Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313-SNP BC PRS were evaluated based on whether it predicts overall, estrogen-receptor (ER)-negative or ER-positive BC; and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (Hazard Ratio (HR) per standard deviation=1.29 (95%CI 1.25-1.33), P=3x10-72). For BRCA2, the strongest association was with overall BC PRS (HR=1.31 (95%CI 1.27-1.36), P=7x10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant-effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR=1.32 (95%CI 1.25-1.40), P=3x10-22) and BRCA2 (HR=1.44 (95%CI 1.30-1.60), P=4x10-12) carriers. The associations in the prospective cohort were similar. Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes