Genetically adjusted PSA levels for prostate cancer screening.
- 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.
- 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.
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.