Evaluation of Multiple Breast Cancer Polygenic Risk Score Panels in Women of Latin American Heritage

Background: A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European (EUR) and Asian ancestries, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L-specific variants among self-reported H/L women. Methods: PRS performance was evaluated using multivariable logistic regression and the area under the ROC curve. Results: Both EUR and Asian PRSs performed worse in H/L samples compared with original reports. The best EUR PRS performed better than the best Asian PRS in pooled H/L samples. EUR PRSs had decreased performance with increasing Indigenous American (IA) ancestry, while Asian PRSs had increased performance with increasing IA ancestry. The addition of two H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry, and did not impact the performance of PRSs in individuals with lower IA ancestry. Conclusions: A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry-specific panels, could be used in clinical practice. Impact: The results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry-specific variants into PRSs for clinical application.