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

Genetically adjusted PSA levels for prostate cancer screening

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  • Media type: E-Article
  • Title: Genetically adjusted PSA levels for prostate cancer screening
  • Contributor: Kachuri, Linda; Hoffmann, Thomas J.; Jiang, Yu; Berndt, Sonja I.; Shelley, John P.; Schaffer, Kerry R.; Machiela, Mitchell J.; Freedman, Neal D.; Huang, Wen-Yi; Li, Shengchao A.; Easterlin, Ryder; Goodman, Phyllis J.; Till, Cathee; Thompson, Ian; Lilja, Hans; Van Den Eeden, Stephen K.; Chanock, Stephen J.; Haiman, Christopher A.; Conti, David V.; Klein, Robert J.; Mosley, Jonathan D.; Graff, Rebecca E.; Witte, John S.
  • imprint: Springer Science and Business Media LLC, 2023
  • Published in: Nature Medicine
  • Language: English
  • DOI: 10.1038/s41591-023-02277-9
  • ISSN: 1078-8956; 1546-170X
  • Keywords: General Biochemistry, Genetics and Molecular Biology ; General Medicine
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>P</jats:italic> &lt; 5 × 10<jats:sup>−8</jats:sup>) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS<jats:sub>PSA</jats:sub>) 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 &lt;7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, <jats:italic>P</jats:italic> = 6.2 × 10<jats:sup>−14</jats:sup>, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, <jats:italic>P</jats:italic> = 1.1 × 10<jats:sup>−12</jats:sup>, 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, <jats:italic>P</jats:italic> = 7.2 × 10<jats:sup>−4</jats:sup>). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.</jats:p>