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表明，与烟草相关的癌症的风险因种族、性别和消费的烟草产品类型而不同。这些重要的公共卫生差异不能用现有的烟草消费模式完全解释。我们假设风险与吸烟的类型有关(例如，致癌物的低和中产量)，个人吸烟习惯调节到达肺部的剂量的方式，激活和解毒烟雾携带的致癌物的代谢能力，以及与可能影响新陈代谢或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记物，以及致癌物激活和解毒的代谢途径。在今后一段时期内，以前的项目(流行病学)将被一个流行病学核心设施(核心C)所取代，以便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(吸烟人群中肺癌和膀胱癌风险的剂量学)是关于吸烟行为如何影响“输送”的致癌物剂量，进而研究剂量与致癌物代谢物的生物标志物之间的关系。项目(美国黑人和白人烟草相关癌症的代谢流行病学)是一项关于非裔美国人和高加索人在吸烟产生的一系列致癌物质的代谢激活和/或解毒方面的差异的研究，这些致癌物质包括NNK(一种强有力的肺癌物质)和4-氨基联苯(一种膀胱癌物质)。它利用代谢和分子技术来研究与肺癌相关的烟草亚硝胺的激活途径，与高加索人相比，非裔美国人的亚硝胺水平更高，以及与膀胱癌相关的芳香胺的解毒作用，后者的比例较低。该项目(UDP葡萄糖醛酸基转移酶、NNK的解毒和肺癌风险)专注于一组解毒酶家族，这些解毒酶家族可能与个人患肺癌或膀胱癌的风险有关，并且存在基因多态，可能解释癌症风险的变化。更广泛地了解这些因素，无论是单独的还是全面的，都将大大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战略。调查人员是各自领域的领导者，有着很强的合作历史。该计划得到了由杰出科学家和社区代表组成的咨询委员会组成的行政核心的支持，由生物统计和计算核心设施支持，以提供有效的数据管理和统计支持，以及由流行病学核心设施支持，以管理受试者、访谈、获取口腔细胞、尿液和血液以进行生物标记物分析和病理审查的应计费用。

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.