Cancer risks in BRCA2 mutation carriers.
Level 3 - non-randomized controlled study
Multicenter family-based cohort study comparing observed cancer incidence to population rates.
PubMed 10433620 · doi:10.1093/jnci/91.15.1310
What was done
Investigators evaluated cancer risks in a multicenter cohort of 3,728 individuals from 173 breast-ovarian cancer families with confirmed BRCA2 mutations across 20 centers in Europe and North America. The cohort included 681 individuals with breast or ovarian cancer and 3,047 individuals who were known mutation carriers or first-degree relatives. Cancer incidence rates were compared with population-specific rates using a maximum likelihood approach to estimate relative risks (RRs) and 95% confidence intervals (CIs).
What was found
Across 333 other cancers observed, BRCA2 carriers showed statistically significant increases in risk for: - Prostate cancer: estimated RR = 4.65 (95% CI: 3.48-6.22), with RR = 7.33 (95% CI: 4.66-11.52) for men under age 65. - Pancreatic cancer: RR = 3.51 (95% CI: 1.87-6.58). - Gallbladder and bile duct cancer: RR = 4.97 (95% CI: 1.50-16.52). - Stomach cancer: RR = 2.59 (95% CI: 1.46-4.61). - Malignant melanoma: RR = 2.58 (95% CI: 1.28-5.17). Among women who had already developed breast cancer, cumulative risks by age 70 were 52.3% (95% CI: 41.7%-61.0%) for contralateral breast cancer and 15.9% (95% CI: 8.8%-22.5%) for ovarian cancer.
Why it matters
This study defined the broader cancer spectrum associated with BRCA2 mutations beyond breast and ovarian malignancies, identifying elevated risks for prostate, pancreatic, gastrointestinal, and melanoma cancers to guide clinical surveillance.
Limits
Families were ascertained through high-risk breast-ovarian cancer clinics, introducing potential ascertainment bias that may overestimate risks compared to unselected carriers. Many cohort members were untested first-degree relatives whose carrier status was estimated probabilistically rather than directly genotyped. Risk estimates for rarer cancers had wide confidence intervals.
Cited by
- supports Men carrying BRCA gene mutations have a higher risk of prostate cancer and other forms of cancer.