Assessing the Risk Stratification of Breast Cancer Polygenic Risk Scores in a Brazilian Cohort

Polygenic risk scores (PRSs) for breast cancer have a clear clinical utility in risk prediction. PRS transferability across populations and ancestry groups is hampered by population-specific factors, ultimately leading to differences in variant effects, such as linkage disequilibrium and differences in variant frequency (allele frequency differences). Thus, locally sourced population-based phenotypic and genomic data sets are essential to assess the validity of PRSs derived from signals detected across populations. Here, we assess the transferability of a breast cancer PRS composed of 313 risk variants (313-PRS) in a Brazilian trihybrid admixed ancestries (European, African, and Native American) whole-genome sequenced cohort, the Rare Genomes Project. We computed 313-PRS in the Rare Genomes Project (n = 853) using the UK Biobank (UKBB; n = 264,307) as reference. We show that although the Brazilian cohorts have a high European ancestry (EA) component, with allele frequency differences and to a lesser extent linkage disequilibrium patterns similar to those found in EA populations, the 313-PRS distribution is inflated when compared with that of the UKBB, leading to potential overestimation of PRS-based risk if EA is taken as a standard. Interestingly, we find that case controls lead to equivalent predictive power when compared with UKBB-EA samples with area under the receiver operating characteristic curve values of 0.66 to 0.62 compared with 0.63 for UKBB.