Influence of MTHFR Genetic Background on p16 and MGMT Methylation in Oral Squamous Cell Cancer

Abstract

Genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) enzyme may influence DNA methylation. Alterations in DNA methylation patterns of genes involved in the regulation of the cell cycle, DNA repair, cell adherence and metastasis process are known to contribute to cancer development. In this study, the influence of the MTHFR C677T and A1298C gene polymorphisms on global DNA methylation and site-specific methylation on p16 and O6-methylguanine-DNA methyltransferase (MGMT) gene promoters was investigated in patients with oral squamous cell cancer (OSCC). To this aim, methylation studies were carried out by using genomic DNA isolated from saliva samples of 58 OSCC patients and 90 healthy controls. The frequency of the CT/AC and TT/AA genotypes was significantly higher in patients than in controls. Whereas no difference in global DNA methylation levels was observed between patients and controls, a higher frequency of methylation at both p16 and MGMT gene promoters was detected in patients compared with controls. A significant association between MTHFR gene polymorphisms and p16 and MGMT gene promoter methylation was found. The frequency of p16 and MGMT methylation was around 60% in patients with either the CT/AC or TT/AA genotype. Our results suggest that hypermethylation of cancer-related genes may be affected by MTHFR polymorphisms.

Response to Letter to the Editor “A window to consolidate the ‘functional hypothesis of bruxism’ through cardiovascular autonomic link”

“…However, we agree with Dr. Meira e Cruz and colleague that the impact of Bruxism and some other conditions such as periodontal, dental disorders (Briguglio, Briguglio, Briguglio, Cafiero, & Isola, 2013;Cannavale, Matarese, Isola, Grassia, & Perillo, 2013;Isola, Cicciù, Fiorillo, & Matarese, 2017), oral cancer (Isola et al, 2015;Ferlazzo et al, 2017), and similar conditions (Korfage & Van Eijden, 1999,2000 may affect, during aging, masticatory muscle structure, and physiology with a specific functional mechanisms.…”

Salivary Biomarkers for Oral Squamous Cell Carcinoma Diagnosis and Follow-Up: Current Status and Perspectives

“…As described in Table 1, many studies have applied salivary ctDNA in the management of head and neck squamous cell carcinoma (HNSCC) (Liao et al, 2000;El-Naggar et al, 2001;Viet and Schmidt, 2008;Sethi et al, 2009;Demokan et al, 2010;Carvalho et al, 2011;Guerrero-Preston et al, 2011;Sun et al, 2012;Rettori et al, 2013;Ramadoss et al, 2015;Wang et al, 2015;Ferlazzo et al, 2017;Lacombe et al, 2017). When HNSCC patients with tumors at the oral cavity, oropharynx, larynx, and hypopharynx were enrolled at the early stages (I and II) and late stages (III and IV), ctDNA was detected, respectively, in 100% of HNSCC patients enrolled at the early stages and in 95% enrolled at the late stages, with an enrichment in saliva of all patients affected by OSCC; this result is very specific for OSCC detection.…”

“…Numerous studies, comparing the methylation rate of genes involved in the cell cycle, proliferation, and apoptosis, found a difference in salivary samples of HNSCC patients and healthy subjects, demonstrating that salivary ctDNA methylation could be considered a very promising biomarker for HNSCC management and specifically OSCC diagnosis, prognosis, and follow-up (Viet et al, 2007;Viet and Schmidt, 2008;Sethi et al, 2009;Puttipanyalears et al, 2014). Epigenetic alterations such as DNA methylation rate can be easily detected in salivary ctDNA, proving to be a valuable sensitive and specific marker for OSCC diagnosis and prognosis (Demokan et al, 2010;Pattani et al, 2010;Guerrero-Preston et al, 2011;Ferlazzo et al, 2017). Moreover, the evaluation of the methylation status of genes, involved in OSCC development at diagnosis, seems to be useful as a predictive factor to develop a personalized therapy and assess the patient response during surveillance (Viet and Schmidt, 2008;Lacombe et al, 2017).…”

Functional and molecular outcomes of the human masticatory muscles

“…These differences also include the expression and composition of the MyLC; that is, compared to limb and trunk muscles, the masseter presents a higher expression of four different MyLC‐ 1emb/atrial, ‐1f, ‐1s, and ‐2s, that determines the tonic regulation of the fibers. Conversely, the muscles of limb and trunk express MyLC‐2f ‐3f, which is absent in the masseter (Ferlazzo et al., ; Soussi‐Yanicostas, Barbet, Laurent‐Winter, Barton, & Butler‐Browne, ; Stal et al., ).…”