PT  - JOURNAL ARTICLE
AU  - Tyler M. Seibert
AU  - Chun Chieh Fan
AU  - Yunpeng Wang
AU  - Verena Zuber
AU  - Roshan Karunamuni
AU  - J. Kellogg Parsons
AU  - Rosalind A. Eeles
AU  - Douglas F. Easton
AU  - ZSofia Kote-Jarai
AU  - Ali Amin Al Olama
AU  - Sara Benlloch Garcia
AU  - Kenneth Muir
AU  - Henrik Gronberg
AU  - Fredrik Wiklund
AU  - Markus Aly
AU  - Johanna Schleutker
AU  - Csilla Sipeky
AU  - Teuvo LJ Tammela
AU  - Børge G. Nordestgaard
AU  - Sune F. Nielsen
AU  - Maren Weischer
AU  - Rasmus Bisbjerg
AU  - M. Andreas Røder
AU  - Peter Iversen
AU  - Tim J. Key
AU  - Ruth C. Travis
AU  - David E. Neal
AU  - Jenny L. Donovan
AU  - Freddie C. Hamdy
AU  - Paul Pharoah
AU  - Nora Pashayan
AU  - Kay-Tee Khaw
AU  - Christiane Maier
AU  - Walther Vogel
AU  - Manuel Luedeke
AU  - Kathleen Herkommer
AU  - Adam S. Kibel
AU  - Cezary Cybulski
AU  - Dominika Wokolorczyk
AU  - Wojciech Kluzniak
AU  - Lisa Cannon-Albright
AU  - Hermann Brenner
AU  - Katarina Cuk
AU  - Kai-Uwe Saum
AU  - Jong Y. Park
AU  - Thomas A. Sellers
AU  - Chavdar Slavov
AU  - Radka Kaneva
AU  - Vanio Mitev
AU  - Jyotsna Batra
AU  - Judith A. Clements
AU  - Amanda Spurdle
AU  - Australian Prostate Cancer BioResource
AU  - Manuel R. Teixeira
AU  - Paula Paulo
AU  - Sofia Maia
AU  - Hardev Pandha
AU  - Agnieszka Michael
AU  - Andrzej Kierzek
AU  - David S. Karow
AU  - Ian G. Mills
AU  - Ole A. Andreassen
AU  - Anders M. Dale
AU  - The PRACTICAL consortium
TI  - A genetic risk score to guide age-specific, personalized prostate cancer screening
AID  - 10.1101/089383
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 089383
4099  - http://biorxiv.org/content/early/2016/11/25/089383.short
4100  - http://biorxiv.org/content/early/2016/11/25/089383.full
AB  - 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.Funding Department of Defense #W81XWH-13-1-0391