title: Identification of a common polymorphism in the TopBP1 gene associated with hereditary susceptibility to breast and ovarian cancer.
abstract: Besides BRCA1 and BRCA2 other genes are also likely to be involved in hereditary predisposition to breast and/or ovarian cancer. TopBP1 (topoisomerase IIbeta binding protein 1) displays sequence homology as well as functional similarities with BRCA1, and the two proteins have been suggested to function partly in the same cellular processes. TopBP1 is crucial for DNA damage and replication checkpoint controls. Based on its biological significance, we reasoned that TopBP1 is a plausible susceptibility gene for hereditary breast and/or ovarian cancer and therefore screened affected index cases from 125 Finnish cancer families for germline changes by conformation sensitive gel electrophoresis (CSGE). Altogether 19 different sequence alterations were detected. A novel heterozygous Arg309Cys variant was observed at elevated frequency in the familial cancer cases compared to healthy controls (15.2% versus 7.0%; P=0.002). Current results suggest that Arg309Cys is a commonly occurring germline alteration possibly associated with a slightly increased breast and/or ovarian cancer risk. This is the first study reporting mutation screening of the TopBP1 gene in a familial cancer material.
authors.affiliation: Department of Clinical Genetics, Oulu University Hospital/University of Oulu, P.O. Box 24, FIN-90029 OYS, Finland.
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Karppinen
authors.forename: Hannele
authors.initials: H
authors.lastname: Erkko
authors.forename: Kaarina
authors.initials: K
authors.lastname: Reini
authors.forename: Helmut
authors.initials: H
authors.lastname: Pospiech
authors.forename: Katri
authors.initials: K
authors.lastname: Heikkinen
authors.forename: Katrin
authors.initials: K
authors.lastname: Rapakko
authors.forename: Juhani E
authors.initials: JE
authors.lastname: Syväoja
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
mesh_terms: D000328:Adult; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors; D017421:Sequence Analysis; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C110513:TOPBP1 protein, human