Mixing Mutation Location With Carcinogen Exposure: A Recipe for Tissue Specificity in BRCA2-Associated Cancers?

Germline mutations in the BRCA2 gene have been shown to confer increased risks of developing multiple cancers. Most pathogenic BRCA2 mutations are associated with remarkable risk of breast cancer (61%–77% to age 80 years) and ovarian cancer (17% to age 80 years, 95% confidence interval = 11%–25%) (1). In addition, epidemiologic studies have observed excess risks of pancreatic and high-grade prostate cancers and melanoma, though the risks are not well quantified (2,3) and there are still no predictors of which carriers will develop these malignancies. Esophageal cancer, sarcoma, and other malignancies have been observed in BRCA2 mutation carriers with moderately increased risks (4,5). To date, there has been no mechanistic evidence or clinically significant data implicating particular BRCA2 genotypes to account for the diversity of phenotype or to provide guidance that would optimize surveillance or prevention interventions for BRCA2 mutation carriers, although evidence of a relative increase in ovarian cancer risk for mutations in the large exon 11 (the Ovarian Cancer Cluster Region) and in breast cancer risk for mutations in the 3' and 5' ends of the molecule has been found in multiple analyses (6,7).

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