Associations of High-Grade Prostate Cancer with BRCA1 and BRCA2 Founder Mutations

Purpose: Protein-truncating mutations in BRCA1 and in particular BRCA2 genes have been associated with prostate cancer. However, there is still uncertainty about the magnitude of association particularly with Gleason score, and family history of prostate, breast, and ovary cancers. Experimental Design: To further examine associations between three founder mutations located in BRCA1 (185delAG, 5382insC) or BRCA2 (6174deIT) genes and prostate cancer, we conducted a study of 979 prostate cancer cases and 1,251 controls among Ashkenazi Jewish men. Detailed information was obtained on prostate cancer pathology, age at diagnosis, and family history of all cancers. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression models. Results: Prostate cancer risk was increased (OR, 1.9; 95% CI 0.9-4.1) for BRCA2 mutation carriers but not for BRCA1 mutation carriers. BRCA2 mutation carriers had an OR of 3.2 (95% CI, 1.4-7.3) for Gleason score of 7 to 10, but no association was observed for Gleason score of <7. Carriers of BRCA1-185delAG mutation also had an OR of 3.5 (95% CI, 1.2-10.3) for Gleason score of >= 7 tumors; however, the association of either BRCA1-185delAG or 5382insC mutation was not statistically significant. Associations between founder mutations and prostate cancer were stronger in men with no first-degree family history of breast and/or ovarian cancers but were unaffected by family history of prostate cancer. Conclusion: These results indicate that the BRCA2 founder mutation confers a 3-fold elevated risk of high-grade prostate cancer. Although BRCA1 mutations were not associated with prostate cancer, the BRCA1-185delAG was associated with high Gleason score tumors. These findings should be carefully considered in genetic counseling and/or evaluating therapeutic options.