colon, Thyroid neoplasms, Breast carcinoma • Genes PTEN located in 10q23

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Anne Marie Capodano 2001

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Citation This paper should be referenced as such : Capodano AM . Familial nervous system tumour syndromes. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/FamilNervousCanID10067.html

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Multiple Endocrine Neoplasia type 2 (MEN2) Identity Note Multiple Endocrine Neoplasia type 2 (MEN2) is defined by the association of C-cell tumors of the thyroid ( medullar thyroid carcinoma), tumors of the adrenal medulla ( pheochromocytoma) and parathyroid hyperplasia or adenoma in a single patient or in close relatives Other Sipple syndrome names Gorlin syndrome (not to be confused with the Gorlin-Goltz/naevoid basal

cell carcinoma syndrome Inheritance MEN2 is an autosomal dominant disorder with a high penetrance. Expressivity is variable but phenotype-genotype correlations have been described. Incidence is estimated at 0.1/105/year. It is generally assumed that 20 to 25% of medullar thyroid carcinomas (MTC) are heritabl Clinics Phenotype Three subtypes have been described: and clinics MEN2A (Sipple syndrome) is the most frequent form, characterized by MTC in 95% of cases, phaeochromocytoma in 50% and parathyroid hperplasia or adenoma in 25%. In familial MTC (FMTC), MTC is the only clinical manifestation. MEN2B (Gorlin syndrome) is the least frequent variant defined by predisposition to MTC and phaechromocytoma and marfanoid habitus, mucosal neuromas and ganglioneuromatosis of the gastrointestinal tract. C-cells secrete the hormon calcitonin which is a valuable marker for early diagnosis and for following the later course of the disease. There is no obvious syndrome of calcitonin overproduction. Pheochromocytoma secrete adrenaline and noradrenaline which are responsible of hypertension but could be undetected and lead to fatal hypertensive episodes. Parathyroid hyperplasia or adenoma lead to hyperparathyroidism; they are often clinically silent but could be revealed by symptomatic hypercalcemia or renal stones. Neoplastic MTC is a malignant tumor, metastasizing at first locally within the neck risk and then to distant sites. Usually pheochromocytoma is non malignant; parathyroid hyperplasia or adenoma are benign Treatment Total thyroidectomy with bilateral radical lymph node dissection is the

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -327- treatment of MTC. Thyroidectomy is recommended for carriers of mutations, in the first years of life in MEN2A and MEN2B families, as soon as elevation CT during pentagastrin test in FMTC families. Pheochromocytoma, hyperplasic parathyroid or adenoma should be surgically removed. Prognosis Pheochromocytoma could be letal by hypertension episodes but prognosis is essentially dependant from MTC. Genes involved and Proteins

Gene RET Name Location 10q11.2 DNA/RNA Description 21 exons; genomic sequence of 55kb Protein Description Three main 3' alternatively spliced forms of 1072 to 1114 aminoacids. There is a cleavable signal sequence of 28 aminoacids, a glycosylated extracellular domain formed of a region of cadherin homology and another cystein-rich region, a transmembrane domain and an intracellular tyrosine kinase domain. Expression RET is expressed predominantly in the developing central and peripheral nervous system, the excretory system and the migratory neural-crest cells during embryogenesis. Function Receptor tyrosine kinase Mutations Germinal In MEN2A and FMTC, mutations are located in the sequence encoding the juxtamembrane cystein-rich domain and involved aminoacids C609, C611, C618, C620, C630, D631 and C634. Most of these mutations result in the substitution of the cystein for a different amino acid. MEN2A is predominantly associated with a mutation of C634, highly predictive for the development of pheochromocytoma and hyperparathyroidism. Until today three duplications in the cystein-rich domain have been published. MEN2B is caused by germline mutations of the tyrosin kinase domain: substitution M918T in more than 95% of cases, A883F in less than 4% of those. Rare mutations at aminoacids 912, 922 and an association of V804M/Y806C have been described. Other mutations of the tyrosin kinase domain have been identified in FMTC families and unusually in MEN2A patients: E768D, L790F, Y791F, V804M, V804L and S891A. Some families with MEN2 and Hirschsprung disease have been described: each of them has a mutation in either C618 or C620. Families with Hirschsprung disease alone have mutations overspread in all the coding region of RET.

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External links OMIM 164761 Orphanet Multiple endocrine neoplasia type 2 HGMD 120346 Other NEM2 - SFE database

Bibliography Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma treatment implications. Block MA, Jackson CE et al. Arch Surg 1980; 115: 142-148.

Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Simpson NE, Kidd KK et al. Nature 1987; 328: 528-530.

Germ-line mutations of the RET proto-oncogene in Multiple Endocrine Neoplasia type 2A. Mulligan LM, Kwok JBJ et al. Nature 1993; 363: 458-460.

A mutation in the RET proto-oncogene associated with multiple endocirne neoplasia type 2B and sporadic medullary thyroid carcinoma. Hofstra RMW, Landsvater RM et al. Nature; 1994; 367: 375-376.

One gene-four syndromes. Van Heyningen V. Nature 1994; 367: 319-320.

RET proto-oncogene mutations in French MEN 2A and FMTC families. Schuffenecker I, Billaud M et al. Hum Mol Genet 1994; 3; nƒ11: 1939-1943.

The c-RET receptor tyrosine kinase gene is required for the development of the kidney and the enteric nervous system. Schuchardt A, D'Agati V et al. Nature 1994; 367: 380-383.

Genetic aspects of multiple endocrine neoplasia. Schimke RN.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -329- Annu Rev Med 1994; 35:25-31.

Germ-line mutations of MEN2A and MEN2B activate RET as dominant transforming gene by different molecular mechanisms. Santoro M, Carlomagno F et al. Science 1995; 267: 381-383.

Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations. Pacini F, Romei C et al. Surgery 1995 Dec;118(6):1031-5.

The relation ship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET Mutation Consortium. Eng C, Clayton D et al. J Am Med Assoc 1996; 276: 1575-1579.

Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumors and Hirschsprung disease. Eng C and Mulligan LM. Hum Mut 1997; 9: 97-109.

Biological properties of RET with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma and Hirschsprung's disease phenotype. Ito S, Iwashita T et al. Cancer Res 1997; 57: 2870-2872.

Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation. Michiels FM, Chappuis S et al. Proc Natl Acad Sci U S A 1997; 94: 3330-5.

A duplication of 9 base pairs in the critical cystein rich domain of the RET proto-oncogen causes multiple endocrine neoplasia type 2A. Hoppner W, Dralle H et al. Hum Mut 1998; 1: 128-130.

Mechanisms of development of multiple endocrine neoplasia type 2 and Hirschsprung's disease by ret mutations. Takahashi M, Asai N et al. Cancer Res 1998; 154: 229-36.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -330- Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma in gene carriers of MEN2 syndrome. Lallier M, St-Vil D et al. J Pediatr Surg 1998 Jun; 33(6): 846-8.

A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. Pigny P et al. J Clin Endocrinol Metab 1999; 84: 1700-1704.

The phenotypes associated with RET mutations in the multiple endocrine neoplasia type 2 syndromes. Ponder BA. Cancer Res 1999; 59: 1736-1742.

Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function? Takahashi M, Iwashita T et al. Hum Mutat 1999;13(4): 331-6.

Le cancer mÈdullaire de la thyroÔde Murat A et Niccoli-Sire P. Mt endocrinologie 2000, 2 (5): 430-437.

A two-hit model for development of Multiple Endocrine Neoplasia type 2B by RET mutations. Iwashita T, Murakami H et al. BBRC 2000; 268: 804-808.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 01- Sophie Giraud 2001 Citation This paper should be referenced as such : Giraud S . Multiple Endocrine Neoplasia type 2 (MEN2). Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/MEN2ID10009.html

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Von Hippel-Lindau (updated: old version not available) Identity Note Von Hippel-Lindau (VHL) disease is a hereditary devastating cancer syndrome, predisposing to the development of various benign and malignant tumours (Central Nervous System [CNS] and retinal hemangioblastomas, endolymphatic sac tumours, renal cell carcinoma (RCC) and/or renal cysts, pheochromocytomas, pancreatic cysts and neuroendocrine tumours, endolymphatic sac tumours, epididymal and broad ligament cystadenomas). VHL disease is the first cause of hereditary kidney cancer Inheritance an autosomal dominant disorder with high penetrance (increasing with age: 97% by age 60 yrs) but variable expressivity (with phenotype/genotype correlations); frequency is estimated at about 2.5/105; neomutations represent about 20% of cases. Clinics Phenotype onset of the disease usually occurs between 18 and 30 yrs, often with and clinics retinal or cerebellar hemangioblastomas, but can also manifests in children, especially by retinal hemangioblastomas and pheochromocytoma. Central nervous system (CNS) hemangioblastomas occur in 60-80% of patients (infratentorial localisation in 60 % of cases, intraspinal in 30- 40%; supratentorial in 1%). Multiple tumours are frequent (hemangioblastomatosis). Retinal hemangioblastomas, often multiple and bilateral, occur in about 50% of patients. Most retinal hemangioblastomas occur peripherally but optic disc (papillary or juxtapapillary) locations are encountered in almost 15% of cases. Renal cell carcinomas occur in up to 75% of cases. They are mostly multifocal and bilateral. Tumors have a classical solid or a more specific mixed cystic/solid appearance and are always of clear cell subtype. Multiple benign cysts are also observed. Pheochromocytomas, often bilateral, are mostly found in a subset of families, where it can be the only sign of VHL. Extraadrenal paragangliomas are sometimes encountered. Pancreas manifestations occur in up to 77% of patients: isolated or multiple cysts and serous cystadenomas are the most frequent lesions, neuroendocrine tumours occur in about 10-15 % of cases. Endolymphatic sac tumours, only recently recognised as a manifestation of VHL disease, occur in up to 11% of cases. Epididymal cysts, often bilateral, occur in about 54% of men.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -332- Cystadenomas of the broad ligament ("adnexal papillary tumour of probable mesonephric origin") are extremely rare but highly specific. There are two main clinical types of VHL according to the absence (type 1) or presence of pheochromocytoma (type 2). The type 2 is subdivised in three subtypes, 2A (with low risk of renal cancer and pancreatic tumors); 2B (the full multi-tissues subtype), and 2C (pheochromocytomas only, recently individualised by molecular genetics). Neoplastic Central nervous system (CNS) hemangioblastomas may cause life- risk threatening complications in spite of their benign nature and classic slow-growing course and remain a major cause of morbidity and mortality in VHL disease. Retinal hemangioblastomas may cause retinal detachment, haemorrhage, glaucoma and cataract, leading to blindness, in absence of early detection and treatment. Renal cell carcinomas is becoming the main cause of death in the disease, because of secondary dissemination mainly due to delay in diagnosis. Pheochromocytomas are malignant in about 5-10% of cases. Neuroendocrine pancreatic tumours tend to be slow growing but have the potential of a truly malignant course with locoregional dissemination. Endolymphatic sac tumours is a low grade papillary adenocarcinoma resulting in progressive hearing loss. It can grow to the pontocerebelline angle and/or the middle ear, then destroying the temporal bone. Epididymal cysts and cystadenomas of the broad ligament are benign tumors. Treatment Regular clinical follow-up of patients and gene-carriers is imperative in order to detect manifestations early and to avoid complications; Treatment of symptomatic CNS hemangioblastoma remains mainly neurosurgical, often in emergency, but stereotactic radiosurgery is emerging as an alternative therapeutic procedure in patients with multifocal solid hemangioblastomas. Retinal hemangioblastoma are treated by cryotherapy or laser depending on the location, size and number of tumours. Endolymphatic sac tumours require surgical treatment with the help of ENT specialists as soon as possible in order to prevent definitive hearing loss. Preoperative embolisation is sometimes performed to avoid bleeding. Renal cell carcinomas have to be treated when their size is about 3 cm in diameter. Nephron sparing surgery is the choice method and may delay bilateral nephrectomy and dialysis. When binephrectomy is inevitable, renal transplantation can be discussed after a 2 year period without metastasis Pheochromocytomas have to be surgically removed, preferentially with the use of laparoscopy. When possible, partial adrenalectomy appears to be a safe method of preserving adrenocortical function and quality of life. Pancreatic neuroendocrine tumours require surgical removal at a 2-3

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -333- cm size in order to avoid metastatic dissemination. Pancreatic cysts and serous cystadenomas do not require resection but sometimes a percutaneous drainage or endoscopic implantation of a biliary stent is indicated in cases of compression. Surgery is indicated for broad ligament cystadenomas and for symptomatic epididymal cystadenomas. Medical perspectives: several clinical studies are on-going with specific drugs that block VEGF in the hope of causing stabilisation or recession of CNS and retinal hemangioblastomas. Such clinical trials are in processing in France, England and Poland. Prognosis according to the severity of the disease in a given patient, and to the quality of a regular follow up. Mean age at death is about 50 yrs and renal cell carcinomas and CNS hemangioblastomas are the major causes of death. As treatment of VHL manifestations in first stages will improve significantly the clinical outcome and the quality of life of patients, early and unambiguous diagnosis is mandatory. Thus, DNA testing is emerging as a major progress in this consideration, pawing the way to an effective presymptomatic diagnosis. Genes involved and Proteins

Gene VHL Name Location 3p25-26 DNA/RNA Description 3 exons Protein

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -334-

Functional domains of pVHL and distribution of germline point mutations.

Description 213 amino acids Expression wide Function tumour-suppressor gene. pVHL interacts with elongins B and C and cullin 2 through a complex exhibiting ubiquitine ligase activity. Its main function is to negatively regulate VEGF mRNAs (and angiogenesis as a result) by targeting hypoxia inducible transcription factors HIF for degradation by the proteasome. pVHL has also major functions in extra cellular matrix formation and cell cycle control. Mutations Germinal causes VHL disease. more than 400 mutations have been identified, comprising for more than 150 independent intragenic mutational events; virtually 100% of mutations are detectable. The majority of mutations are represented by point mutations including missense, nonsense mutations, splicing, microinsertions or microdeletions. In about 25 % of cases, a large deletion of the VHL gene is observed. Mutations resulting in a truncated protein are mostly associated with type 1 VHL. In type 2, mutations are generally missense mutations affecting preferentially the critical contact region between pVHL and elongin C (residues 157-171) with an hot-spot at codon 167. In type 2A there is a founder effect for a specific missense mutation at codon 98. In type 2C, mutations occur in regions potentially involved in critical function exclusive to the adrenals (as codon 188). Last, patients with

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -335- identical VHL germline mutations may display different phenotypes, indicating that the issue of genotype-phenotype correlations is complex in VHL. Evidence was recently provided that unknown modifier genes and environmental influences could play an additional role in the clinical expression of the disease. Somatic Somatic VHL gene inactivation is frequent in sporadic hemangioblastomas and moreover in sporadic renal cell carcinoma, representing a significant event in the development of these tumors. Different mutational mechanisms lead to the inactivation of the VHL gene including loss of heterozygosity, small intragenic mutations or hypermethylation of the promoter.

External links GeneCards VHL GDB VHL OMIM 193300 Orphanet Von Hippel-Lindau disease HGMD 120488 Other VHL mutation database database

Association VHL Famimy Alliance

Bibliography Von Hippel-Lindau disease affecting 43 members of a single kindred Lamiell JM, Salazar FG, Hsia YE Medicine 1989; 68: 1-29.

Clinical features and natural history of Von Hippel-Lindau disease Maher ER, Yates JRW, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA Q J Med 1990; 77: 1151-1156.

Identification of the von Hippel-Lindau disease tumor suppressor gene Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng Y, Duan DR, Dean A, Glavac D, Richards FM, Crossey P.A, Ferguson- Smith MA, Le Paslier D, Chumakov I, Cohen D, Chinault CA, Maher E.R, Linehan WM, Zbar B Science 1993; 260: 1317-132

Identification of the von Hippel-Lindau (VHL) gene. Its role in renal cancer Linehan W.M.. Lerman M.I.. Zbar B. JAMA 1995 : 273: 564-70.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -336- Medline 95139199 von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany : Evidence for a founder effect. Brauch H, Kishida T, Glavac D, Chen F, Pausch F, Höfler H, Latif F, Lerman M, Zbar B, Neumann HPH : Hum Genet 1995 : 95 : 551-556. Medline 95278911

Von Hippel-Lindau syndrome (REVIEW) Neumann HP, Lips CJ, Hsia YE, Zbar B Brain Pathol 1995; 5: 181-193.

