RT Journal Article
SR Electronic
T1 A genetic risk score to guide age-specific, personalized prostate cancer screening
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 089383
DO 10.1101/089383
A1 Tyler M. Seibert
A1 Chun Chieh Fan
A1 Yunpeng Wang
A1 Verena Zuber
A1 Roshan Karunamuni
A1 J. Kellogg Parsons
A1 Rosalind A. Eeles
A1 Douglas F. Easton
A1 ZSofia Kote-Jarai
A1 Ali Amin Al Olama
A1 Sara Benlloch Garcia
A1 Kenneth Muir
A1 Henrik Gronberg
A1 Fredrik Wiklund
A1 Markus Aly
A1 Johanna Schleutker
A1 Csilla Sipeky
A1 Teuvo LJ Tammela
A1 Børge G. Nordestgaard
A1 Sune F. Nielsen
A1 Maren Weischer
A1 Rasmus Bisbjerg
A1 M. Andreas Røder
A1 Peter Iversen
A1 Tim J. Key
A1 Ruth C. Travis
A1 David E. Neal
A1 Jenny L. Donovan
A1 Freddie C. Hamdy
A1 Paul Pharoah
A1 Nora Pashayan
A1 Kay-Tee Khaw
A1 Christiane Maier
A1 Walther Vogel
A1 Manuel Luedeke
A1 Kathleen Herkommer
A1 Adam S. Kibel
A1 Cezary Cybulski
A1 Dominika Wokolorczyk
A1 Wojciech Kluzniak
A1 Lisa Cannon-Albright
A1 Hermann Brenner
A1 Katarina Cuk
A1 Kai-Uwe Saum
A1 Jong Y. Park
A1 Thomas A. Sellers
A1 Chavdar Slavov
A1 Radka Kaneva
A1 Vanio Mitev
A1 Jyotsna Batra
A1 Judith A. Clements
A1 Amanda Spurdle
A1 Australian Prostate Cancer BioResource
A1 Manuel R. Teixeira
A1 Paula Paulo
A1 Sofia Maia
A1 Hardev Pandha
A1 Agnieszka Michael
A1 Andrzej Kierzek
A1 David S. Karow
A1 Ian G. Mills
A1 Ole A. Andreassen
A1 Anders M. Dale
A1 The PRACTICAL consortium
YR 2016
UL http://biorxiv.org/content/early/2016/11/25/089383.abstract
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