Lung cancer is the most common cause of cancer mortality among both men and women in the United States. Although up to 90 percent of lung cancer is attributable to cigarette smoking, only 10-20 percent of smokers develop bronchogenic carcinoma over their lifetimes. This observation, along with substantial literature implicating heritable polymorphic factors, indicates that other environmental and host factors influence individual susceptibility to tobacco smoke. This proposal will take advantage of recent advances in molecular epidemiology in this competing continuation (R01 CA 74386) by expanding our original aims of evaluating six xenobiotic metabolic polymorphisms in lung cancer to include the assessment of more recently described polymorphic genes that control oxidative metabolism (Phase I) and the conjugation of reactive intermediates (Phase II). In addition, a number of other polymorphic genes that affect lung inflammatory processes, DNA repair, growth factor function, and tumor suppression (oncogenes) will be evaluated, as there is accumulating evidence supporting the role of these non-metabolism polymorphic alleles in lung cancer development. Moreover, this proposal addresses the role of smoking, diet, and genetic factors as effect modifiers for the association between polymorphisms and lung cancer risk, and the potential roles of age and gender in these associations. To assess these gene-environment and gene gene associations in this expanded group of polymorphic genes, our proposal will build on our productive R01 by increasing our sample size and including greater population diversity by increasing minority recruitment. A better understanding of these risks will lead to improved preventive strategies. The proposal directly addresses two """"""""Extraordinary Opportunities"""""""" of the National Cancer Institute, specifically the aim to identify genetic variations that affect cancer risk in concert with environmental factors, and research on tobacco-related concerns.
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