Haplotype of Aryl Hydrocarbon Receptor Gene Affects Lung Cancer Development

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MM1-O-02 Introduction: Lung cancer is a leading cause of cancer-related death in worldwide. Extensive epidemiologic data clearly establish cigarette smoking as the major cause of this malignancy. Although up to 90% of lung cancer is attributable to smoking, only 10% of smokers develop lung cancer. This observation suggests a possibility that individual variation of aryl hydrocarbon receptor (AhR), gene related in the metabolism of tobacco carcinogens, may determine susceptibility to lung cancer. Therefore, in the present study, we tried to evaluate the role of AhR genetic polymorphisms in the etiology of lung cancer. Methods: Three AhR SNPs (Ex1+185A>G, IVS7+33T>G, and Ex10+501G>A) were selected using the SNP500Cancer database (http://snp500cancer.nci.nih.gov/home.cfm) and Dan Stram's haplotype-tagging SNP program (tagSNPsv2.exe) and then genotyped by SNP-IT or SNaPShot assay in 616 lung cancer cases and 616 cancer-free controls. Individual haplotypes were estimated from genotype data using the PHASE program (ver. 2.0.2) and unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence interval (95% CI) according to genotypes, haplotypes, and diplotypes of the AhR gene. Results: When the effect of selected AhR alleles on lung cancer risk was evaluated separately, any AhR genotype did not show the association with lung cancer risk. However, when haplotypes were constructed with selected AhR alleles (Ex1+185A>G, IVS7+33T>G, and Ex10+501G>A), GTA or AGG haplotype was found to reduce the risk of lung cancer compared with GGG, most common haplotype (GTA, adjusted OR, 0.799; 95% confidence interval [CI], 0.646–0.989; and AGG, adjusted OR, 0.802; 95% CI, 0.645–0.997, respectively). Moreover, subjects with 1 or 2 GGG haplotype showed significantly increased risk of lung cancer than those without GGG haplotype (adjusted OR, 1.377; 95% CI, 1.080–1.755). Particularly, smokers with 1 or 2 GGG haplotype showed highly significant and increased risk of lung cancer than nonsmokers without GGG haplotype (OR, 3.388; 95% CI, 2.310–4.971). Interestingly, this interactive effect between AhR haplotype (gene) and smoking (environment) was apparent in squamous cell carcinoma (OR, 10.189; 95% CI, 4.810–21.584). Discussion and Conclusions: Our results suggest that haplotypes of AhR gene play an important role in the development of lung cancer and have interactive effect with smoking for the lung cancer risk.

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