Tobacco consumption, genetic susceptibility, gene-environment interaction and lung cancer risk

Introduction. Lung cancer is the most common cancer and the leading cause of cancer death worldwide. Tobacco smoking has been established as the most important etiological factor of lung cancer for both men and women. However only a fraction of the smokers will eventually develop lung cancer, depending on the extent of smoking, exposure to other environmental carcinogens and individual susceptibility. To elucidate the etiological mechanism of lung carcinogenesis, and identify high-risk individuals for disease prevention and control, we studied host susceptibility and its interactions with environmental factors on the risk of lung cancer.;Methods. There are three parts in this dissertation. First, to evaluate the effects of different tobacco consumption habits (smoking, chewing) on lung cancer risks, data from a hospital-based case-control study from southern India comprised of 778 male lung cancer cases and 3430 male controls were analyzed. Second, to assess the relationship between genetic variations and lung cancer risks, and their possible gene-gene and gene-environmental interactions, genetic polymorphisms were assayed in a multicenter case-control study in Eastern Europe that included 2188 lung cancer cases and 2198 hospital controls. Third, to demonstrate the application of hierarchical modeling, a case-control study of bladder cancer was used.;Results. Bidi smoking was found to be at least equally carcinogenic as cigarette smoking. Genetic polymorphisms may influence individual susceptibility to lung cancer. The magnitude of the effect is modulated by levels and types of exposures to carcinogens. The effect of genetic polymorphism is often moderate. However, when considering multiple genes simultaneously, number of prior risk alleles is associated with a significant increase of lung cancer risk. Moreover, the combination of certain occupational exposures and risk genotypes may increase lung cancer risk to a considerable extent. Hierarchical modeling may improve the estimation by increased precision and incorporating prior knowledge.;Significance. The results of this proposed study may offer a more complete picture of the association of lung cancer risk with tobacco consumption, genetic susceptibility and gene-environmental interaction. The findings of the study will help to clarify etiological mechanisms of lung cancer development for effective cancer prevention and control.