Investigating the prognostic utility of GSTP1 promoter methylation in prostate cancer

Objectives: We aim to determine the prognostic significance of glutathione S-transferase Pi 1 DNA methylation (mGSTP1) in two independent prostate cancer cohorts with long-term clinical follow-up data. Subjects/Patients and Methods: We first re-examined a published, in-house whole genome bisulphite sequencing (WGBS) prostate cancer dataset, derived from radical prostatectomy (RP) tissue (n = 15) with median follow-up 19.5 years, to confirm and visualise the association between mGSTP1 and patient mortality. To validate prognostic significance, we used a quantitative methylation-specific head-loop (MS-HL) assay to measure mGSTP1 levels in a larger, independent cohort (n = 186), and performed univariable and multivariable Cox survival analysis. Results: Re-analysis of WGBS data showed a significant increase in mGSTP1 in RP samples from patients with lethal versus non-lethal disease. Subsequent analysis in the larger cohort using the MS-HL assay confirmed that mGSTP1 was detectable in 97% of RP samples, validating the diagnostic potential of mGSTP1. Univariable Cox survival analysis revealed a significant association between mGSTP1 levels and biochemical recurrence and metastatic relapse free survival, with a near-significant association with prostate cancer specific mortality. Notably, multivariable Cox models demonstrated that mGSTP1 did not add independent prognostic value beyond standard clinicopathological features. Conclusion: Our study supports the importance of DNA methylation as a tissue-based prostate tumour biomarker. GSTP1 methylation is well established as a diagnostic marker, and in this study, we find that GSTP1 methylation levels are also associated with disease prognosis. Further research is required into the clinical utility of prognostic methylation markers and their functional role in disease progression.