A genetic register for von Hippel-Lindau disease Maddock IR, Moran A, Maher ER, Teare MD, Norman A, Payne SJ, Whitehouse R, Dodd C, Lavin M, Hartley N, Super M, Evans DG J Med Genet 1996; 33: 120-127.

Renal involvement in von Hippel-Lindau disease Chauveau D, Duvic C, Chrétien Y, Paraf F, Droz D, Melki P, Hélénon O, Richard S, Grünfeld JP Kidney Int.1996; 50: 944-951.

Germline mutations in the von Hippel Lindau (VHL) gene in families from North America. Europe and Japan. Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CH, Lerman M, et al Hum Mutation 1996 : 8 : 348-57. Medline 97114291

The Von Hippel-Lindau tumor suppressor gene. (REVIEW) Decker H.J, Weidt E. J.,. Bieger J. Cancer Genet, Cytogenet 1997 : 93 : 74-83. Medline 97216326 von Hippel-Lindau disease (REVIEW) Maher ER, Kaelin WG Jr Medicine 1997; 76: 381-391.

Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Prowse AH, Webster AR, Richards FM, Richard S, Olschwang S, Resche F, Affara NA, Maher ER Am J Hum Genet 1997; 60: 765. Medline 9106522

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Epididymal cystadenomas in von Hippel-Lindau disease Choyke PL, Glenn GM, Wagner JP, Lubensky IA, Thakore K, Zbar B, Linehan WM, Walther MM Urology 1997; 49: 926-931.

Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel- Lindau disease Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, Lebovics R, Sledjeski K, Choyke PL, Zbar B, Linehan WM, Oldfield EH JAMA 1997; 277: 1461-1466.

Prevalence, morphology and biology of renal cell carcinoma in von Hippel- Lindau disease compared to sporadic renal cell carcinoma. Neumann HP, Bender BU, Berger DP, Laubenberger J, Schultze-Seemann W, Wetterauer U, Ferstl FJ, Herbst EW, Schwarzkopf G, Hes FJ, Lips CJ, Lamiell JM, Masek O, Riegler P, Mueller B, Glavac D, Brauch H J Urol 1998; 160:1248-1254.

Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene Stolle C, Glenn G, Zbar B, Humphrey JS, Choyke P, Walther M, Pack S, Hurley K, Andrey C, Klausner R, Linehan WM Hum Mutat 1998; 12: 417-423

The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal Pause A, Lee S, Lonergan KM, Klausner RD Proc Natl Acad Sci USA 1998; 95: 993-998.

Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma Olschwang S, Richard S, Boisson C, Giraud S, Laurent-Puig P, Resche F, Thomas G Hum Mutat 1998; 12: 424-340.

An analysis of phenotypic variation in the familial cancer syndrome von Hippel- Lindau disease: evidence for modifier effects. Webster AR, Richards FM, MacRonald FE, Moore AT, Maher ER Am J Hum Genet 1998; 63: 1025-1035.

The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, Gavin BJ, Kley N, Kaelin WG Jr, Iliopoulos O Mol Cell 1998; 1: 959-968.

Software and database for the analysis of mutations in the VHL gene

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -338- Béroud C, Joly D, Gallou C, Staroz F, Orfanelli MT, Junien C Nucleic Acids Res 1998; 26: 256-258.

The VHL tumour-suppressor gene paradigm (REVIEW) Kaelin WG Jr, Maher ER Trends Genet 1998; 14: 423-426

La maladie de von Hippel-Lindau: une maladie à impact tissulaire multiple (REVIEW) Richard S, Giraud S, Hammel P, Béroud C, Joly D, Olschwang S, Resche F.E Medline Presse

Management of renal cell carcinoma in von Hippel-Lindau disease Hes FJ, Slootweg PJ, van Vroonhoven TJ, Hene RJ, Feldberg MA, Zewald RA, Ploos van Amstel JK, Hoppener JW, Pearson PL, Lips CJ Eur J Clin Invest 1999; 29: 68-75.

Expression of von Hippel-Lindau protein in normal and pathological human tissues Sakashita N, Takeya M, Kishida T, Stackhouse TM, Zbar B, Takahashi K Histochem J 1999; 31: 133-144.

Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC Gallou C, Joly D, Méjean A, Staroz F, Martin N, Tarlet G, Orfanelli MT, Bouvier R, Droz D, Chrétien Y, Maréchal JM, Richard S, Junien C, Béroud C Hum Mutat 1999; 13: 464-475

Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery Walther MM, Choyke PL, Glenn G, Lyne JC, Rayford W, Venzon D, Linehan WM J Urol 1999; 161: 1475-1479

Management of hereditary pheochromocytoma in von Hippel-Lindau kindreds with partial adrenalectomy Walther MM, Keiser HR, Choyke PL, Rayford W, Lyne JC, Linehan WM J Urol 1999; 161: 395-398.

The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system Glasker S, Bender BU, Apel TW, Natt E, van Velthoven V, Scheremet R, Zentner J, Neumann HP J Neurol Neurosurg Psychiatry 1999; 67: 758-762.

Clinical and genetic characterization of pheochromocytoma in von Hippel- Lindau families: comparison with sporadic pheochromocytoma gives insight

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -339- into natural history of pheochromocytoma Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, Gnarra JR, Reynolds JC, Glenn GM, Zbar B, Linehan WM J Urol 1999; 162: 659-664

Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation Webster AR, Maher ER, Moore AT Arch Ophthalmol 1999; 117: 371-378.

Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function Stebbins CE, Kaelin WG Jr, Pavletich NP Science 1999; 284: 455-461.

Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization Pack SD, Zbar B, Pak E, Ault DO, Humphrey JS, Pham T, Hurley K, Weil RJ, Park WS, Kuzmin I, Stolle C, Glenn G, Liotta LA, Lerman MI, Klausner RD, Linehan WM, Zhuang Z Cancer Res 1999; 59: 5560-5564.

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ Nature 1999; 399: 271-275.

The von Hippel-Lindau tumour suppressor protein: new perspectives. (REVIEW) Ohh M, Kaelin WG Jr Mol Med Today 1999; 5: 257-263.

Third International Meeting on von Hippel-Lindau disease (REVIEW) Zbar B, Kaelin W, Maher E, Richard S Cancer Res 1999; 59: 2251-2253.

Von Hippel-Lindau syndrome : a pleomorphic condition.(REVIEW) Friedrich CA Cancer 1999 ; 86 (Suppl): 24787-2482.

Von Hippel-Lindau syndrome: target for anti-vascular endothelial growth factor (VEGF) receptor therapy. Harris A Oncologist 2000 ; 5(S1) : 32-36.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -340- Opinion of patients with VHL disease towards presymptomatic genetic testing for their children and prenatal diagnosis Lévy M, Richard S J Med Genet 2000; 37: 476-478.

Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents Sgambatti MT, Stolle C, Choyke PL, Wakther MM, Zbar B, Linehan WM, Glenn GM Am J Hum Genet 2000; 66: 84-91.

Pancreatic involvement in von Hippel-Lindau's disease: prevalence, course and impact in the management of patients Hammel P, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Corréas JM, Chauveau D, Balian A, Beigelman C, O'Tolle P, Bernades Ruszniewski P, Richard S Gastroenterology 2000; 119: 1087-1095.

Central nervous system hemangioblastomas, endolymphatic sac tumors and von Hippel-Lindau disease Richard S, David Ph, Marsot-Dupuch K, Béroud C, Giraud S, Resche F Neurosurg Rev 2000; 23: 1-22.

Comparative sequence analysis of the VHL tumor suppressor gene Woodward E, Buchberger A, Clifford SC, Hurst LD, Affara NA, Maher ER Genomics 2000 ; 65 : 253-265.

Mechanism of regulation of the hypoxia-inducible factor by the von Hippel- Lindau tumor suppressor protein. Tanimoto K, Makino Y, Pereira T, Poellinger L EMBO J 2000 ; 19 : 4298-4309.

Von Hippel-Lindau disease (REVIEW) Couch V, Lindor NM, Karnes PS, Michels VV. Mayo Clin Proc 2000 ; 75 : 265-272.

REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 04- Anne Marie Capodano 1998 Updated 01- Stéphane Richard 2001 Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -341- Capodano AM . Von Hippel-Lindau. Atlas Genet Cytogenet Oncol Haematol. April 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/VHLKpr10010.html Richard S . Von Hippel-Lindau. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/VHLKpr10010.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -342- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Neurofibromatosis type 2 (NF2) (updated: old version not available) Identity Other Central neurofibromatosis names Bilateral acoustic neurofibromatosis Bilateral acoustic neurinoma Bilateral acoustic schwannomas Inheritance autosomal dominant with almost complete penetrance; frequency is 3/105 newborns; neomutation represent 50% of cases; variable expressivity from mild disease through life (Gardner type) to severe condition at young age (Wishart type: with more than 3 tumours) Clinics Note NF2 is an hamartoneoplastic syndrome; hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia Phenotype bilateral vestibular (8th cranial pair) schwannomas; other central or and clinics peripheral nerve schwannomas; meningiomas; ependymomas. hearing loss (average age 20 yrs), tinnitus, imbalance, headache, cataract in 50%, facial paralysis. café-au-lait spots and cutaneous and peripheral neurofibromas may be present, but far less extensively than in neurofibromatosis type 1 Neoplastic NF2 cases represent about 5 % of schwannomas and meningiomas (i.e. risk risk increased by 2000), appearing at the age of 20, while they are found in the general population at the age of 50 and over Prognosis these tumours are usually benign, but their location within the central nervous system gives them a grave prognosis; patients with the Wishart severe form usually do not survive past 50 yrs Cytogenetics Inborn normal conditions Cytogenetics chromosome 22 loss is very frequent both in sporadic and in NF2 of cancer schwannomas and meningiomas Genes involved and Proteins

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -343- Gene NF2 (neurofibromatosis 2) Name Location 22q12 DNA/RNA Description 17 exons (1-15, 17 constitutive, 16 alternatively spliced) Protein Description Isoform 1 595 amino acids, isoform 2 590 amino acids (due to inclusion of exon 16 in transcript); contains a FERM domain and a large a helix domain Expression wide Function membrane-cytoskeleton anchor; tumour suppressor Homology band 4.1 family , ezrin, radixin, moesin Mutations Germinal germ-line mutations in NF2 patients lead to protein truncation; splice- site or missense mutations are also found; phenotype-genotype correlations are observed (i.e. that severe phenotype are found in cases with protein truncations rather than those with amino acid substitution) Somatic mutation and allele loss events in tumours in neurofibromatosis type 2 and in sporadic schwannomas and meningiomas are in accordance with the two-hit model for neoplasia

External links GeneCards NF2 GDB NF2 OMIM 101000 Orphanet Neurofibromatosis 2 HGMD 120232 Other Neurofibromatosis Type 2 - GeneClinics database

Bibliography Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B, et al Nature 1993 Jun 10;363(6429):515-21 Medline 93281181

A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, et al

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -344- Cell 1993 Mar 12;72(5):791-800 Medline 8453669

Diagnostic issues in a family with late onset type 2 neurofibromatosis. Evans DG, Bourn D, Wallace A, Ramsden RT, Mitchell JD, Strachan T J Med Genet 1995 Jun;32(6):470-4 Medline 95395825

Merlin: the neurofibromatosis 2 tumor suppressor.(REVIEW) Gusella JF, Ramesh V, MacCollin M, Jacoby LB Biochim Biophys Acta 1999 Mar 25;1423(2):M29-36 Medline 10214350

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -345- Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M, Abramowski V, Goutebroze L, Woodruff JM, Berns A, Thomas G. Genes Dev 2000 Jul 1;14(13):1617-30 Medline 10887156

Advances in Neurofibromatosis 2 (NF2): A Workshop Report .(REVIEW) Lim DJ, Rubenstein AE, Evans DG, Jacks T, Seizinger BG, Baser ME, Beebe D, Brackmann DE, Chiocca EA, Fehon RG, Giovannini M, Glazer R, Gusella JF, Gutmann DH, Korf B, Lieberman F, Martuza R, McClatchey AI, Parry DM, Pulst SM, Ramesh V, Ramsey WJ, Ratner N, Rutkowski JL, Ruttledge M, Weinstein DE. J Neurogenet. 2000 Jun;14(2):63-106. Medline 10992163 REVIEW articles automatic search in PubMed Last year automatic search in PubMed publications Contributor(s) Written 09- Jean-Loup Huret 1997 Updated 03- Jean-Loup Huret 1998 Updated 02- James F Gusella 2001 Citation This paper should be referenced as such : Huret JL . Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol. September 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/NF2Kpr10007.html Huret JL . Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol. March 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/NF2Kpr10007.html Gusella JF . Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/NF2Kpr10007.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -346- Atlas of Genetics and Cytogenetics in Oncology and Haematology

Nucleotide excision repair

Leon H.F. Mullenders (1), Anne Stary (2) and Alain Sarasin (2) 1) Department.of Radiation Genetics and Chemical Mutagenesis, -MGC Leiden University Medical Center, P.O.Box 9503, 2300 RA Leiden and J.A. Cohen Institute, Interuniversity Research Institute for Radiopathology and Radiation Protection, Leiden, The Netherlands 2) Laboratory of Genetic Instability and Cancer, UPR 2169, CNRS, BP 8, 94801 Ð Villejuif, France. February 2001

All living organisms are equipped with DNA repair systems that can cope with a wide variety of DNA lesions. Among these repair pathways, nucleotide excision repair (NER) is a versatile repair pathway, involved in the removal of a variety of bulky DNA lesions such as UV induced cyclobutane pyrimidine dimers (CPD) and pyrimidine 6-4 pyrimidone photoproducts (6-4PP). NER is a complex process in which basically the following steps can be distinguished:

• (i) recognition of a DNA lesion; • (ii) separation of the double helix at the DNA lesion site; • (iii) single strand incision at both sides of the lesion; • (iv) excision of the lesion-containing single stranded DNA fragment; • (v) DNA repair synthesis to replace the gap and • (vi) ligation of the remaining single stranded nick.

The importance of NER for human health is illustrated by the occurrence of rare autosomal recessive disorder xeroderma pigmentosum (XP). Patients characteristically show severe photosensitivity and abnormal pigmentation, often accompanied by mental retardation, and they usually develop skin cancer at very young age (Bootsma et al., 1998) . Cells from these patients are also extremely sensitive to UV light and have a defect in NER. Complementation studies revealed that eight genes are involved in XP: XPA through XPG and XPV (XP-Variant). Mutations in the XP genes (except XP-variant) lead to defective NER and hypersensitivity to UV. The XP variant cells are proficient in NER but deficient in lesion bypass when the replication fork encountered a bulky adduct. Normally, the translesion synthesis is carried out by the polymerase eta, which is mutated in the XP variant. XP-V patients are more UV-sensitive than normal individuals but less than classical XP. They develop skin cancers around the age of 20-30 and exhibit less neurological abnormalities. In addition to XP, other UV sensitive syndromes exist. Cockayne' syndrome (CS) is a rare disorder that is associated with a wide variety of clinical symptoms. Beside other symptoms, the patients generally show dwarfism, mental retardation and photosensitivity. In contrast to XP, CS is not associated with an enhanced incidence

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -347- of skin cancer. Cells from CS patients are hypersensitive to the cytotoxic effects of UV and are characterized by the inability to resume UV inhibited DNA and RNA synthesis. Two CS complementation groups (A and B) have been established. A third group encompasses patients exhibiting both XP and CS symptoms, they belong to XP groups B, D or G. The progressive neurological abnormalities associated with CS may be due to the inability of CS cells to repair oxidatice DNA lesions (LePage et al., 2000). PIBIDS is a photosensitive variant of Trichothiodystrophy (TTD) and the third syndrome that can be associated with NER defects (PIBIDS is the acronym of the characteristic clinical symptoms of the patients for Photosensitivity, Ichthyosis, Brittle hair, Impaired intelligence, Decreased fertility and Short stature) (Itin et al., 2000). Certain mutations in the XPB and XPD genes have been shown to cause the PIBIDS phenotype, but not in combination with the specific XP characteristics like cancer proneness. Name when Usual Other Alias Location Disease cloned Name XPA XPA XPAC 9q22.3 Ð 9q22.3 XP ERCC3 XPB XPBC 2q21 Ð 2q 21 XP ;CS; TTD XPC XPC XPCC 3p25.1 Ð 3p25.1 XP XP; XP/ CS; ERCC2 XPD XPDC 19q13.2 - 19q13.3 TTD XPEC p48 = 11p12 - p11 p48; p125 XPE DDB1, p125 =11q12 - XP DDB2 q13 ERCC4 XPF XPFC 19q13.3 - 19q13.3 XP ERCC5 XPG XPGC 13q32 Ð 13q 32 XP; XP/ CS (5pter Ð 5 qter) ERCC8 CSA CS unapprouved ERCC6 CSB 10q11 Ð 10 q 21 CS Pol eta XPV 6p21.1 Ð 6p12 XP variant It has been shown that NER can operate via two subpathways. The first pathway is global genome repair (GGR) and involves repair activity that acts on DNA lesions across the genome. Although the efficiency of this pathway can be influenced by various parameters, it is not actively targeted to specific regions of the genome. A second NER pathway is coupled to active transcription and is called transcription coupled repair. This pathway involves repair activity that is directed to the transcribed strand of active genes. The cloning of the XP genes and the isolation of the encoded proteins has lead to the elucidation of the core NER reactions and ultimately to the reconstitution of the process in vitro (Aboussekhra et al., 1995 ; Mu et al., 1995). NER proteins and their functions DNA damage recognition. Two proteins have been identified and implicated in (one of) the first steps of NER, i.e. the recognition of lesions in the DNA: the XPA gene product and the XPC gene product in complex with HR23B. In addition, the XPE protein has been shown to have a high affinity for damaged DNA, but whether it is required for the damage recognition step of NER remains unclear. Cells from XPA

