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A genetic risk score to guide age-specific, personalized prostate cancer screening

By Tyler M Seibert, Chun Chieh Fan, Yunpeng Wang, Verena Zuber, Roshan Karunamuni, J. Kellogg Parsons, Rosalind A. Eeles, Douglas F. Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch Garcia, Kenneth Muir, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Johanna Schleutker, Csilla Sipeky, TLJ Tammela, Børge G Nordestgaard, Sune F. Nielsen, Maren Weischer, Rasmus Bisbjerg, M. Andreas Røder, Peter Iversen, Tim J. Key, Ruth C. Travis, David E Neal, Jenny L. Donovan, Freddie C. Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S. Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Hermann Brenner, Katarina Cuk, Kai-Uwe Saum, Jong Y. Park, Thomas A Sellers, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Judith A. Clements, Amanda Spurdle, Australian Prostate Cancer BioResource, Marta Cardoso, Paula Paulo, Sofia Maia, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, David S. Karow, Ian Mills, Ole Andreassen, Anders M. Dale, The PRACTICAL consortium

Posted 25 Nov 2016
bioRxiv DOI: 10.1101/089383

Background: Prostate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to a high false-positive rate, among other concerns, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patient's risk. Genetic risk may provide key information to guide the decisions of whether and at what age to screen an individual man for PCa. Methods: Genotype, PCa status, and age from 34,444 men of European ancestry from the PRACTICAL consortium database were analyzed to select single-nucleotide polymorphisms (SNPs) associated with prostate cancer diagnosis. These SNPs were then incorporated into a survival analysis to estimate their effects on age at PCa diagnosis. The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was validated in an independent dataset comprised of 6,417 men with screening PSA and genotype data. PHS was calculated for these men to test for prediction of PCa-free survival. PHS was also combined with age-specific PCa incidence data from the U.S. population to generate a PCa-Risk (PCaR) age that relates a given man's risk to that of the population average. PHS and PCaR age were evaluated for prediction of positive predictive value (PPV) of PSA screening. Findings: PHS calculated from 54 SNPs was very highly predictive of age at PCa diagnosis for men in the validation set (p=10^-53). PPV of PSA screening varied from 0.18 to 0.52 for men with low and high genetic risk, respectively. PHS modulates PCa-free survival curves by an estimated 20 years between men in the 1st or 99th percentiles of genetic risk. Interpretation: Polygenic hazard scores give personalized genetic risk estimates and can inform the decisions of whether and at what age to screen a man for PCa.

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