Article: Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent

Abstract

Purpose: Polygenic risk scores (PRS) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi-Jews-(AJ) are assumed to be of White-European-(WE) origin in some commercially-available PRS despite differing effect-allele-frequencies-(EAFs). We conducted a case-control study of WE and AJ women from the PROCAS-(Predicting-Risk-of-Cancer-at-Screening) study. The BCINIS-(Breast-Cancer-in-Northern-Israel-study) provided a separate AJ population-based case-control validation series. Methods: All women underwent Illumina Oncoarray SNP-analysis. Two PRS were assessed, SNP142&SNP78. 221/2243 WE (Discovery:cases=111;controls=110;Validation:cases=651;controls=1772) and 221 AJ (cases=121;controls=110) women were included from the UK study; the Israeli series consisted of 2045 AJ women (cases=1331;controls=714). EAFs were obtained from gnomAD. Results: In the UK study the mean SNP142PRS demonstrated good calibration and discrimination in WEs: mean PRS in cases=1.33-(95%CI=1.18-1.48) and controls=1.01-(95%CI=0.89-1.13). In AJs from Manchester, the mean PRS in cases=1.54-(1.38-1.70) and controls=1.20-(1.08-1.32) demonstrated good discrimination but overestimation of BC relative-risk. After adjusting for AJ EAFs, mean risk was corrected (mean SNP142-PRS cases=1.30-(95%CI=1.16-1.44) and controls=1.02-(95%CI=0.92-1.12)). This was recapitulated in the larger Israeli dataset with good discrimination (AUC=0.632-(95%CI=0.607-0.657) for SNP142). Conclusion: AJ women should not be given BC relative-risk predictions based on PRS calibrated to EAFs from WEs. PRS need to be recalibrated using AJ-derived-EAFs. A simple recalibration using the mean PRS adjustment ratio likely performs well.