Environmental Exposure and DNA Damage

我的这个研究领域测试了环境暴露会产生DNA损伤模式的假设。这种模式既可以用来识别目标基因，也可以用来提示环境因素导致癌症的突变机制。如果特定的致癌物在肿瘤中产生特定的基因突变模式，那么对这些模式的检测将是研究环境风险和用于预防、早期诊断和预后的有力工具。我们正在进行的分子流行病学和临床研究中探索这一概念，旨在观察肿瘤前组织和靶组织正常组织以及正常淋巴细胞的小活检中的DNA损伤。长期目标是开发一种正常组织或“体细胞突变负荷”中DNA突变水平的定量测量方法。这样的指标可以提供一个组织特异性的终身环境暴露测量，综合饮食、遗传易感性和修复，并可能提供更精确的癌症、神经系统、生殖和其他疾病的风险估计，其中DNA损伤起作用。

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.