A DNA Methylation Signature Predicts Survival and Platinum Response in HNSCC

Objective We aimed to develop and validate a DNA methylation–based risk score to identify patients at higher risk of poor survival and platinum non‐response. Methods Genome‐wide DNA methylation and clinical data, including treatment response and survival, were analyzed from platinum‐treated patients with head and neck squamous cell carcinoma in The Cancer Genome Atlas ( n = 153). A weighted DNA methylation risk score was constructed from response‐associated methylation features and evaluated for associations with overall survival and platinum treatment response. Prognostic performance was assessed using Kaplan–Meier analysis and multivariable Cox regression. Predictive performance for platinum response was evaluated by comparing models incorporating methylation features with models based on clinical variables alone. External validation was performed in an independent oral rinse–based methylation cohort (GSE52793, n = 82). Results The methylation risk score significantly stratified overall survival (HR = 3.03, 95% CI: 1.20–7.65; p = 0.019). Incorporation of the risk score improved prediction of platinum response compared with clinical variables alone in both logistic regression (AUC 0.58 vs. 0.80) and random forest models (AUC 0.66 vs. 0.90). Prognostic performance was preserved in an independent oral rinse–based validation cohort (HR = 1.043; p = 0.019). Conclusion A DNA methylation–based risk score stratifies survival and improves prediction of platinum response in head and neck squamous cell carcinoma beyond standard clinical factors. Validation in an oral rinse–based cohort highlights the potential clinical applicability of methylation biomarkers for non‐invasive treatment risk stratification and supports prospective evaluation. Level of Evidence 3.