BRCA1 and BRCA2: Risk Beyond Breast and Ovarian Cancer

Germline mutations in BRCA1 and BRCA2 are known to increase the risk for several cancers, including breast, ovarian, pancreatic, and prostate. Reports have suggested that risk for biliary tract, cervical, colorectal, endometrial, esophageal, and gastric cancer may also be increased in those harboring pathogenetic variants of BRCA1 and BRCA2, and data suggest that elevation of risk for specific cancers may vary across populations in different regions of the world. Investigators undertook a large-scale, registry-based study to analyze DNA and clinical information from individuals across Japan from 2003 through 2018. More than 65,000 patients (median age, 64 years; 42% female) and about 38,000 controls (median age, 62 years; 47% female) were included.

Pathogenic variants in BRCA1 were significantly associated with increased risk for five cancer types: ovarian, female breast, biliary tract, gastric, and pancreatic. Pathogenic variants in BRCA2 increased risk for seven cancer types: female breast, gastric, ovarian, male breast, pancreatic, prostate, and esophageal. The elevated risk for breast and ovarian cancer in those with BRCA1/2 mutations follows patterns seen in other parts of the world. The elevated risk for other cancers reflects a generally higher incidence of those cancers in Asia than in Western countries. In addition, the carrier frequency for BRCA1/2 mutations varied across the seven regions of Japan from which the data was collected, likely reflecting the difference in distribution of founder pathogenic variants.