Association of TET3 epigenetic inactivation with head and neck cancer

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.

Prostanoid receptor genes confer poor prognosis in head and neck squamous cell carcinoma via epigenetic inactivation

“…DNA methylation is a frequent and key epigenetic mechanism underlying the regulation of processes associated with neoplastic transformation [38]. Recently, TET proteins have been identified as important epigenetic modifiers via their dioxygenase activity [39]. TET expression and activity are inhibited by genetic mutations and high methylation of their own promoters [40].…”

Epigenetic Modifications in Head and Neck Cancer

“…They showed that reduced methyl donor was associated with increased expression of TET-1 in HPV-positive HNSCC cell line. The aberrantly methylated TET enzymes in HNSCC patients were studied by Misawa et al (2018a), who reported lower expression of TET-1 and TET-3 in HNSCC, while methylation level of these genes was higher in cancer cells, suggesting that downregulation of TET-1 and TET-3 must have been associated with their promoter methylation. Moreover, the multivariate analysis revealed that TET-3 methylation in OSCC and oropharyngeal cancer was connected with poor survival of HNSCC patients (Misawa et al 2018a).…”

Genes Located on 18q23 Are Epigenetic Markers and Have Prognostic Significance for Patients with Head and Neck Cancer

“…Dissociation curves were carried out at the end of each PCR by following a 3-step procedure. Analysis was performed using the software (version 1.03A) for the Thermal Cycler Dice Real Time System TP800 (TaKaRa), according to the manufacturer’s directions [33,34].…”