Risk of melanoma among people with BRCA1 and BRCA2 pathogenic variants: A systematic review and meta-analysis.

Patients with BRCA1/2 pathogenic gene variants (PGVs) have an increased risk for breast, ovarian, pancreatic, and prostate cancer, with emerging evidence suggesting an association with melanoma. We aim to evaluate the strength of the melanoma association to guide cancer risk-management recommendations. This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42024519298). Key electronic databases were searched to identify studies evaluating the association of melanoma with germline BRCA1/2 PGV status. Data from eligible studies were meta-analyzed. Thirty-nine studies were included in this review. Among 7142 patients with melanoma, the pooled prevalence of BRCA1/2 PGVs was 1.7 % (95 % CI 1.1 % - 2.6 %). Among 2340 patients with melanoma compared to 116,501 controls, the pooled odds ratio (OR) of having a BRCA1/2 PGV was 2.8 (95 % CI 1.5-5.4), with similar ORs for BRCA1 (3.2 [95 % CI 1.6-6.3]) and BRCA2 (2.8 [95 % CI 1.2-6.6]) independently. Of 14,293 BRCA1/2 PGV carriers, 1.3 % (95 % CI 0.9-1.8) developed melanoma. The risk of melanoma among 11,154 BRCA1 PGV carriers was not different to that among 11,553 controls (OR 1.0 [95 % CI 0.3-3.6]), with insufficient data to meta-analyze risk for BRCA2. Our meta-analysis demonstrates that individuals with melanoma have a pooled OR of 2.84 for carrying a BRCA1 or BRCA2 PGV compared to controls; however, limited data suggest no difference in the relative risk of developing melanoma among BRCA1 PGV carriers compared to controls, with insufficient data for relative risk with BRCA2 PGV. These results suggest that although BRCA1/2 PGVs may be associated with melanoma, the magnitude of increased risk is likely relatively low. Well-designed cohort studies are warranted to further investigate the magnitude of melanoma risk among BRCA1/2 PGV carriers and providers should consider this potential risk when counseling patients.