The leading known cause of lung cancer is cigarette smoking, and current research indicates that genetically-determined polymorphisms in aryl hydrocarbon hydroxylase (AHH), glutathione (GSH)-S-transferase mu and debrisoquine hydroxylation also affect the risk of lung cancer in smokers. Other work indicates that asbestos exposure and dietary intake of carotenoids are additional factors that modify lung cancer risk. The mechanisms underlying these important interactions are unknown; however, the formation of carcinogen-DNA adducts is thought to play a crucial role in smoking-related carcinogenesis and is considered a measure of biologically effective dose. We propose to test whether the aforementioned genetic and environmental factors are associated with variations in the burden of DNA damage in the target tissue (lung) by examining DNA adducts. DNA from nontumorous lung samples from 330 patients with lung cancer will be isolated and the levels of DNA adducts determined by the nuclease-P1 32P-postlabeling assay. The effects of genetic polymorphisms associated with increased cancer risk on lung DNA adduct levels will then be assessed. The effects of asbestos exposure and carotenoid intake on DNA adducts levels will also be assessed. Measurements of DNA damage in peripheral blood cells are used as surrogate markers for DNA damage in the lung. We will measure DNA adduct levels in blood mononuclear cells (MNCs) from lung cancer cases and examine the relationship of DNA adduct levels of lung tissue and those observed in the DNA from peripheral blood MNCs and determine whether genetic factors modify blood MNC adduct levels. In addition, we will measure DNA adducts in blood MNCs from the 330 control subjects and assess whether genetic factors also modify adduct levels in blood MNCs from persons without lung cancer. In all cases and controls, the MNC adduct levels will be correlated with other markers of genotoxicity (sister chromatid exchange, hprt mutation). These studies will indicate the extent to which genetic markers of cancer risk are associated with increased DNA adduct levels and whether DNA adduct levels in MNCs are predictive of DNA damage in lung tissue and whether they are associated with cytogenetic and mutational changes in blood lymphocytes. The data generated will represent the most extensive analysis of DNA adducts as indicators of biologically effective dose that has yet been carried out in humans.
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