Genetically adjusted PSA levels for prostate cancer screening

Linda Kachuri, Thomas J Hoffmann, Yu Jiang, Sonja I Berndt, John P Shelley, Kerry R Schaffer, Mitchell J Machiela, Neal D Freedman, Wen-Yi Huang, Shengchao A Li, Ryder Easterlin, Phyllis J Goodman, Cathee Till, Ian Thompson, Hans Lilja, Stephen K Van Den Eeden, Stephen J Chanock, Christopher A Haiman, David V Conti, Robert J KleinJonathan D Mosley, Rebecca E Graff, John S Witte

Research output: Contribution to journalArticlepeer-review

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. In this study, 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 up to 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, area under the curve (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.

Original languageEnglish
Pages (from-to)1412-1423
JournalNature Medicine
Volume29
Issue number6
Early online date2023
DOIs
Publication statusPublished - 2023

Subject classification (UKÄ)

  • Urology and Nephrology
  • Cancer and Oncology

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