Abstract
The aim of this study was to clarify the epigenetic regulation of ten eleven translocation protein (TET) family genes, which can provide insights into the mechanisms of tumorigenesis and the risk of disease recurrence in head and neck squamous cell carcinoma (HNSCC). We generated methylation profiles of TET1, TET2 and TET3 genes in tumor samples obtained from 233 patients with HNSCC; these included 57 hypopharynx, 44 larynx, 69 oral cavity, and 63 oropharynx tumor samples. The mRNA expression and promoter DNA methylation of TET family genes were examined via quantitative RT-PCR and methylation-specific PCR, respectively. Promoter methylation was compared with various clinical characteristics and the TET methylation index (TE-MI). The TE-MI, representing the number of methylation events in TET family genes, was positively correlated with alcohol consumption (P = 0.004), high-risk human papilloma virus (HPV) status (P = 0.004) and disease recurrence (P = 0.002). The simultaneous methylation analysis of TET family genes was correlated with reduced disease-free survival in unfavorable event groups (log-rank test, P = 0.026). In the multivariate Cox proportional hazards analysis, TET3 methylation in T1 and T2 tumor stages, oropharyngeal cancer, and oral cancer patients exhibited high association with poor survival (hazard ratio: 2.64, P = 0.014; 3.55, P = 0.048; 2.63, P = 0.028, respectively). A joint analysis of the tumor suppressor gene methylation index showed a significant trend toward a higher TE-MI. The methylation status of TET3 was independently associated with aggressive tumor behavior and a global effect on DNA methylation status in HNSCC.