Genetic traits that confer increased susceptibility to DNA and chromosomal damage by reactive epoxide and peroxides could be important individual risk factors in the development of human cancers. In the present study we will focus on polymorphisms within the glutathione S-transferase (GST) family of enzymes as potential markers of susceptibility to carcinogen exposure. The special focus of these studies is to explore in depth the relationship of a newly discovered deletion polymorphism in GSTT1 with biomarkers of exposure, early biologic effect, and cancer occurrence--specifically childhood leukemia, and bladder cancer. Because the prevalence of the GSTT1 deletion is unknown in different populations, it is important to obtain background data on the distribution of the trait in different ethnic and racial groups. We will compare the prevalence of the GSTT1 deletion using a PCR based assay in various ethnic and racial groups including:Caucasian, Chinese, korean, African-American, and mexican, and Mexican Hispanic subjects. Next, studies will be undertaken to examine the role of the GSTT1 polymorphism as a modifier of biomarkers of genotoxicity associated with endogenous and environmental exposures. In vitro studies will be undertaken o test whether individuals deficient in GSTT1 are hypersensitive to chromosomal damage and DNA adducts induced by lipid hydroperoxides, which may be derived from the diet or through exposure to halogenated hydrocarbons. In addition, because of the possible involvement of chlorinated hydrocarbons contaminated drinking water and bladder cancer and leukemia, we will test the effects of GSTT1 deletion on trihalomethanes. Because GSTT1 is associated with background variations in SCE frequencies and is implicated in the detoxification of diet-related fatty acid hydroperoxides, we will examine the potential role of diet on the SCE marker and will correlate the SCE data with the levels of lipid peroxide DNA adducts. To examine the potential modification of cancer risk we will carry out case-control comparisons of the prevalence of the GSTM1 and GSTT1 deletion in childhood leukemia and correlate GSTT1 status with the mutational spectra within the p53 gene in bladder tumors. Mutation data and genotyping data will be merged with the ongoing epidemiologic projects to assess the possible relationships of GDT polymorphisms with dietary and environmental risk factors for childhood leukemia and bladder cancer.
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