TOBACCO AND CANCER RISK--DOSE, METABOLISM AND GENETICS

描述（申请人的描述）我们小组和其他人的研究已经证明，烟草相关癌症的风险因种族、性别和所消费的烟草产品类型而异。 这些重要的公共健康差异不能完全用现有的烟草消费模式来解释。 我们假设风险与吸烟的类型有关（例如，这些因素包括：致癌物的浓度（低与中等）、个人吸烟习惯调节到达肺部的剂量的方式、激活和解毒烟雾传播的致癌物的代谢能力，以及与可能影响代谢或DNA修复的遗传因素有关的癌症易感性。 在研究的前三年，该计划侧重于流行病学，剂量和剂量的生物标志物，以及致癌物活化和解毒的代谢途径。 在未来一段时期，前项目（流行病学）将由流行病学核心设施（核心C）取代，为两个持续项目和一个新项目提供适当的研究课题。 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“递送”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（黑人和白色美国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高加索人在代谢活化和/或来自吸烟的一系列致癌物（如NNK（一种强效肺癌原）和4-氨基联苯（一种膀胱癌原））的解毒方面的差异。 它利用代谢和分子技术来研究与肺癌相关的烟草衍生亚硝胺的活化途径，与高加索人相比，非洲裔美国人的亚硝胺含量更高，以及膀胱癌中涉及的芳香胺的解毒，其比率较低。项目（UDP葡萄糖醛酸转移酶，NNK的解毒和肺癌风险）专注于解毒酶家族，可能与患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。 对这些因素的更广泛的理解，无论是单独的还是全面的，都将大大有助于我们理解与烟草有关的癌症的原因，从而有助于改进我们的预防战略。 研究人员是各自领域的领导者，具有强大的合作历史。 该计划由一个由杰出科学家和社区代表组成的咨询委员会的行政核心支持，由生物统计学和计算核心设施提供有效的数据管理和统计支持，并由流行病学核心设施管理受试者，访谈，获取颊细胞，尿液和血液用于生物标志物测定和病理学审查。

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.