Prognostic value of DNA methylation in head and neck cancer: a systematic review and meta-analysis

The clinical relevance of DNA methylation in head and neck cancer (HNC) is increasingly recognized, yet controversies persist regarding its prognostic significance. We conducted a systematic review and meta-analysis adhering to the PRISMA 2020 guidelines to synthesize evidence on this association.

A comprehensive literature search was performed across five databases (PubMed, Web of Science Core Collection, Cochrane Library, Embase, and Scopus) from inception to October 31, 2025. Eligible studies included original clinical investigations (prospective/retrospective cohort, case-control) reporting prognostic outcomes [overall survival (OS), disease-free survival (DFS)] stratified by DNA methylation status in histologically confirmed HNC patients. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random-effects models.

Nineteen studies involving 3,251 patients were included. High DNA methylation was significantly associated with poor prognosis in HNC: OS (HR =1.50, 95% CI: 1.19-1.90, P=0.001) and DFS (HR =2.44, 95% CI: 1.74-3.47, P<0.001). Significant heterogeneity was observed for OS (I²=71%, P<0.001) and moderate heterogeneity for DFS (I²=42%, P=0.10), partially attributed to regional differences and variability in detection methods. Confounding adjustment status confirmed the robustness of the results.

DNA methylation plays a pivotal role in HNC carcinogenesis and progression, emerging as a robust and promising prognostic biomarker. However, its predictive value for treatment response remains unproven, requiring further investigation in treatment-stratified cohorts.