Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases

Abstract

<div><h3>Background</h3><p>Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed.</p><h3>Methods</h3><p>Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach.</p><h3>Results</h3><p>Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the <i>MGMT</i> (rs2308327; HR 0.90; <i>p</i>-value = 3.5 × 10⁻²) and <i>IL4</i> (rs2070874; HR 1.22; <i>p</i>-value = 1.1 × 10⁻³) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in <i>AKT1</i>, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; <i>p</i>-value = 3.6 × 10⁻²).</p><h3>Conclusions</h3><p>This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.</p></div>