Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer

Background: We assessed the evidence for association between 23 recently reported prostate cancer (PCa) variants and early-onset PCa and the aggregate value of 63 PCa variants for predicting early-onset disease using 931 unrelated men diagnosed with PCa prior to age 56 years and 1126 male controls. Methods: Logistic regression models were used to test the evidence for association between the 23 new variants and early-onset PCa. Weighted and unweighted sums of total risk alleles across these 23 variants and 40 established variants were constructed. Weights were based on previously reported effect size estimates. Receiver operating characteristic curves and forest plots, using defined cut-points, were constructed to assess the predictive value of the burden of risk alleles on early-onset disease. Results: Ten of the 23 new variants demonstrated evidence (p < 0.05) for association with early-onset PCa, including four that were significant after multiple test correction. The aggregate burden of risk alleles across the 63 variants was predictive of early-onset PCa (Area Under Curve = 0.71 using weighted sums), especially in men with a high burden of total risk alleles. Conclusions: A high burden of risk alleles is strongly associated with early-onset PCa. Impact: Our results provide the first formal replication for several of these 23 new variants and demonstrate that a high burden of common-variant risk alleles is a major risk factor for early-onset PCa.