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -348- patients are extremely sensitive to UV and have very low nucleotide excision repair activity. In vitro the XPA protein binds preferentially to damaged DNA compared to nondamaged DNA. The XPA protein binds to replication protein A (RPA) which enhances the affinity of XPA for damaged DNA and is essential for NER. The other complex that has been implicated in DNA damage recognition is XPC-HR23B. XPC cells have low NER repair capacity, but the residual repair has been shown to occur specifically in transcribed genes. It is very likely that the XPC-HR23B complex is the principal damage recognition complex i.e. essential for the recognition of DNA lesions in the genome (Sugasawa et al, 1998). Binding of XPC-HR23B to a DNA lesion causes local unwinding, so that the XPA protein can bind and the whole repair machinery can be loaded onto the damaged site. This would imply that the XPA protein has binding affinity for other repair proteins. Indeed, the XPA protein has been shown to bind to ERCC1 and TFIIH. The XPC-HR23B complex is only required for global genome repair. In case of transcription coupled repair when an RNA polymerase is stalled at a lesion, the DNA is unwound by the transcription complex and XPA can bind independently of XPC- HR23B complex. XPE patients show mild dermatological symptoms and cells from these patients have a relatively high repair capacity. The function of the gene product is not completely clarified yet. Band shift assays suggested that the XPE gene product acts as a damaged DNA binding protein (DDB), with high affinity to UV-induced 6-4PP. However, defective DDB binding activity is not a common feature of XPE mutant cell lines and in fact two (or even more) proteins may be involved in the binding activity: p48 and p125. In cells from several XPE patient mutations in p48 have been found but so far no mutations have been found in the p125 gene. XPE cells are not necessarily defective in repair: p125 is proposed to play a role in opening up chromatin to make CPD accessible to the NER machinery, but is not required for repair of 6-4PP. Interestingly, cell lines and primary tissues from rodents are fully deficient in the expression of the p48 protein (Tang et al., 2000). This explains the absence of GGR of CPD in these cells. Exogenous expression of p48 in hamster cells confers enhanced removal of CPD from genomic DNA and nontranscribed strand of active genes. Damage demarcation. The striking discovery that subunits of basal transcription factor TFIIH were involved in NER sheds light on a new aspect of NER : a close coupling to transcription via common use of essential factors. Two repair proteins, encoded by XPB and XPD genes, appeared to be identical to components of the basal transcription factor TFIIH, a large complex involved in the initiation of transcription.The XPB and XPD proteins displayed 3'-5' and 5'-3' helicase activity respectively (Schaeffer et al., 1994). TFIIH fulfills a dual role in transcription initiation and NER and the role of TFIIH in NER might closely mimic its role in the transcription initiation process. In transcription initiation TFIIH is thought to be involved in unwinding of the promoter site and to allow promoter clearance. In the NER process TFIIH causes unwinding of the damage containing region that has been localized by XPC-HR23B and XPA-RPA, enabling the accumulation of NER proteins around the damaged site. Among the XP patients, XPB patients are extremely rare (only 3 patients known in the world) due to the fact that the XPB gene product is essential for transcription initiation and in all cases, these patients show the double symptoms of XP and CS. The helicase activity of XPD is indispensable for NER but not for transcription initiation. So , there is much more XPD patients, and only two patients have been described as XP and CS.

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -349- Incision. The XPF protein and the ERCC1 protein form a complex that exhibits structure specific endonuclease activity that is responsible for the 5' incision during the NER reaction. XPF-ERCC1 also binds to XPA (through ERCC1) and to RPA (through XPF) but not preferentially to damaged DNA. The XPG protein has DNA endonuclease activity without preference for damaged DNA and is responsible for the 3' incision made during NER. At the site of a lesion NER proteins create a DNA bubble structure over a length of approximately 25 nucleotides and the XPG protein incises the damaged DNA strand 0-2 nucleotides 3' to the ssDNA-dsDNA junction. In most studies the 3'-incision made by the XPG protein appeared to be made prior to and independently of the 5'-incision by XPF-ERCC1. Patients belonging to the XP-G complementation group clinically exhibit heterogeneous symptoms, from mild to very severe, sometimes associated with CS. XP-G cells are almost completely repair- deficient and as UV-sensitive as XP-A cells. About half of the described XPG patients exhibit also CS symptoms. In contrast to XPG, XP-F patients have a relatively mild XP phenotype without neurological abnormalities. Cells from XP-F patients are slightly UV-sensitive and exhibit low levels of repair initially after UV-irradiation. Repair patch synthesis and ligation. Proliferating Cell Nuclear Antigen (PCNA) is required for DNA synthesis by DNA polymerases delta and epsilon. PCNA has also been shown to be required for NER in vitro i.e. for the DNA resynthesis step, suggesting that DNA polymerase delta or epsilon is involved in NER. Biochemical analysis and fluorescence microscopy revealed that in quiescent cells upon UV- irradiation PCNA (that usually resides in the cytoplasm) becomes rapidly bound to chromatin. The enzymes involved in these pathways are normal in DNA repair- deficient cells. Global genome repair (GGR) GGR acts on DNA lesions throughout the genome, but the kinetics of repair can be influenced by a number of parameters related to DNA lesion structure and chromatin configuration. It is conceivable that the damage recognition step is a rate-limiting step in the repair process and that more efficient recognition of DNA lesions will lead to more rapid repair. The lesion recognition and binding potency of proteins that are involved in damage recognition, depends on the chemical structure of the DNA lesion itself or the way it interferes with the DNA helical structure. Some lesions such as ultraviolet light induced 6-4PP and CPD, are large bulky lesions located in the minor groove of the DNA helix and are recognized by NER proteins as being abnormal structures in the DNA. DNA is thought to be a dynamic molecule subject to an extremely rapid process of bending, twisting, unwinding and rewinding ('breathing'). Lesions that interfere with these dynamic properties of the DNA may be recognized by repair proteins. Lesions that have been shown to be a good substrate for NER often cause local unwinding of a few DNA bases around the damaged site. UV- induced CPD as well as cisplatinum-induced intrastrand crosslinks are a better substrate for in vitro NER when they are superimposed on a mismatch than in normally base paired DNA. The unwinding of a few basepairs energetically favours bending of the DNA and this may facilitate further unwinding by NER enzymes. Repair of DNA lesions that are substrates for NER by themselves, is strongly stimulated by disruption of base pairing at the site of the lesion. The role of chromatin structure in governing the repair efficiency is indicated by the notion that repair in the nontranscribed strand of active genes or chromatin poissed for transcription, is faster than in inactive X- chromosomal genes (Venema et al., 1992). The latter are known to consist of heavily methylated DNA sequences and their chromatin structure is relatively inaccessible to molecular probes such as DNAse1. Thus, the efficiency of

