Carcinogenesis Advance Access published online on March 6, 2009
Carcinogenesis, doi:10.1093/carcin/bgp058
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Genetic Susceptibility to Esophageal Cancer: The Role of the Nucleotide Excision Repair Pathway
1 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
2 Department of GI Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
3 Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
* Correspondence should be addressed to: Xifeng Wu, M.D., Ph.D., Department of Epidemiology, Unit 1340, The University of Texas M.D. Anderson Cancer Center, 1155 Hermann Pressler Blvd., Houston, Texas 77030. Telephone: (713) 745-2485, Fax: (713) 792-4657, E-mail: xwu{at}mdanderson.org
In this case-control study with 387 White esophageal patients and 462 White controls matched to cases by age and sex, we evaluated the associations between thirteen potential functional polymorphisms in eight major nucleotide excision repair (NER) genes and esophageal cancer risk. In individual SNP analysis, after adjustment for multiple comparisons, the heterozygous GT genotype of the ERCC1 3’UTR was associated with an increased risk, while the homozygous variant genotype TT was associated with 60% reduction in risk with an odds ratio (OR) of 0.40 (95% CI = 0.19-0.86). The heterozygous AG genotype of XPA 5’UTR was at 2.11-fold increased risk (95% CI = 1.33-3.35) and the risk reached 3.10 fold (95% CI = 1.94-4.95) for the homozygous variant GG genotype. These associations were also significant when restricted the analyses in patients with esophageal adenocarcinoma. Further, the CT genotype of the RAD23B Ala249Val was associated with increased esophageal cancer risk (OR = 1.44; 95% CI = 1.05-1.97) while the PAT-/+ genotype of the XPC intron9 conferred a decreased risk (OR = 0.71, 95% CI = 0.51-0.97). In joint analysis, individuals carrying 1 (OR = 2.64, 95%CI = 1.57-4.52), 2 or more (OR = 2.74, 95%CI = 1.58-4.75) unfavorable genotypes exhibited significantly increased risk for esophageal cancer risk with significant dose-response trend (P for trend = 0.006). The pathway-based risk was more evident in ever smokers, overweight/obese individuals, men, and ever drinkers. Our results support the hypothesis that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of esophageal cancer. These findings warrant further replications in different populations.
Key Words: Nucleotide excision repair • esophageal cancer • case-control study
Received September 19, 2008; revised March 2, 2009; accepted March 3, 2009.