Abstract 1297: Genetic reclassification of prostate-specific antigen levels for personalized prostate cancer screening
Authors: Graff Rebecca E. , Hoffmann Thomas J. , Passarelli Michael N. , Emami Nima C. , Sakoda Lori C. , Jorgenson Eric , Habel Laurel A. , Shan Jun , Ranatunga Dilrini K. , Quesenberry Charles P. , Chao Chun R. , Ghai Nirupa R. , Aaronson David , Presti Joseph , Nordström Tobias , Wang Zhaoming , Berndt Sonja I. , Chanock Stephen J. , Mosley Jonathan D. , Klein Robert J. , Middha Mridu , Lilja Hans , Melander Olle , Kvale Mark N. , Kwok Pui-Yan , Schaefer Catherine , Risch Neil , Risch Neil , Eeden Stephen K. Van Den , Witte John S. 
Published: July 2017

Abstract
Background: Prostate-specific antigen (PSA) screening for prostate cancer results missed diagnoses as well as many unnecessary biopsies and their associated morbidities. Because PSA levels are heritable, traditional PSA screening may be improved by adjustment for constitutive germline genetics that influence PSA independently of prostate cancer.
Methods: In a previous genome-wide association study in non-Hispanic white men without prostate cancer in the Kaiser Permanente Research Program on Genes, Environment and Health cohort, we identified 40 single nucleotide polymorphisms (SNP) independently and significantly associated with PSA levels. Among them, 24 were not associated with prostate cancer risk. To calculate genetically normalized PSA (i.e., PSA’), we multiplied each man’s most recent PSA measurement by a factor that adjusted for the amount by which his 24 PSA-specific SNPs may have increased his PSA level. We then compared how men without prostate cancer were classified based on their PSA and PSA’ levels with regard to decisions for diagnostic testing.
Results: PSA and PSA’ were highly correlated among non-Hispanic white men without prostate cancer (r2: 0.959; 95% CI: 0.958-0.960). Still, 4.6% were reclassified from above to below a cutpoint of 2.5 ng/ml when using the PSA’ measure, and 2.7% were reclassified from below to above this cutpoint (4.6% - 2.7% = 1.9% net reclassified to below the cutoff). The reclassification was even more pronounced when restricting to controls with a negative prostate biopsy: 5.0% downward and 1.5% upward (3.5% net reclassified to below the cutoff).
Conclusions: Normalizing PSA levels using germline PSA variants may reduce the number of subjects without prostate cancer receiving unnecessary biopsies.
Citation Format: Rebecca E. Graff, Thomas J. Hoffmann, Michael N. Passarelli, Nima C. Emami, Lori C. Sakoda, Eric Jorgenson, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Charles P. Quesenberry, Chun R. Chao, Nirupa R. Ghai, David Aaronson, Joseph Presti, Tobias Nordström, Zhaoming Wang, Sonja I. Berndt, Stephen J. Chanock, Jonathan D. Mosley, Robert J. Klein, Mridu Middha, Hans Lilja, Olle Melander, Mark N. Kvale, Pui-Yan Kwok, Catherine Schaefer, Neil Risch, Neil Risch, Stephen K. Van Den Eeden, John S. Witte. Genetic reclassification of prostate-specific antigen levels for personalized prostate cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2017-1297