A Breast Cancer Polygenic Risk Score Validation in 15,490 Brazilians using Exome Sequencing

BackgroundBrazil has a highly admixed population. Polygenic Risk Scores (PRS) have mostly been developed from European population studies, and their application to other populations is challenging. To assess the use of PRS for breast cancer (BC) risk in Brazil, we evaluated four PRSs in the Brazilian population. MethodsWe analyzed a Brazilian cohort composed of 6,206 women with a history of breast cancer and 8,878 unphenotyped adults as controls. Genomic variants were imputed from exomes and scores were calculated for all samples. ResultsAfter excluding individuals with known pathogenic or likely pathogenic variants in BRCA1, BRCA2, PALB2, PTEN, or TP53 genes, and first-degree relatives of the probands, 5,598 cases and 8,767 controls remained. Four PRS models were compared, and PRS3820 from Mavaddat et al. 2019 study showed the best performance, with an Odds Ratio (OR) of 1.43 per standard deviation increase (p-value: < 0.001) and an OR of 1.88 (p-value: < 0.001) for the top decile. PRS3820 also performed well for different ancestry groups: East Asian majority (OR 1.59, p-value 0.004), Non-European majority (OR 1.45, p-value: <0.001), and European majority (OR: 1.43, p-value: <0.001). ConclusionAmong different PRS, the PRS3820 performed better in the highly admixed Brazilian population. This will allow a more precise BC risk assessment of mutation-negative women in Brazil.