DNA methylation as prognostic factors in non-muscle-invasive bladder cancer: a systematic review and meta-analysis

Early prognostication in non-muscle-invasive bladder cancer (NMIBC) is essential for optimizing therapy and follow-up. Epigenetic mechanisms, particularly DNA methylation, have emerged as promising biomarkers for predicting disease outcome.

A systematic review and meta-analysis were conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate the prognostic significance of promoter DNA methylation in NMIBC. Comprehensive searches of PubMed, Web of Science, Embase, MEDLINE, and the Cochrane Library (January 2010-October 2022) identified eligible studies. The Newcastle-Ottawa scale was used for quality assessment, and pooled hazard ratios with 95% confidence intervals were calculated using random-effects models.

Eleven studies with 3,065 NMIBC patients were analyzed. Promoter methylation was significantly associated with poor progression-free survival (pooled hazard ratios (HR) = 2.88; 95% CI = 2.03-4.09; p < 0.0001) and recurrence-free survival (pooled HR = 2.65; 95% CI = 1.93-3.63; p < 0.0001). Although overall survival showed pathway-specific variation (pooled HR = 0.96; 95% CI = 0.36-2.60; p = 0.94), methylation of adhesion and apoptosis-related genes exhibited the strongest associations. Subgroup analyses revealed a greater prognostic impact in Asian cohorts (p < 0.0001), suggesting regional differences in epigenetic susceptibility.

Promoter DNA methylation constitutes a robust prognostic biomarker for recurrence and progression in NMIBC, with stronger effects in Asian populations. Standardization of validated gene panels, assay thresholds, and cross-regional prospective validation will be essential for clinical translation. Integrating methylation-based classifiers into risk stratification models could improve individualized management and long-term outcomes in NMIBC.