SUSCEPTIBILITY TO MOLECULAR ALTERATION: EPITHELIAL CELLS

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The objectives for this K23 Mentored Patient Oriented Research Award are to acquire conceptual and technical skills in cancer genetics, molecular epidemiology, and patient oriented research and subsequently to apply these skills to improve the survival of patients with lung cancer or at risk for developing lung cancer. These goals will be achieved through a comprehensive program that includes formal education, patient oriented research and clinical activities. The educational program will include courses on molecular genetics, clinical epidemiology and clinical research. Regular participation in national meetings and symposia related to cancer and molecular genetics will be an essential part of the educational program. The clinical activities will be focused on lung cancer. The long-term objective for the patient oriented research project is to identify the environmental and genetic factors that are responsible for the increased incidence of lung cancer in women. Recent statistical trends and case-control studies suggest that women are more susceptible to lung cancer than men with similar tobacco exposure. The goal for this research project is to determine if biomarkers of DNA exposure to carcinogens (DNA adducts) and biomarkers of effect (loss of heterozygosity and p53 mutations) in epithelial cells are involved in lung cancer susceptibility in women. The specific aims of the project are to determine if the extent of epithelial cell DNA adducts, LOH, and p53 mutations in women is different than in men with similar tobacco exposure and to determine the effect of gender, genetic polymorphisms, and diet on the relationships among these biomarkers of exposure and biomarkers of effect. This study will evaluate 60 female and 60 male middle aged smokers. Biomarkers will be evaluated in epithelial cells from the lung, bladder and oropharynx from all individuals. Polymorphisms of CYP1A1 and GSTM1 and dietary intake of vitamins and carotenoids will be characterized. These experiments will provide important information on how genetic and environmental factors are involved in lung cancer susceptibility in women. The definition of these mechanisms may allow the prospective identification of individuals at increased risk for developing lung carcinoma.