Association of Genomic Domains in <i>BRCA1</i> and <i>BRCA2</i> with Prostate Cancer Risk and Aggressiveness

Abstract

Pathogenic sequence variants (PSV) in <i>BRCA1</i> or <i>BRCA2</i> (<i>BRCA1/2</i>) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in <i>BRCA1/2</i> were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 <i>BRCA1</i> and 171 <i>BRCA2</i> male PSV carriers with prostate cancer, and 3,388 <i>BRCA1</i> and 2,880 <i>BRCA2</i> male PSV carriers without prostate cancer. PSVs in the 3' region of <i>BRCA2</i> (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; <i>P</i> = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; <i>P</i> = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; <i>P</i> = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; <i>P</i> = 0.0002). No genotype-phenotype associations were detected for PSVs in <i>BRCA1</i>. These results demonstrate that specific <i>BRCA2</i> PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.