Potential of polygenic risk scores for improving population estimates of women’s breast cancer genetic risks

Purpose Breast cancer risk has conventionally been assessed using family history (FH) and rare high/moderate penetrance pathogenic variants (PVs), notably in BRCA1/2 , and more recently PALB2 , CHEK2 , and ATM . In addition to these PVs, it is now possible to use increasingly predictive polygenic risk scores (PRS) as well. The comparative population-level predictive capability of these three different indicators of genetic risk for risk stratification is, however, unknown. Methods The Canadian heritable breast cancer risk distribution was estimated using a novel genetic mixing model (GMM). A realistically representative sample of women was synthesized based on empirically observed demographic patterns for appropriately correlated family history, inheritance of rare PVs, PRS, and residual risk from an unknown polygenotype. Risk assessment was simulated using the BOADICEA risk algorithm for 10-year absolute breast cancer incidence, and compared to heritable risks as if the overall polygene, including its measured PRS component, and PV risks were fully known. Results Generally, the PRS was most predictive for identifying women at high risk, while family history was the weakest. Only the PRS identified any women at low risk of breast cancer. Conclusion PRS information would be the most important advance in enabling effective risk stratification for population-wide breast cancer screening.