CDKN2A alterations in oral squamous cell carcinoma: A systematic review of diagnostic and prognostic significance.

Oral squamous cell carcinoma (OSCC) remains a significant global health burden with limited improvement in survival rates. CDKN2A, a tumour suppressor gene encoding the p16^INK4a protein, is frequently altered in OSCC through promoter methylation, gene deletion, or expression downregulation. This systematic review aimed to evaluate the diagnostic and prognostic value of CDKN2A alterations in OSCC. A systematic search of PubMed, Scopus, Web of Science, and EMBASE identified case-control studies published between 2015 and 2025. Only human tumour-normal comparative studies (including primary case-control and in silico comparative transcriptomic analyses) analyzing human-derived tissue or blood samples for CDKN2A alterations (methylation, expression, or copy number changes) and reporting clinical outcomes were included. Risk of bias was assessed using the Newcastle-Ottawa Scale. No quantitative meta-analysis was performed due to heterogeneity in effect measures (hazard ratio [HR] vs odds ratio [OR]), alteration types/assays, and the limited number of studies reporting extractable survival data. Five case-control studies (≈500 participants) met eligibility criteria, spanning diverse regions, methods, and sample sizes. In four studies, CDKN2A disruption-via promoter methylation, copy-number loss, or reduced expression-aligned with worse endpoints (recurrence, metastasis, or survival), while one polymorphism-focused study was null. Because effect metrics were incompatible (HR vs OR), assays varied, and few studies reported extractable survival data, results could not be pooled. However, qualitative synthesis showed convergent adverse associations in four of five studies, with overall moderate-high quality on the Newcastle-Ottawa Scale. Unlike previous reviews that combined heterogeneous study designs, this analysis focused on human tumour-normal comparative studies (primary case-control and in silico analyses), providing a more direct evaluation of CDKN2A status in clinically matched populations. The findings confirm that CDKN2A alterations are strongly associated with poor prognosis in OSCC and highlight their value as one of the most consistent biomarkers for prognostic assessment. This case-control-focused appraisal offers unique evidence to guide risk stratification and supports further prospective validation.