title: Identification of genetic variants in base excision repair pathway and their associations with risk of esophageal squamous cell carcinoma.
abstract: The etiology of esophageal squamous 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 resequencing 27 DNA samples. We then identified and genotyped for important tagging single nucleotide polymorphisms (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, 4 SNPs, including 2 in the coding regions (ADPRT Val762Ala and MBD4 Glu346Lys) and others in noncoding 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 (CI) 1.02-1.53] for the ADPRT 762Ala allele, 1.25 (95% CI 1.02-1.53) for the MBD4 346 Lys allele, 0.78 (95% CI 0.63-0.97) for the LIG3 3704G allele, and 1.38 (95% CI 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.
authors.affiliation: Laboratory of Systems Biology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
authors.forename: Bingtao
authors.initials: B
authors.lastname: Hao
authors.forename: Haijian
authors.initials: H
authors.lastname: Wang
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhou
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Gangqiao
authors.initials: G
authors.lastname: Zhou
authors.forename: Yunping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.forename: Dongxin
authors.initials: D
authors.lastname: Lin
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D036002:ADP Ribose Transferases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human