Environmental Exposure and DNA Damage

点击翻译按钮获取中文摘要

This area of my research tests the hypothesis that environmental exposures produce patterns of DNA damage. Such patterns can be used both to identify target genes and to suggest mutational mechanisms by which an environmental agent causes cancer. If specific carcinogens produce characteristic patterns of gene mutation in tumors, the detection of those patterns would be a powerful tool in studies of environmental risk and for use in prevention, early diagnosis, and prognosis. We are exploring this concept in our ongoing molecular epidemiologic and clinical studies designed to look at DNA damage in small biopsies of preneoplastic and normal tissue from target tissues and in normal lymphocytes. A long term goal is to develop a quantitative measure of the level of DNA mutation in normal tissue or "somatic mutational load". Such a metric could provide a tissue specific measure of lifetime environmental exposure, integrated across diet, genetic susceptibility, and repair, and might offer a more precise estimate of risk for cancer, neurologic, reproductive, and other diseases where DNA damage plays a role. Fluorescence Bronchoscopy and Molecular Characterization of Abnormal Bronchial Lesions (LIFE Study): This ongoing molecular clinical study at UNC Hospitals GCRC is designed to test the hypothesis that exposure correlates with the pattern of mutation in premalignant and normal lung tissues and that such mutations may have prognostic significance for lung cancer development. We are using the Lung Imaging Fluorescent Endoscope (LIFE), a sensitive bronchoscopy technique to collect normal, premalignant, and neoplastic tissue samples from patients at high risk of lung cancer from smoking, occupational exposures, or because of family history. These people are followed over a 2 year period with repeat bronchoscopies and biopsy allowing us to follow the molecular changes in individual lesions over time. In addition we have a small pilot project the VALID study, jointly funded with UNC, to obtain optimally-collected tumor and normal tissue from patients undergoing thoracotomy for lung cancer. Colon Cell DNA Damage Study: We have initiated a new pilot study at UNC Hospitals GCRC entitled: Inhibition of Fried Meat-Induced DNA Damage: A Dietary Intervention Study. The primary aim of this study is to assess genetic damage to colonic epithelium and blood lymphocytes induced by compounds in certain foods, in particular the pyrolysis products formed in cooked meat, as well as the putative protective effects of certain dietary compounds against that damage. This study will be among the few to examine the interaction of genotoxic dietary components with ?protective? components on a molecular level. It is the first use of the alkaline single cell-gel (Comet) assay in a controlled feeding study to detect DNA damage in colonic epithelial cells, rather than in target tissue surrogates like lymphocytes. In addition, this research will have implications for choosing the most appropriate intermediate outcomes that would be predictive of cancer in prospective cohort studies; it will also have implications for dietary recommendations and the methodological approach to future feeding studies of genotoxicity in humans.