| Lung cancer is the leading cause of death from cancer in North America. While the vast majority of lung cancer cases are attributable to cigarette smoke exposure, among smokers there are substantial differences in the risk for lung cancer even taking into account cigarettes per day and years of smoking. Identifying and characterizing genetic factors that influence the relationship between smoking and lung cancer continues to be a priority. Among the thousands of chemicals in cigarette smoke, nicotine is critical in establishing and maintaining smoking behaviours, while nitrosamines are an important class of carcinogens that require metabolic processing by the body to exert their full carcinogenicity. Owing to the structural similarities between nicotine and nitrosamines, these chemicals interact with many of the same enzymes and receptors in the body. We demonstrate that genetic variation in the nicotine/nitrosamine metabolizing genes, CYP2A6 and CYP2B6, and in the nicotinic receptor subunit genes, CHRNA5- CHRNA3-CHRNB4, influence lung cancer risk among smokers, and that individuals with high-risk genotypes at more than one gene locus are at even greater risk of lung cancer. Importantly, CYP2A6 and CHRNA5-CHRNA3-CHRNB4 remain significantly associated with lung cancer risk after adjusting for daily cigarette consumption, suggesting that variation in these genes may be affecting lung cancer risk by influencing the carcinogenicity of nicotine/nitrosamines in addition to influencing carcinogen exposure through smoking behaviours. While these findings were in European Americans, a typically heavy smoking population, African Americans, a typically light smoking population, appear to suffer disproportionately from lung cancer risk. We demonstrate that variation in CYP2A6 also significantly influences lung cancer risk in this population. The findings from these studies implicate altered nicotine and nitrosamine pharmacology in the mechanism of lung carcinogenesis among smokers and may help inform the identification of smokers at increased risk of developing lung cancer, as well as inform the discovery of novel drug targets for lung cancer prevention and treatment. |
