Interaction between the MTHFR C677T Polymorphism and Alcohol—Impact on Oral Cancer Risk and Multiple DNA Methylation of Tumor-related Genes

Abstract

Several studies have reported Oral Squamous Cell Carcinoma ( OSCC) association with etiological factors, such as smoking and alcohol. The aim of the present study was to establish whether the methylenetetrahydrofolate reductase ( MTHFR) C677T genotype and a high alcohol intake, solely or in interaction, have an impact on the oral cancer risk, DNA methylation, or multiple methylation of tumor-related genes. MTHFR C677T genetic polymorphism was determined by the PCR/RFLP method, and DNA methylation was assessed by nested methylation-specific PCR. The risk for multiple methylation was significantly increased in heavy-drinking patients with the TT genotype, compared with CC and CT patients (OR = 10.873; 95% CI, 1.134-104.24). Multiple methylation was significantly associated with tumor stage ( p = 0.018), and showed a trend of association with the presence of nodal metastases ( p = 0.058). A significant association was found between TT genotype and methylation status of the RASSF1A gene in OSCC patients ( p = 0.012). Heavy-drinking individuals with the TT genotype showed increased oral cancer risk compared with the CC genotype (OR = 3.601; 95% CI, 1.036-12.513), and compared with the CC and CT genotypes (OR = 4.288; 95% CI, 1.325-13.877). Our study suggested gene-environment interactions between high alcohol intake and the MTHFR 677TT genotype for elevated oral cancer risk, with a significant impact on multiple methylation of cancer-related genes.