Identification Of Genetic Variants In Base Excision Repair Pathway And Their Associations With Risk Of Esophageal Squamous Cell Carcinoma

The etiology of esophageal sguamous cell carcinoma (ESCC) has been shown to be associated with genetic and certain environmental factors that produce DNA damage. Base excision repair (BER) genes are responsible for repair of DNA damage caused by reactive oxygen species and other electrophiles and therefore are good candidate susceptibility genes for ESCC. We first screened eight BER genes for new and potential functional polymorphisms by re-sequencing 27 DNA samples of Chinese population. We then identified and genotyped for important tagging SNPs in a case-control study of 419 patients with newly diagnosed esophageal cancer and 480 healthy controls by frequency-matching on age and sex. The association between genotypes and ESCC risk was estimated by unconditional multivariate logistic regression analysis, and stepwise regression procedure was used for constructing the final logistic regression model. We identified 129 SNPs in the eight BER genes, including 18 SNPs that cause amino acid changes. In the final model, four SNPs, including two in the coding regions {ADPRT Val 762Ala and MBD4 Glu346Lys) and others in non-coding regions (LIG3 A3704G and XRCC1 T-77C), remained as significant predictors for the risk of ESCC. The adjusted odd ratios were 1.25 (95% confidence interval 1.02-1.53) for the ADPRT 762Ala allele, 1.25 (95% confidence interval 1.02-1.53) for the MBD4 346 Lys allele, 0.78 (95% confidence interval 0.63-0.97) for the LIG3 3704G allele, 1.38 (95% confidence interval 1.01-1.89) for the XRCC1 -77C allele. In addition, we observed a significant gene-gene interaction between XRCC1 Gln399Arg and ADPRT Val762Ala. The results suggest that the polymorphisms in five BER genes may be associated with the susceptibility to ESCC in a Chinese population.