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -350- repair might be influenced by accessibility of DNA lesions to repair proteins. Indeed, when repair was investigated at the nucleotide level, profound differences in repair rate were found due to protein binding in promotor regions. Transcription-coupled repair The NER subpathway transcription-coupled repair (TCR) first described by Mellon and Hanawalt for cultured mammalian cells (Mellon et al., 1987), specifically removes DNA lesions from the transcribed strand of an active gene. Subsequently, TCR was shown to operate in a variety of organisms including bacteria and yeast. All data indicate that TCR is directly coupled to active transcription and it is generally assumed that a stalled transcript provides a strong signal to attract the repair machinery. All classical XP cells are deficient in TCR except the group C that is fully deficient in GGR but proficient in TCR (Van Hoffen et al., 1995).However, until now it is not clear how repair is coupled to transcription. A major obstacle that prevents a major breakthrough, is the lack of a cell free system capable to perform TCR. Genetic analysis has put some light on specific factors that play a role in TCR. In an E. coli mdf- mutant strain a protein has been identified called transcription-repair coupling factor (TRCF, the mdf gene product), that actively couples repair to a stalled RNA polymerase at the site of a DNA lesion (Selby and Sancar, 1993). In mammalian cells such factor has not been found yet, but it was suggested that the proteins mutated in the Cockayne' syndrome might fulfill such a function. Similarly to the mdf bacteria strain, Cockayne syndrome cells are unable to perform transcription- coupled repair, whereas the global repair pathway is functioning normally. The defect in transcription-coupled repair has been related to the inability of CS cells to restore UV-inhibited RNA synthesis (Mayne and Lehmann 1982). Slow removal of DNA lesions from transcription templates would prevent efficient transcription and this could lead to cell death if essential genes are involved. Moreover, by analogy to bacteria such a factor could attract NER proteins. Indeed, several investigators showed that CSB can be copurified with RNA polymerase II but could not detect interaction of CSB with any other tested NER component. In cells that have been treated with UV, a small fraction of RNA polymerase II becomes ubiquitinated within 15 minutes after treatment and this fraction persists for about 8 hours (Bregman et al., 1996). However, neither in CS-A nor in CS-B cells this specific response was observed. One explanation favoured by several studies, is that the polymerase could be ubiquitinated as a signal for degradation of the protein so that the lesion becomes accessible for repair enzymes. In this model, CS proteins would be required to make lesions (at stalled transcripts) repairable.

References

1. Failure of RNA synthesis to recover after UV irradiation : an early defect in cells from individuals with Cockayne's syndrome and xeroderma pigmentosum. Mayne L.V., Lehmann A.R. Cancer Res 1982; 42: 1473-1478. Medline 2. Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Mellon I., Spivak G., Hanawalt P.C. Cell 1987; 51: 241-249. Medline 3. Transcription affects the rate but not the extent of repair of cyclobutane pyrimidine dimers in the human adenosine deaminase gene Venema J,

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -351- Bartosova Z, Natarajan A.T., Van Zeeland A.A., L.H.F. Mullenders, L. J Biol Chem 1992; 267: 8852-8856. Medline 4. Molecular mechanism of transcription-repair coupling Selby C.P., Sancar A. Science 1993; 260: 53-58. Medline 5. The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. Schaeffer L., Moncolin V., Roy R., Staub A., Mezzina M., SarasinA., Weeda G., J.H.J. Hoeijmakers J.H.J., Egly J.M. The EMBO Journal 1994; 13: 2388-2392. Medline 6. Mammalian DNA nucleotide excision repair reconstituted with purified protein components. Aboussekhra A., Biggerstaf M., Shivji M.K.K., Vilpo J.A., Moncollin V., Podust V.N., Proti M., HŸbscher U., Egly J-M, Wood, R.D. Cell 1995; 80: 859-868 Medline 7. Reconstitution of human DNA repair excision nuclease in a highly defined system. Mu D., Park C.H., Matsunaga T., Hsu D.S., Reardon J.T., Sancar A J Biol Chem 1995; 270: 2415-2418. Medline 8. Transcription-coupled repair removes both cyclobutane pyrimidine dimers and 6-4 photoproducts with equal efficiency and in a sequential way from transcribed DNA in xeroderma pigmentosum group C fibroblasts. Van Hoffen A., Venema J., Meschini R., van Zeeland A.A. and Mullenders L.H.F. EMBO J 1995; 14: 360-367. Medline 9. UV-induced ubiquitination of RNA polymerase II: a novel modification deficient in Cockayne syndrome cells. Bregman D.B., Halaban R., van Gool A.J., Henning K.A., Friedberg E.C. Warren S.L. Proc Natl Acad Sci USA 1996; 93: 11586-11590. Medline 10. Nucleotide excision repair syndromes: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Bootsma D., Kraemer K.H., Cleaver J., Hoeijmakers J.H.J. In: B Vogelstein and KW Kinzler (ed) The Genetic Basis of Human Cancer 1998; pp 245-274, McGraw-Hill (New York). 11. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Sugasawa K., Ng J.M.Y., Masutani C., Iwai S., van der Spek P.J., Eker A.P.M., Hanaoka F., Bootsma D., Hoeijmakers J.H.J. Mol Cell 1998; 2, 223-232. Medline 12. TrichothiodystrophyÊ: uptake on the sulfur-deficient brittle hair syndromes. Itin P.H., Sarasin A., Pittelkow M.R. (2000) J. Am. Acad. Dermatol. 2000; In press. 13. Transcription-coupled repair and mutation avoidance at 8- oxoguanineÊ: Requirement for XPG, TFIIH, and CSB and implications for Cockayne Syndrome. Le Page F., Kwoh E.E., Avrutskaya A., Gentil A., Ledon S.A. , Sarasin A., Cooper P.K. Cell 2000; 101,159-171. Medline 14. Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutations Tang J.Y., Hwang B.J., Ford J.M., Hanawalt P.C.,Chu G. Cell 2000; 5, 737-744. Medline

This paper should be referenced as such : Atlas Genet Cytogenet Oncol Haematol February 2001. URL : http://www.infobiogen.fr/services/chromcancer/Deep/TcellClassif.html

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -352- Atlas of Genetics and Cytogenetics in Oncology and Haematology

HARDY-WEINBERG MODEL * I THE INTUITIVE APPROACH II THE HARDY-WEINBERG EQUILIBRIUM II-1 FOR AN AUTOSOMAL, DIALLELE, CO-DOMINANT GENE EXERCISE III THE HW LAW III-1 DEMONSTRATION OF THE LAW III-2 EXERCISES III-3 CONSEQUENCES OF THE LAW

III-3.1 WHAT IS THE ALLELE FREQUECY IN THE n+ 1 GENERATION?

III-3.2 WHAT IS THE GENOTYPE FREQUENCY IN THE n+ 1 GENERATION? III-3.3 EXAMPLE IV EXTENSION OF HW TO OTHER GENE SITUATIONS IV-1 TO AN AUTOSOMAL, TRIALLELE, CO-DOMINANT GENE IV-2 TO AN AUTOSOMAL, DIALLELE, NON CO-DOMINANT GENE IV-3 TO AN AUTOSOMAL, TRIALLELE, NON CO-DOMINANT GENE IV-3.1 BERNSTEIN's EQUATION IV-4 TO A HETEROSOMAL (= gonosomic) GENE IV-4.1 Y CHROMOSOME IV-4.2 X CHROMOSOME V SUMMARY- CONSEQUENCES OF HW's LAW * I- THE INTUITIVE APPROACH

The Hardy-Weinberg law can be used under some circumstances to calculate genotype frequencies from allele frequences. Let A1 and A2 be two alleles at the same locus, p is the frequency of allele A1 0 =< p =< 1 q is the frequency of allele A2 0 =< q =< 1 and p + q = 1 where the distribution of allele frequencies is the same in men and women, i.e.: hommes (p,q) femmes (p,q) if they procreate : (p + q)2 = p2 + 2pq + q2 = 1 where:

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -353- p2 = frequency of the A1 A1 genotype <-- HOMOZYGOTE 2pq = frequency of the A1 A2 genotype <-- HETEROZYGOTE q2 = frequency of the A2 A2 genotyp <-- HOMOZYGOTE these frequencies remain constant in successive generations.

Example : autosomal recessive inheritance with alleles A and a, and allele frequencies p and q: --> frequency of the genotypes: : [A] = p2 + AA = p2 and the phenotypes [ ]: 2pq Aa = 2pq [a] = q2 aa = q2 Example : phenylketonuria (recessive autosomal), of which the deleterious gene has a frequency of 1/100: --> q = 1/100 therefore, the frequency of this disease is q2 = 1/10 000, and the frequency of heterozygotes is 2pq = 2 x 99/100 x 1/100 = 2/100; Note that there are a lot of heterozygotes: 1/50, two hundred times more than there are individuals suffering from the condition. . For a rare disease, p is very little different from 1, and the frequency of the heterozygotes = 2q. We use these equations implicitly, in formal genetics and in the genetics of pooled populations, usually without considering whether, and under what conditions, they are applicable.

