title: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers.
abstract: Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovarian:breast cancer in female carriers than were mutations 5' or 3' of this region (P<.0001), extending previous observations. The optimal definition of the OCCR, as judged on the basis of deviance statistics, was bounded by nucleotides 3059-4075 and 6503-6629. The relative and absolute risks of breast and ovarian cancer associated with OCCR and non-OCCR mutations were estimated by a conditional likelihood approach, conditioning on the set of mutations observed in the families. OCCR mutations were associated both with a highly significantly lower risk of breast cancer (relative risk [RR] 0.63; 95% confidence interval (95% CI) 0.46-0.84; P=.0012) and with a significantly higher risk of ovarian cancer (RR = 1.88; 95% CI = 1.08-3.33; P=.026). No other differences in breast or ovarian cancer risk, by mutation position, were apparent. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation (RR = 0.52; 95% CI = 0.24-1.00; P=.05), but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92% (95% CI = 1.20%-38.57%). Possible mechanisms for the variation in cancer risk are suggested by the coincidence of the OCCR with the RAD51-binding domain.
authors.affiliation: CRC Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, United Kingdom. douglas@srl.cam.ac.uk
authors.forename: D
authors.initials: D
authors.lastname: Thompson
authors.forename: D
authors.initials: D
authors.lastname: Easton
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics; D018567:Breast Neoplasms, Male / Q000235:genetics; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics; D012307:Risk Factors; D013223:Statistics as Topic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors