A polygenic two-hit hypothesis for prostate cancer

Abstract

Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

Figure 1.

Genetic risk inversely associated with somatic mutation burden. A) Schematic of polygenic risk score (PRS) associations with the somatic mutational landscape of prostate cancer. The PRS was negatively associated with percent genome altered in both the discovery cohort (B) and the replication cohort (C). Green dots indicate discovery cohort and purple dots indicate replication cohort. The PRS was also negatively associated with the number of driver mutations in both the discovery (D) and replication (E) cohorts. F) PRS is not significantly associated with any individual somatic driver (false discovery rate [FDR] > 0.05). Forest plot shows odds ratio along with 95% confidence interval (x-axis) of PRS associated with each somatic driver (y-axis). Covariate on right indicates the mutation type of each somatic driver while the covariate along the top indicates the direction of effect (ie, whether high inherited risk prevents or promotes the acquisition of each driver mutation). WGS = whole genome sequencing; PGA = percent genome copy number altered; SNV = single nucleotide variant; CNA = copy number aberration.

Figure 2.

Genetic risk inversely associated with age at diagnosis. Kaplan-Meier curves of time to diagnosis (age) stratified by high (>75%) vs low (<25%) polygenic risk score (PRS) in discovery (A) vs replication (B). C) Coefficients from linear model quantifying association between PRS and proportion of the genome with a copy number aberration (PGA) (Box Cox-transformed) or number of driver mutations with or without adjustment of age of diagnosis. Error bars show 95% confidence interval and background shading reflects P value less than .05. D) PRS is negatively associated with relapse after primary treatment in both the discovery and replication cohort. Scatterplot shows the hazard ratio and 95% confidence intervals from a CoxPH model correcting for the first 5 genetic principal components and age. Biochemical recurrence (BCR), progression-free survival (PFI), and metastasis-free survival (MFS) were used as endpoints. HR = hazard ratio.