THE HARDY-WEINBERG EQUILIBRIUM The Hardy-Weinberg equilibium, which is also known as the panmictic equilibrium, was discovered at the beginning of the 20th century by several researchers, notably by Hardy, a mathematician and Weinberg, and physician. The Hardy-Weinberg equilibrium is the central theoretical model in population genetics. The concept of equilibrium in the Hardy-Weinberg model is subject to the following hypotheses/conditions:

1. The population is panmictic (couples form randomly (panmixia), and their gametes encounter each other randomly (pangamy)) 2. The population is "infinite" (very large: to minimize differences due to sampling). 3. There must be no selection, mutation, migration (no allele loss /gain). 4. Successive generations are discrete (no crosses between different generations).

Under these circumstances, the genetic diversity of the population is maintained and must tend towards a stable equilibrium of the distribution of the genotype. II-1. FOR AN AUTOSOMAL, DIALLELE, CO-DOMINANT GENE (Alleles A1 and A2) Let:

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -354- The frequencies of genotypes F(G) be called D, H, and R with 0 =< [D,H,R] = < 1 and D + H + R = 1 The frequencies of alleles F(A) be called p, and q with 0 =< [p,q] =< 1 and p+q = 1 Génotypes A1A1 A1A2 A2A2 Number of subjects DN HN RN (total number N) Frequencies F(G) D H R with (D+H+R) = 1 allele frequencies F(A) : de A1 D + H/2 = p de A2 R + H/2 = q with p+q=1 NOTES The genotype frequencies F(G) can always be used to calculate the allele frequencies F(A) F(A) contains less information than F(G) if p = 0: allele is lost; if p = 1: allele is fixed.. first demonstration that p = D + H/2, by counting the alleles:

• size of the population = N -> number of alleles = 2N • p = nb A1 / nb total = (2DN + HN) / 2N = D + H/2 • p = nb A1 / nb total = (2DN + HN) / 2N = D + H/2 similarly for A2 • q = nb A2 / nb total = (2RN + HN) / 2N = R + H/2 (note the symmetry between p and q)

second demonstration, by calculating the probabilities: proba of drawing A1 = drawing A1A1: : D x 1 then drawing A1 into A1A1 or drawing A1A2: H x 1/2 then drawing A1 amongst A1A2 sum: -> -> P(A1) = D + H/2 similarly for A2 ...; EXERCISE let les phénotypes [A1] [A1A2] [A2] A2A les génotypes A1A1 A1A2 2 number of subjects 167 280 109 total N : 556 calculate the following frequencies: F(P: phenotypes), F(G: genotypes), F(A: alleles), F (gametes) : F(A) = F(gam), because there is 1 allele (of each gene) per gamete In addition, here F(p) = F(G), because these are co-dominant alleles F(P) = F(G) 167/556 280/556 109/556 Where : D=0.300 H=0.504 R=0.196 confirm: (D,H,R)=2 F(A) = F(gam.) p = D+H/2 = (167+280/2)/ 556 or 0.300+0.504/2 = 0.552 q = R+H/2 = (109+280/2)/ 556 or 0.196 + 0.504/2 = 0.448 confirm: (p,q)=1

III- LOI DE HW In a population consisting of an infinite number of individuals (i.e. a very large population), which is panmictic (mariages occur randomly), and in the absence of

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -355- mutation and selection, the frequency of the genotypes will be the development of (p+q)2, p and q being the allele frequencies.

FIG.1

The figure shows the correspondence between the allele frequency q of a and the genotype frequencies in the case of two alleles in a panmictic system. The highest frequency of heterozygotes, H, is then reached when p = q and H = 2pq = 0.50. In contrast, when one of the alleles is rare (i.e. q is very small), virtually all the subjects who have this allele are heterozygotes.

III-1. DEMONSTRATION OF THE LAW Let A be an autosomal gene that is found in a population in two allele forms, A1 and A2 (with the same frequencies in both sexes of course). As there is codominance, 3 genotypes can be distinguished. According to the hypotheses/conditions of Hardy- Weinberg (HW), the individuals of the n + 1 generation will be assumed to be the descendants of the random union of a male gamete and a femal gamete. . Consequently, if, by generation n, the probability of drawing an A1 allele is p, then that of producing an A1A1 zygote after fertilization is p x p = p2 and similarly for A2, that of producing an A2A2 zygote is q x q = q2. The probability of producing a heterozygote is pq + pq = 2pq. Finally, p2 + 2pq + q2 = (p+q)2 = 1 A1A1 A1A2 A2A2 D = p2 H=2pq R = q2  seulement sous HW Table of gametes A1 A2 (p) (q) ______A1 (p) A1A1 (p2) A1A2 (pq) A2 (q) A1A2 (pq) A2A2 (q2) (The allele frequencies can only be used to calculate the genotype frequencies if they are subject to HW) the allele frequencies remain the same from one generation to another the genotype frequencies remain the same from one generation to another III-2. EXERCICES

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -356- exercise : Show that, in the absence of panmixia, two populations with similar allele frequencies can have different genotype frequencies (by doing this, you show that there is a loss of information between genotype and allele frequencies): example : for p = q = 0,5 answer if H = 0 p = D + H/2 = 0.5  D = 0.5 H = 0 R = 0.5

if H = 1 D = R = 0  D = 0 H = 1 R = 0 exercise : calculation of the genotype and allele frequencies, calculation of the numbers predicted by HW (theoretical numbers of individuals), and confirmation that we are indeed in a situation subject to HW : AA AB BB

1787 3039 1303 N=6129 DN HN RN answer: F(A) = (1787 + 3039/2) / 6129 = 0.54 = p F(B) = (1303 + 3039/2) / 6129 = 0.46 = q … and (p,q)=1 genotype frequencies predicted by HW genotype frequencies predicted by HW

AA : p2 = (0.54)2 = 0.2916 AB = 2pq = 2x 0.54 x 0.46 = 0.4968 BB : q2 = (0.46)2 = 0.2116

Numbers predicted by HW

AA : p2N = 0.2916 x 6129 = 1787.2 AB : 2pqN = 0.4968 x 6129 = 3044.9 BB : q2N = 0.2116 x 6129 = 1296.9 Confirmation: : (0i - Ci)2 (1787 - 1787.2)2 + (3039 - 3044.9)2 + (1303 - 1296.9)2 2 = = = NS Ci 1787.2 3044.9 1296.9 --> we are in a situation subject to HW

III-3. CONSEQUENCES OF THE LAW Change in HW across the generations (demonstration that the frequencies are invariable). In a population subject to HW, an equilibrium involving the distribution of the genotype frequencies is reached after a single reproductive cycle. . Is a population in the n generation III-3.1. WHAT WILL THE ALLELE FREQUENCY BE IN THE n+1 GENERATION?

A1A1 A1A2 A2A2 n p2 2pq q2 n + 1 F(A1) = D + H/2 = p2 +1/2 (2pq) = p (p+q) = p

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -357- F(A2) = R + H/2 = q2 +1/2 (2pq) = q (p+q) = q -> no change in allele frequencies: in the n generation, we have p and q in the n+1 generation, we have p and q III-3.2. WHAT WILL THE GENOTYPE FREQUENCY BE IN THE n+1 GENERATION ? male p2 2pq q2 female A1A1 A1A2 A2A2 no A1A1 A1A1 A1A1 p2 A1A1 2pq A1A2 1/2A1A1 1/4A1A1 no A1A1 Generation n+1 q2 A2A2 no A1A1 no A1A1 no A1A1 Frequency of (A1A1) in the generation = (p2)2 + 1/2 (2 pq.p2) + 1/2 (p2.2pq) + 1/4 n+1 (2pq)2

= p4 + p3q + p3q + p2q2 = p2 (p2 + 2pq + q2) =

p2 The frequency of the (A1A1) genotype does not change between generation n and generation n+1 (same demonstration for the (A2A2 ) and (A1A2) genotypes). The genotype structure no longer undergoes any further changes once the population reaches the Hardy Weinberg equilibrium. In very many examples, the frequencies seen in natural populations are consistent with those predicted by the Hardy-Weinberg law. III-3.3. EXAMPLE The MN human blood groups. Group MM MN NN Number: 1787 3039 1303 Total, N = 6129

Frequency of M = (1787 + 3039/2)/ 6129 = 0.540 = p Frequency of N = (1303 + 3039/2)/6129 = 0.460 = q Predicted proportion of MM = p2 = (0.540)2 = 0,2916 Predicted proportion of MN = 2pq = 2(0.540)(0.460) = 0.4968 Predicted proportion of NN = q2 = (0.460)2= 0.2116 Numbers predicted by Hardy-Weinberg : for MM = p2N = 0,2916 x 6129 = 1787.2 for MN = 2pqN = 0,4968 x 6129 = 3044.9 for NN = q2N = 0,2116 x 6129 = 1296.9 In the present situation, there is no need to do 2 test to see that the actual numbers are not statistically different from those predicted.

