Abstract
BackgroundEsophageal squamous cell carcinoma (ESCC) is very common in China and is also one of the most common cancers worldwide. The purpose of this study was to examine the associations between genetic variants of various cancer-related genes and the risk of ESCC.MethodsIn this study, we first examined the association between 18 potentially disruptive genetic variants of 17 genes, including alcohol dehydrogenase 4 (ADH4) and checkpoint kinase 2 (CHEK2), and ESCC risk in a Hangzhou population of 617 patients matched with 534 controls. Among the 18 single nucleotide polymorphisms (SNPs), two were validated in a Jinan population of 540 patients matched with 550 controls.ResultsSixteen SNPs in 15 genes, including CHEK2, did not have significantly different allele frequency distributions between ESCC patients and control subjects. A significantly increased risk of developing ESCC was revealed in subjects with the AA genotype of rs3805322 (ADH4) compared with those with the AG or GG genotype by unconditional univariate logistic regression analysis. Using a dominant model, the CC genotype of rs4822983 (CHEK2) had a marginally significant protective effect compared to the CT and TT genotypes. The association of ESCC risk with these two SNPs (rs3805322 and rs4822983) was further validated in a Jinan case-control set. Individuals with the ADH4 rs3805322 AA or AG genotype had ORs of 1.10 (95% CI = 0.81–1.49, P < 0.001) or 1.86 (95% CI = 1.33–2.59, P = 0.559), respectively, for developing ESCC compared with individuals with the GG genotype. CHEK2 rs4822983 CC carriers showed a marginally significantly decreased ESCC risk compared with those carrying the CT and TT genotypes in the validation set (95% CI = 0.61–1.01, P = 0.064). However, no evidence of interaction existed between the two SNPs and smoking or drinking in the Jinan case-control set.ConclusionsIn conclusion, this current study provides substantial evidence that genetic polymorphisms of rs3805322 in the ADH4 gene may be associated with an increased risk of developing ESCC in two Chinese Han populations. Future studies to address the biological function of this polymorphism in the development of ESCC are warranted.
Highlights
Esophageal cancer (EC) is regarded as one of the most common and fatal malignant tumors in the world
A significantly increased risk of developing Esophageal squamous cell carcinoma (ESCC) was revealed in subjects with the AA genotype of rs3805322 (ADH4) compared with those with the AG or GG genotype by unconditional univariate logistic regression analysis
Individuals with the alcohol dehydrogenase 4 (ADH4) rs3805322 AA or AG genotype had odds ratio (OR) of 1.10 or 1.86, PLOS ONE | DOI:10.1371/journal.pone
Summary
Esophageal cancer (EC) is regarded as one of the most common and fatal malignant tumors in the world. More than 90% of esophageal cancers are esophageal squamous cell carcinomas (ESCCs), which is the most common pathologic type in developing nations [1]. Accumulating epidemiological evidence indicates that tobacco smoking, substantial alcohol intake, micronutrient deficiency, and dietary carcinogen exposure can greatly increase the risk of developing squamous cell carcinoma [5]. All these factors can induce or enhance DNA damage, which initiates and/or promotes carcinogenesis. Various genes are involved in alcohol-associated carcinogenesis and DNA repair. Esophageal squamous cell carcinoma (ESCC) is very common in China and is one of the most common cancers worldwide.
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