Aberrant DNA methylation of the p16, APC, MGMT, TIMP3 and CDH1 gene promoters in tumours and the surgical margins of patients with oral cavity cancer

Abstract

Oral cavity cancer is a type of head and neck squamous cell carcinoma (HNSCC) and contributes to significant morbidity and mortality each year. An epigenetic pathway of transcriptional inactivation for many genes has been described in various cancers, including HNSCC. For our study, we selected genes for which silencing caused by hypermethylation can promote cancer development. In 75 primary HNSCC tumours and paired surgical margins, we investigated the methylation status of the p16, APC, MGMT, TIMP3 and CDH1 gene promoters by methylation-specific PCR after bisulphite treatment. The promoter methylation rates of p16, APC, MGMT, TIMP3 and CDH1 in tumours were 58.67%, 49.33%, 58.67%, 50.67%, and 57.33% and 50.67%, 41.33%, 37.33%, 42.67%, and 25.33% in the surgical margin, respectively. Our observations confirm the presence of epigenetic changes not only in the cancer cells, but also in the surrounding mucosa and represent a basis for further analysis to unravel these complicated issues. Appropriate cancer risk assessment based on epigenetic alterations in surgical margins may influence a patient's diagnosis and cure.

DNA Methylome Distinguishes Oropharyngeal and Oral Cancer from Oral Lesions and Healthy Oral Mucosa

“…Of particular interest in HNSCC diagnostic, clinical prognosis and/or risk assessment could be the methylation of CDH1, which was also previously described as possible biomarker for the early detection and treatment of HNSCC (43,47,57,58). Herein, we found the CDH1 gene to be signi cantly hypermethylated on speci c sites in the genome (body) on high second place in cancer tissues in comparison to control tissues.…”

“…Among them, CDH1, ETNK2, ADARB2 and RAB40C are found to be aberrantly methylated in different cancers (43)(44)(45)(46). For instance, altered methylation levels of CDH1 (Cadherin 1), whose loss contributes to cancer progression by increasing proliferation, invasion, and/or metastasis are recorded in oral cavity (43), oral (47) and in cervical cancer (48) The external validation of our top thirty differentially methylated gene promoters in HNSCC vs. control tissue with gene expression data in human cancer through Wanderer, an interactive viewer, gave a very good agreement. In summary, the majority of hypermethylated gene promoters in HNSCC in our study (10 of 15) were found to be either under-expressed or hypermethylated in TCGA cancer cases.…”

“…. The study of Strzelczyk et al(43) reported a signi cantly higher methylation level of CDH1 in tumor tissues compared to surgical margins (57% vs. 25% p < 0.001) in patients with oral cavity cancer. The meta-analysis of the gene promoter hypermethylation in oral cancer, that included 29 studies of which 13 were about CDH1 methylation, showed signi cant correlation of CDH1 hypermethylation with oral cancer risk(47).…”

Hypermethylation status of DAPK, MGMT and RUNX3 in HPV negative oral and oropharyngeal squamous cell carcinoma

“…CpG island hypermethylation in promoter region of TGSs as death-associated protein kinase (DAPK), O 6 -methylguanine DNA methyltransferase (MGMT) and runt-related transcription factor 3 (RUNX3) have been consistently observed in many human cancers (Kito et al, 2001;Raveh and Kimchi, 2001;Esteller and Herman, 2004;Subramaniam et al, 2009;Asada et al, 2013). These genes act in pathways of apoptosis, DNA repair and proliferative block, respectively, (Supic et al, 2011) and their inactivation can favor oncogenesis and progression of oral tumors (Towle and Garnis, 2012;D'Souza and Saranath, 2015).…”

Hypermethylated PAX1 and ZNF582 genes in the tissue sample are associated with aggressive progression of oral squamous cell carcinoma

“…Smoking, alcoholic consumption, and areca‐nut chewing are well‐known risk factors of OSCC 1 . The relationships between gene DNA methylation and habits of smoking or alcohol consumption are still uncertain 28‐30 . Additionally, the impact of risk factors on the correlation between hypermethylation of PAX1 and ZNF582 was still limited.…”