Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis.

Pashayan N1, Duffy SW2, Neal DE3, Hamdy FC4, Donovan JL5, Martin RM5, Harrington P6, Benlloch S6, Amin Al Olama A6, Shah M7, Kote-Jarai Z8, Easton DF6, Eeles R8, Pharoah PD6.

Author information

Abstract

Purpose:This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk.Methods:We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50-69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis.Results:Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles.Conclusion:Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer.Genet Med advance online publication 08 January 2015Genetics in Medicine (2014); doi:10.1038/gim.2014.192.