Genetic Risk Assessment of Lethal Prostate Cancer Using Polygenic Risk Score and Hereditary Cancer Susceptibility genes

Abstract Background The genetic risk of aggressive prostate cancer (PCa) is hard to be assessed due to the lack of aggressiveness-related single-nucleotide polymorphisms (SNPs). Prostate volume (PV) is a potential well-established risk factor for aggressive PCa, we hypothesize that polygenic risk score (PRS) based on benign prostate hyperplasia (BPH) or PV-related SNPs may also predict the risk of aggressive PCa or PCa death. Methods We evaluated a PRS using 27 BPH/PV-associated SNPs, two established PCa risk-related PRS and 10 guideline-recommended hereditary cancer risk genes in the population-based UK Biobank cohort (N = 209,910). Results The BPH/PV PRS was significantly inversely associated with the incidence of lethal PCa as well as the natural progress in PCa patients (hazard ratio, HR = 0.92, 95% confidence interval [CI]: 0.85–0.99, P = 0.03; HR = 0.92, 95%CI: 0.86–0.99, P = 0.02). Compared with men at top 25th PRS, PCa patients with bottom 25th PRS would have a 1.40-fold (HR, 95%CI: 1.16–1.69, P = 0.001) increased PCa fatal risk and shorter survival time at 0.37 year (95%CI: 0.14–0.61, P = 0.002). In addition, patients with BRCA2 or PALB2 pathogenic mutations would also have a high risk of PCa death (HR = 3.91, 95%CI: 2.34–6.51, P < 0.001; HR = 4.24, 95%CI: 1.34–13.34, P = 0.01, respectively). However, no interactive but independent effects were detected between this PRS and pathogenic mutations. Conclusions Our findings provide a new measurement of PCa patients’ natural disease outcomes via genetic risk ways.