Developing a germline prostate cancer risk test incorporating rare and common variants, to inform clinical decisions: a route to precision oncology

Pathogenic germline variants in DNA damage response and repair (DDR) genes are established risk factors for prostate cancer (PrCa). Genetic testing for inherited PrCa is usually limited to small gene panels, even though common variants are recognised as harbouring a significant proportion of heritable risk. We have developed a genetic test to identify individuals with a genetic predisposition to PrCa from rare and/or common risk variants, with added potential to inform clinical management of PrCa patients, by detecting targets for personalised treatment, and gather further evidence for candidate genes. Germline genetic testing was offered to 1095 PrCa patients, as part of a research study, to inform on genetic predisposition and determine eligibility for personalised treatment options. Targeted sequencing of 117 DDR genes and HOXB13 was performed together with genotyping of 130–396 common PrCa risk variants. This test we have called PRODICT. Genetic reports were provided to participants including (A) rare variant status and (B) polygenic risk score (PRS). Pathogenic or likely pathogenic (P/LP) variants were detected in 16.7% of cases, most frequently in MUTYH (2.5%), CHEK2 (2.2%), ATM (1.4%) and BRCA2 (1.3%) and 46.0% of study participants had a PRS in the top quintile of the risk distribution. Univariate analyses of the predominantly European cohort showed that carriers of P/LP variants in PrCa predisposition genes were more likely to be Grade Group ≥ 4 (odds ratio (OR) = 4.57, 95% confidence interval (CI) = 1.33–15.73, p = 0.02) and have metastatic disease (OR = 2.12, 95% CI = 1.09–4.12, p = 0.03), however, once all genes with a P/LP variant were included in the analysis, the associations were not statistically significant. Carriers of a P/LP variant in any DDR gene, were more likely to have a PRS in the bottom quintile of the risk distribution than the top, compared to non-carriers (OR = 2.39, 95% CI = 1.17–4.89, p = 0.02). Overall, based on the PRODICT test, we found that 48.3% of study participants had increased germline genetic predisposition to PrCa. Our single germline genetic test for rare and common risk variants, identifies a significant number of individuals with a genetic predisposition to PrCa and has potential to inform clinical decision making for these patients.