EXPOSURE SPECIFIC MUTATION IN CRITICAL TARGET GENES

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Summary of Work: Carcinoma of the lung, bladder, liver, and pancreas cancers have strong associations with environmental exposures, making them appropriate tumors in which to test the hypothesis that different environmental exposures cause different patterns of mutations in genes that initiate carcinogenesis. Laboratory analysis for two studies have recently been completed in the Molecular and Genetic Epidemiology Section (MAGES) in LMC: Dr. Stern has completed a study of p53 mutation in 64 aflatoxin-associated hepatocellular carcinomas from the Peoples Republic of China and Dr. Slebos has completed a study of K-ras mutation in pancreatic cancers where we have extensive exposure data on DDT, DDE and lifestyle risk factors. Both studies utilized laser capture microdissection to provide enriched tumor cell populations for study. Data analysis is still underway for both studies, although aspects of both studies were presented as posters at AACR. We are currently completing a manuscript on Polb mutation and alternative splicing in bladder tumors. Under a support contract with UNC we are just completing p53 mutational analysis for 200 bladder cancer cases for which we have detailed occupational exposure and extensive genotyping data. Microdissection of these tumors is providing purified tumor cell samples for the next task in this support contract: characterizing the tumors for chromosomal instability using LOH. In collaboration with Dr. Packenham and Ms Devereux we are completing a manuscript on comparative genomic hybridization analysis of selected bladder tumors from arylamine-exposed individuals. A new field study is in the final stages of development and will soon be ready for pilot field work. Fluorescence bronchoscopy and molecular characterization of abnormal bronchial lesions: novel approaches for early detection of lung cancer in high-risk patients obtains preneoplastic lesions in the endobronchial tree from people at high risk of developing lung cancer. Molecular alterations will be determined in these lesions and related to exposure history and probability of progression to higher grade lesions and frank carcinoma. - molecular epidemiology, mutation,carcinogenesis, bladder cancer, lung cancer, tumor suppressor gene, oncogene - Human Subjects