Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer
Document Type
Article
Publication Date
6-1-2021
Abstract
Background Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). Materials and method 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. Results 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. Conclusions Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
Keywords
Polygenic hazard scores (PHS), Prostate cancer
Divisions
fac_med
Funders
United States National Institute of Health/National Institute of Biomedical Imaging and Bioengineering [Grant No: K08EB026503],University of California System [Grant No: C21CR2060],Research Council of Norway [Grant No: 223273],KG Jebsen Stiftelsen,South East Norway Health Authority
Publication Title
Prostate Cancer and Prostatic Diseases
Volume
24
Issue
2
Publisher
Springernature
Publisher Location
CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND