Abstract
BackgroundEsophageal squamous cell carcinoma (ESCC) develops as a result of complex epigenetic, genetic and environmental interactions. Epigenetic changes like, promoter hypermethylation of multiple tumour suppressor genes are frequent events in cancer, and certain habit-related carcinogens are thought to be capable of inducing aberrant methylation. However, the effects of environmental carcinogens depend upon the level of metabolism by carcinogen metabolizing enzymes. As such key interactions between habits related factors and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of genes are likely. However, this remains largely unexplored in ESCC. Here, we studied the interaction of various habits related factors and polymorphism of GSTM1/GSTT1 genes towards inducing promoter hypermethylation of multiple tumour suppressor genes.Methodology/Principal FindingsThe study included 112 ESCC cases and 130 age and gender matched controls. Conditional logistic regression was used to calculate odds ratios (OR) and multifactor dimensionality reduction (MDR) was used to explore high order interactions. Tobacco chewing and smoking were the major individual risk factors of ESCC after adjusting for all potential confounding factors. With regards to methylation status, significantly higher methylation frequencies were observed in tobacco chewers than non chewers for all the four genes under study (p<0.01). In logistic regression analysis, betel quid chewing, alcohol consumption and null GSTT1 genotypes imparted maximum risk for ESCC without promoter hypermethylation. Whereas, tobacco chewing, smoking and GSTT1 null variants were the most important risk factors for ESCC with promoter hypermethylation. MDR analysis revealed two predictor models for ESCC with promoter hypermethylation (Tobacco chewing/Smoking/Betel quid chewing/GSTT1 null) and ESCC without promoter hypermethylation (Betel quid chewing/Alcohol/GSTT1) with TBA of 0.69 and 0.75 respectively and CVC of 10/10 in both models.ConclusionOur study identified a possible interaction between tobacco consumption and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of tumour suppressor genes in ESCC.
Highlights
The Esophageal cancer (EC) is the sixth most common cancer in men worldwide with distinct geographical differences in its incidence rate and pattern
Our study identified a possible interaction between tobacco consumption and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of tumour suppressor genes in Esophageal squamous cell carcinoma (ESCC)
The incidence and mortality rate of EC is highest in certain Asian countries, stretching from Northern Iran through the central Asian republics to North-Central China, referred to as the ‘‘esophageal cancer belt.’’ Around 90% of the esophageal cancers in these areas are squamous cell carcinomas (SCCs) and are thought to develop as a result of complex interactions between environmental, genetic and epigenetic factors [1]
Summary
The Esophageal cancer (EC) is the sixth most common cancer in men worldwide with distinct geographical differences in its incidence rate and pattern. The incidence and mortality rate of EC is highest in certain Asian countries, stretching from Northern Iran through the central Asian republics to North-Central China, referred to as the ‘‘esophageal cancer belt.’’ Around 90% of the esophageal cancers in these areas are squamous cell carcinomas (SCCs) and are thought to develop as a result of complex interactions between environmental, genetic and epigenetic factors [1]. These interactions are not well understood in ESCC. We studied the interaction of various habits related factors and polymorphism of GSTM1/GSTT1 genes towards inducing promoter hypermethylation of multiple tumour suppressor genes
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