As with other solid tumor types, head and neck squamous cell carcinoma (HNSCC) has been identified as an epigenetic, as well as genetic, disease. Consequently, promoter hypermethylation, being the most important aberrant epigenetic characteristic, has been intensively investigated for its biomarker potential in this cancer type. As many of these evaluations are obscured by a heterogeneity of treatments, the current study aimed to evaluate the incidence and prognostic value of the promoter hypermethylation of TIMP3, CDH1, DAPK, RASSF1A, p16INK4A and MGMT in HNSCC treated solely by radiotherapy. In 46 patients with advanced HNSCC treated with a hybrid accelerated fractionation radiotherapy schedule, DNA extracted from pretreatment paraffin-embedded tumor biopsies was used to determine the methylation status of the genes of interest by methylation-specific PCR (MSP). The detected epigenetic silencing was related with outcome in terms of locoregional control (LRC), and overall (OS), disease-free (DFS) and disease-specific survival (DSS). Tumor biopsies revealed the epigenetic silencing of MGMT in 42.5% (17 of 40) of patients and of TIMP3 in 40.5% (17 of 42) of cases. For the remaining investigated genes, a lower methylation percentage was detected: 13.2% (5 of 38) for CDH1, 11.4% (4 of 44) for DAPK, 4.8% (2 of 42) for p16INK4A and 2.4% (1 of 41) for RASSF1A. The promoter hypermethylation of TIMP3 and CDH1 was significantly related with better LRC (p=0.009 and p=0.02, respectively), OS (p=0.005 and p=0.002, respectively), DFS (p=0.02 and p=0.004, respectively) and DSS (p=0.12 and p=0.007, respectively). In conclusion, in this representative group of 46 patients with advanced HNSCC treated by radiotherapy only, the epigenetic silencing of TIMP3 and CDH1 predicted a better outcome.

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