DNA promoter methylation is one of the main epigenetic mechanisms of silencing of tumor-suppressor genes in cancer. Accumulating scientific evidence has shown various genes with aberrant DNA methylation in oral cancer (OC), however, the magnitude of the association between DNA methylation and OC risk remains controversial.

To evaluate the overall and specific impact of DNA promoter methylation on the risk of OC development.

PubMed, EMBASE, Web of Science, and the Cochrane Library were searched for eligible studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate the methodological quality of the included studies with a case-control design. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the associations with R software; and Egger’s test was used to detect publication bias.

A total of 41 studies including 4218 OC patients and 3478 noncancer controls were included in the meta-analysis. Overall, a significant association was found between DNA promoter methylation and OC risk (OR = 5.83, 95% CI 4.14-8.20; P < .001). In addition, the pooled ORs showed a significant association between specific tumor-related genes and OC risk: p16 (5.77; 95% CI 3.95-8.45; P < .001), ECAD (4.47; 95% CI 2.77-7.21; P < .001), MGMT (3.85; 95% CI 2.48-5.97; P < .001), DAPK (5.58; 95% CI 2.14-14.56; P < .001), hMLH1 (10.48; 95% CI 1.04-106.1; P = .047), p14 (3.21; 95% CI 1.78-5.78; P < .001), and p15 (5.02; 95% CI 2.76-9.12; P < .001).

A significant overall association was found between gene promoter methylation and OC risk. Specifically, the promoter methylation of p16, ECAD, MGMT, DAPK, hMLH1, p15, and p14 displayed a significant role in oral carcinogenesis, acting as promising biomarkers for OC prediction and prognosis.

Oral cancer

DNA methylation

Epigenetics

Meta-analysis

Biomarkers

Odds ratio

© 2025 The Authors. Published by Elsevier Inc.