TOBACCO AND CANCER RISK--DOSE, METABOLISM AND GENETICS

描述（申请人描述）我们小组和其他人的研究表明，烟草相关癌症的风险因种族、性别和消费的烟草产品类型而异。这些重要的公共卫生差异不能用现有的烟草消费模式来充分解释。我们假设风险与吸烟类型有关（例如，致癌物的低产量与中等产量），个人吸烟习惯调节到达肺部的剂量的方式，激活和解毒烟雾致癌物质的代谢能力，以及与可能影响代谢或DNA修复的遗传因素相关的癌症易感性。在研究的前三年，该项目侧重于流行病学，剂量和剂量的生物标志物，以及致癌物质激活和解毒的代谢途径。在未来一段时间内，前项目（流行病学）将被一个流行病学核心设施（C核心）所取代，为两个继续进行的项目和一个新项目提供适当的研究对象。目前的项目（吸烟者肺癌和膀胱癌风险的剂量测定）是关于吸烟行为如何影响“传递”的致癌物剂量，以及剂量如何与致癌物代谢物的生物标志物相关。项目（美国黑人和白人烟草相关癌症的代谢流行病学）是一项研究非裔美国人和白种人在吸烟引起的一系列致癌物的代谢激活和/或解毒方面的差异，如NNK（一种强效肺癌致癌物）和4-氨基联苯（一种膀胱癌致癌物）。它利用代谢和分子技术研究与肺癌相关的烟草衍生亚硝胺的激活途径，非洲裔美国人的肺癌发病率高于高加索人，以及膀胱癌中涉及的芳香胺的解毒作用，其发病率较低。项目（UDP葡萄糖醛酸糖基转移酶，NNK解毒和肺癌风险）关注的是一个解毒酶家族，该家族可能与肺癌或膀胱癌的个体风险有关，并且存在可能解释癌症风险变化的遗传多态性。更广泛地了解这些因素，无论是单独的还是全面的，将极大地有助于我们了解与烟草有关的癌症的原因，从而有助于改进我们的预防策略。两位研究者都是各自领域的领导者，有着悠久的合作历史。该项目由一个由杰出科学家和社区代表组成的顾问委员会组成的行政核心机构提供支持，由一个生物统计学和计算核心机构提供有效的数据管理和统计支持，由一个流行病学核心机构管理受试者的累积、访谈、口腔细胞、尿液和血液的采集，用于生物标志物分析和病理检查。

DESCRIPTION (Applicant's Description) Studies from our group and others have demonstrated that the risk for tobacco-related cancers differs by race, gender and type of tobacco product consumed. These important public health differences cannot be fully explained by existing patterns of tobacco consumption. We hypothesize that risk is related to the type of cigarette smoked (e.g., low versus medium yield of carcinogens), the manner in which an individual's smoking habit regulates the dosage that reaches the lungs, metabolic capacity to activate and detoxify smoke-borne carcinogens, and susceptibility to cancer related to genetic factors that may affect metabolism or DNA repair. During the first three years of the study, the program focused on epidemiology, dosage and biomarkers of dose, and metabolic pathways of carcinogen activation and detoxification. In the coming period, the former Project (epidemiology) will be replaced by an epidemiological core facility (Core C) to provide appropriate study subjects for the two continuing projects and one new project. The current Project (Dosimetry of Lung and Bladder Cancer Risk among Cigarette Smokers) is about how smoking behavior affects the "delivered" carcinogen dose, and in turn how dose is related to biomarkers of carcinogen metabolites. Project (Metabolic Epidemiology of Tobacco-Related Cancers in Black and White Americans) is a study of differences between African Americans and Caucasians in metabolic activation and/or detoxification of an array of carcinogens derived from cigarette smoking, such as NNK (a potent lung carcinogen) and 4-aminobiphenyl (a bladder carcinogen). It utilizes metabolic and molecular techniques to study pathways of activation of tobacco-derived nitrosamines related to lung cancer, which is higher in African Americans compared to Caucasians, as well as detoxification of aromatic amines involved in bladder cancer, the rate of which is lower. Project (UDP Glucuronosyltransferases, Detoxification of NNK and Lung Cancer Risk) focuses on a family of detoxification enzymes that may be related to individual risk for developing lung or bladder cancer, and for which genetic polymorphisms exist that might explain variation in cancer risk. A broader understanding of these factors, both individually and comprehensively, will contribute greatly to our understanding of the causes of tobacco-related cancers in a way that can help improve our prevention strategies. The investigators are leaders in their respective fields with a strong history of collaboration. The program is supported by an Administrative Core with an Advisory Board of distinguished scientists and a community representative, by a Biostatistics and Computing Core Facility to provide efficient data management and statistical support, and by an Epidemiology Core Facility to manage accrual of subjects, interviews, acquisition of buccal cells, urine, and blood for biomarker assays, and pathological review.