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

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