IV- EXTENSION OF HW TO OTHER GENE SITUATIONS IV-1.TO AN AUTOSOMAL, TRIALLELE, CO-DOMINANT GENE 3 alleles

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -358- A1A1 A1A2 A1A3 A2A2 A2A3 A3A3 Genotype frequencies p2 2pq 2pr q2 2qr r2 according to HW

p q r

A1 A2 A3

p A1 p2 pq pr q A2 pq q2 qr r A3 pr qr r2 IV-2. TO AN AUTOSOMAL, DIALLELE, NON CO-DOMINANT GENE A is dominant over a, which is recessive; in this case the genotypes (AA) and (Aa) cannot be distinguished within the population. Only the individuals with the phenotype [A], who number N1, will be distinguishable from the individuals with the phenotype [a], who number N2. Genotypes AA Aa aa

Phenotypes [A] [a] Number N1 N2 N Frequency of genotype 1-q2 q2 with q2 = N2/N = N2 / (N1 + N2) and the frequency of the allele a = F(a) =(q2)1/2 = (N2/(N1 + N2))1/2 This is a method commonly used in human genetics to calculate the frequency of rare, recessive genes. Frequencies of homozygotes and heterozygotes for rare recessive human genes. Gene Incidence in Frequency Frequency of Gene population q2 of allele q heterozygotes 2pq Albinism 1/22 500 1/150 1/75 Phenylketonuria 1/10 000 1/100 1/50 Mucopolysaccharidosis 11/90 000 1/300 1/150 IV-3. TO AN AUTOSOMAL, TRIALLELE, NON CO-DOMINANT GENE Example: the ABO blood group system. Although the human (ABO) blood group system is often taken to be a simple example of polyallelism, it is in fact a relatively complex situation combining the codominance of A and B, the presence of a nul O allele and the dominance of A and B over O. If we take p to designate the frequency of allele A q to designate the frequency of allele B

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(p + q + r = 1) rdiffering genotype and phenotype frequencies are found by applying the Hardy- Weinberg law. . Phenotype Genotype Genotype frequency Phenotype frequency [A] (AA) p2 (AO) 2pr p2+2pr [B] (BB) q2 (BO) 2qr q2+2qr [AB] (AB) 2pq 2pq [O] (OO) r2 r2 Using:: p2 +2pr +r2 = (p+r)2 q2 +2qr +r2 = (q+r)2 where F[A] + F[O] = (p+r)2 F[B] + F[O] = (q+r)2 et F[O] = r2

IV-3.1. BERNSTEIN's EQUATION (1930) Bernstein's equation (1930) simplifies the calculations: p = 1 - (F[B] + F[O])1/2 q = 1 - (F[A] + F[O])1/2 r = (F[O])1/2 then, if p+q+r # 1, correction by the deviation D = 1 - (p + q + r) --> p'= p (1 + D/2) q'= q (1 + D/2) r'= (r + D/2) (1 + D/2) Example : Group A B O AB

Number 9123 2987 7725 1269 Frequency 0.4323 0.1415 0.3660 0.601 p = 1 - (0.3660+0.1415)1/2 = 0.2876 q = 1 - (0.3660+0.4323)1/2 = 0.1065 r = = 0.6050 p+q+r = 0.9991 ... --> p'= 0.2877, q'= 0.1065, r'= 0.6057. IV-4. TO A HETEROSOMAL (= gonosomic) GENE IV-4.1. Y CHROMOSOME: frequency p and q in subjects XY; transmission to male descendants. IV-4.2. X CHROMOSOME: Female XA1XA1 XA1XA2 XA2XA2 p2 2pq q2 M&ale XA1/Y XA2/Y p q i.e. the frequency of the q allele, is qx in men, and qxx in women: the X chromosome of the boys (in generation n) has been transmitted from the (n) (n-1) mothers (generation n-1) --> qx(n) = qxx(n-1) qx = qxx

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -360- the X chromosome carrying the q allele in the daughters has: 1/2 chance of coming from their father, 1/2 chance of coming from their mother 1/2 chance de venir du père (n) (n-1) (n-1) --> qxx = ( qx + qxx )/2 the frequency of the allele in men = the frequency in women in the previous generation the frequency of the allele in women = mean of the frequencies in the 2 sexes in the previous generation. * calculation of the difference in allele frequencies between the 2 sexes: (n) (n) (n-1) (n-1) (n-1) (n-1) (n-1) qx - qxx = qxx - (qxx )/2 - (qxx ) /2 = - 1/2 (qx - qxx )

(n) (n) n (0) (0) --> qx - qxx = (- 1/2) (qx - qxx ) : tends towards zero in 8 to 10 generations * mean frequency q: : (n) 1/3 of the X chromosomes belong to men, 2/3 to women: q = 1/3 qx + (n) 2/3 qxx the mean frequency is invariable (develop q1 into q0 ...... --> q1 = q0) (e) (e) (e) (e) at equilibrium, q est : qx = qxx = q * exercise : For generation G0, consisting of 100% of normal men and 100% of color-blind women, calculate the frequencies of the gene up to G6: answer G0: XNY XDXD G0 : qx(0) = 0.00 qxx(0) = 1.00 G1 : qx(1) = 1.00 qxx(1) = 0.50 G2 : qx(2) = 0.50 qxx(2) = 0.75 G3 : qx(3) = 0.75 qxx(3) = 0.63 G4 : qx(4) = 0.63 qxx(4) = 0.69 G5 : qx(5) = 0.69 qxx(5) = 0.66 G6 : qx(6) = 0.66 qxx(6) = 0.60

FIG.2

Therefore:

Atlas Genet Cytogenet Oncol Haematol 2001; 2 -361- For a sex-linked locus, the Hardy Weinberg equilibrium is reached asymptotically after 8-10 generations, whereas it is reached after 1 generation for an autosomal locus.

V- CONSEQUENCES OF THE HW LAW Regardless of whether we are in a situation subject to HW or not, the genotype frequencies (D, H, R) can be used to calculate the allele frequencies (p,q), from : p = D + H/2, q = R + H/2. Whereas, if and only if we are subject to HW, the genotype frequencies can be calculated from the allele frequencies, from D = p2, H = 2pq, R = q2. The dominance relationships between alleles have no effect on the change in allele frequencies (although they do affect how difficult the exercises are!) The allele frequencies remain stable over time; and so do the genotype frequencies. The random mendelian segregation of the chromosomes preserves the genetic variability of populations. Since "evolution" is defined as a change in allele frequencies, an ideal diploid population would not evolve. It is only violations of the properties of an ideal population that allow the evolutionary process to take place. The practical approach to a problem is always the same:

1. The Numbers Observed --> the (Observed) Genotype Frequencies; 2. Calculate the Allele Frequencies: p=D/2 + S Hi/2 , q = ... 3. If we are subject to HW (hypothetically), then D=p2, H= 2pq, etc ... : we calculate the Theoretical Genotype Frequencies according to HW. 4. The Calculated Genotype Frequencies --> the Calculated Numbers; 2 2 5. Comparison of Observed Numbers - Calculated Numbers: : = (Oi - Ci) /Ci 2 6. If is significant: we are not in accordance with HW; this ---> Consanguinity? ---> Selection? ---> Mutations ?

Contributor(s) Written 02- Robert Kalmes, Jean-Loup Huret. 2001 Citation This paper should be referenced as such : Kalmes R, Huret JL . Hardy-Weinberg model. Atlas Genet Cytogenet Oncol Haematol. February 2001 . URL : http://AtlasGeneticsOncology.org/Educ/HardyEngl.html

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