Additional SNPs improve the performance of a polygenic hazard score for prostate cancer

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. Conclusion: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men.

“…The focus of this study was the important endpoint of prostate cancer death, but, consistent with prior work, germline SNP associations here are not specific to fatal or aggressive prostate cancer. Finally, the performance of PHS166 may have been influenced by incorporation of COSM data in the prior development of the PHS166 model (done via a LASSO-regularized Cox regression framework) 24 ; however, potential bias is likely low, given that COSM data represent less than 4% of the data used in that study. Despite these limitations, our results indicate that polygenic scores like PHS may significantly improve strategies to identify men at highest (or lowest) risk of dying from prostate cancer.…”

“…Recognizing that more SNPs associated with prostate cancer have been reported since the development of the original and adapted PHS 23 , a PHS model has also recently been developed that incorporates 166 total SNPs (PHS166) 24 , drawing from the SNPs in PHS46 and SNPs reported in a meta-analysis of genome-wide association studies 23 . PHS166 improved the hazard ratios (HRs) for prostate cancer over PHS46.…”

Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men

“…The focus of this study was the important endpoint of prostate cancer death, but, consistent with prior work, germline SNP associations here are not specific to fatal or aggressive prostate cancer. Finally, the performance of PHS166 may have been influenced by incorporation of COSM data in the prior development of the PHS166 model (done via a LASSO-regularized Cox regression framework) 24 ; however, potential bias is likely low. Despite these limitations, our results indicate that polygenic scores like PHS may significantly improve strategies to identify men at highest (or lowest) risk of dying from prostate cancer.…”

“…Recognizing that more SNPs associated with prostate cancer have been reported since the development of the original and adapted PHS23 , a PHS model has also recently been developed that incorporates 166 total SNPs (PHS166)24 , drawing from the SNPs in PHS46 and SNPs reported in a meta-analysis of genome-wide association studies23 . PHS166 improved the hazard ratios (HRs) for prostate cancer over PHS46.…”