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About this Publication
Title
Genetically adjusted PSA levels for prostate cancer screening.
Pubmed ID
37264206 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Nat Med. 2023 Jun; Volume 29 (Issue 6): Pages 1412-1423
Authors
Kachuri L, Hoffmann TJ, Jiang Y, Berndt SI, Shelley JP, Schaffer KR, Machiela MJ, Freedman ND, Huang WY, Li SA, Easterlin R, Goodman PJ, Till C, Thompson I, Lilja H, Van Den Eeden SK, Chanock SJ, Haiman CA, Conti DV, Klein RJ, ...show more Mosley JD, Graff RE, Witte JS
Affiliations
  • Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
  • Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
  • Biological and Medical Informatics, University of California, San Francisco, San Francisco, CA, USA.
  • Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • CHRISTUS Santa Rosa Medical Center Hospital, San Antonio, TX, USA.
  • Departments of Laboratory Medicine, Surgery and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
...show more
  • Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
  • Center for Genetic Epidemiology, Department of Population and Preventive Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA. Rebecca.Graff@ucsf.edu.
  • Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA. jswitte@stanford.edu.
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 (PGSPSA) 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.

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