Gene hypermethylation in tumor tissue of advanced oral squamous cell carcinoma patients.

Oral squamous cell carcinoma (OSCC) is characterized by high mortality rate and rising incidence. The aim of this study was to examine the methylation of particular tumor suppressor genes promoters in OSCC and to correlate the methylation status with the tumor-host features and patients survival. The genes selected for our investigation are involved in key cellular processes of malignant transformation, including cell cycle control (p16), apoptosis (Death Associated Protein Kinase, DAPK), Wnt signaling (Adenomatous Polyposis Coli, APC), cell-cell adhesion (E-cadherin, E-cad), and DNA repair (O(6)-methylguanine-DNA methyltransferase, MGMT, Werner syndrome gene, WRN). In 77 patients with OSCC, hypermethylation was determined by nested methylation-specific PCR method. Methylation of p16 gene promoter was detected in 58.4% of samples, E-cad in 42.9%, DAPK in 36.8%, MGMT in 33.8%, WRN in 23.8%, and APC in 18.2% of OSCC samples. Patients with E-cad promoter methylation had significantly worse overall survival (p=0.039, log-rank test), while hypermethylation of other genes did not have prognostic significance. Stratified analysis by the lymph node involvement and tumor stage showed that E-cad promoter methylation is associated to poor survival in N positive (p=0.024), and stage III tumors (p=0.027), as an opposite to N0 and stage II tumors, where E-cad methylation did not have prognostic significance (p=0.849, p=0.794, respectively). Our findings indicate that multiple genes are frequently aberrantly methylated in OSCC, and that E-cad promoter methylation should be considered as a potential molecular marker for the poor survival in advanced OSCC.