Genetically Adjusted PSA Levels for Prostate Cancer Screening

ABSTRACT Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. We discovered 128 genome-wide significant associations ( P <5×10 -8 ) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS PSA ) that explains 9.61% of constitutive PSA variation. We found that in men of European ancestry, using PGS-adjusted PSA would avoid 31% of negative prostate biopsies, but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR)=3.44, P =6.2×10 -14 ; AUC=0.755) than unadjusted PSA (OR=3.31, P =1.1×10 -12 ; AUC=0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC=0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC=0.786, P =7.2×10 -4 ). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.