Association of p16 INK4A Methylation With Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review and Meta-Analysis.

INTRODUCTION

Methylation of tumor-suppressor gene promoters, particularly p16 INK4A , is implicated in oral carcinogenesis. Although associations with oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMD) have been reported, no systematic review has examined these conditions while assessing evidence certainty. This review evaluated whether p16 INK4A promoter methylation is associated with OSCC and OPMD.

MATERIALS AND

METHODS

PubMed, Embase, Web of Science, Scopus, Livivo, and Google Scholar were searched. Studies were selected by title/abstract and then full-text review. Eligible studies investigated p16 INK4A methylation in OSCC or OPMD with comparator groups. Data were meta-analyzed using random-effects models to obtain pooled odds ratios (OR). Heterogeneity, publication bias, sensitivity analyses, and prediction intervals were assessed. Evidence certainty was rated using GRADE.

RESULTS

Twenty-four studies were included, comprising 1330 OSCC patients, 606 OPMD patients, and 681 healthy controls. Meta-analyses demonstrated a strong association between p16 INK4A methylation and OSCC when compared with healthy controls (OR = 11.59; 95% CI = 6.01-22.37; p < 0.0001), with surgical margins (OR = 3.24; 95% CI = 1.86-5.65; p < 0.0001) and with OPMD (OR = 3.72; 95% CI = 2.47-5.59; p < 0.0001). OPMD also showed increased methylation versus healthy controls (OR = 24.8; 95% CI = 7.4-83.14; p < 0.0001).

CONCLUSIONS

p16 INK4A methylation is strongly associated with OSCC and OPMD; however, due to heterogeneity and low certainty of evidence, these findings should be interpreted cautiously. Further standardized, well-designed studies are needed to clarify the role of p16 INK4A methylation in oral carcinogenesis.

TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO): CRD42023410477.