Generalizability of PGS313 for breast cancer risk in a Los Angeles biobank

Abstract

Polygenic scores (PGSs) summarize the combined effect of common risk variants and are associated with breast cancer risk in patients without identifiable monogenic risk factors. One of the most well-validated PGSs in breast cancer to date is PGS₃₁₃, which was developed from a Northern European biobank but has shown attenuated performance in non-European ancestries. We further investigate the generalizability of the PGS₃₁₃ for American women of European (EA), African (AFR), Asian (EAA), and Latinx (HL) ancestry within one institution with a singular electronic health record (EHR) system, genotyping platform, and quality control process. We found that the PGS₃₁₃ achieved overlapping areas under the receiver operator characteristic (ROC) curve (AUCs) in females of HL (AUC = 0.68, 95% confidence interval [CI] = 0.65-0.71) and EA ancestry (AUC = 0.70, 95% CI = 0.69-0.71) but lower AUCs for the AFR and EAA populations (AFR: AUC = 0.61, 95% CI = 0.56-0.65; EAA: AUC = 0.64, 95% CI = 0.60-0.680). While PGS₃₁₃ is associated with hormone-receptor-positive (HR+) disease in EA Americans (odds ratio [OR] = 1.42, 95% CI = 1.16-1.64), this association is lost in African, Latinx, and Asian Americans. In summary, we found that PGS₃₁₃ was significantly associated with breast cancer but with attenuated accuracy in women of AFR and EAA descent within a singular health system in Los Angeles. Our work further highlights the need for additional validation in diverse cohorts prior to the clinical implementation of PGSs.

Keywords: PRS313; Polygenic scores; big data; biobank; bioinformatics; breast cancer; cancer risk prediction; genetic admixture.

Figure 1

Distribution of PGS₃₁₃ in cases and controls Kernel distribution estimation plots of PGS₃₁₃ scores in cases and controls by genetically inferred ancestry (GIA). The orange curves represent scores for cases and blue curves represent scores for controls. The raw PGS₃₁₃ scores of the European population (European ancestry [EA]) was normalized to a standard deviation of 1 and a mean of 0. The remaining GIAs were normalized to the average and standard deviation of EA samples.

Figure 2

Association of PGS₃₁₃ deciles with breast cancer relative to the 50th percentile Association between PGS₃₁₃ and breast cancer diagnoses in American women of African (AA), European (EA), East Asian American (EAA), and Hispanic (HL) ancestry, based on GIAs, where the OR is plotted on the y axis and percentiles of the PGS₃₁₃ are plotted on the x axis. ORs and 95% confidence intervals are shown. ORs are for different deciles of the PGS relative to the 50th percentile of the PGS.