The leading cause of lung cancer is well known to be cigarette smoking. The incidence of this disease is alarmingly high, and despite the use of modern diagnostic and treatment modalities, the overall cure rate for lung cancer remains low. Thus, preventive efforts based upon knowledge of risk factors are of paramount importance in controlling this deadly disease. A better understanding of the molecular and cellular biology of lung cancer is clearly important for development of truly effective strategies for prevention. Among the most promising research in this area is that which has identified three genes associated with susceptibility to lung cancer. Polymorphisms in debrisoquine sulfate metabolism (controlled by the CYP 2D6 gene), aryl hydrocarbon hydroxylase inducibility (controlled by the CYP 1A1 gene), and glutathione (GSH)-S-transferase mu activity (controlled by the GST-1 gene), have all been independently associated with lung cancer susceptibility. We propose a large case-control study integrated with a molecular biologic approach to definitively study these polymorphisms and their association with lung cancer risk. The debrisoquine hydroxylation and Aryl Hydrocarbon Hydroxylase (AHH) inducibility polymorphisms are hypothesized to act by the metabolic enhancement of the production of tobacco-related carcinogens. The dominantly inherited absence of glutathione-S-transferase mu is hypothesized to confer susceptibility through its inability to bind and detoxify reactive carcinogens. We hypothesize that the population with the combination of (1) the traits enhancing production of carcinogenic metabolites (high risk metabolic polymorphisms in debrisoquine hydroxylase and AHH inducibility) and (2) the trait that results in absence of the ability to detoxify reactive production (GSH-S-transferase mu deficiency), will be at greatly increased lung cancer risk. We further hypothesize that this risk will be significantly modified by asbestos exposure, occupational exposure to substrate carcinogens and diet. We also propose, as part of the project, to process tissue from all volunteers for testing other hypotheses in the companion projects.
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