Project 1: Lung carcinogen biomarkers in long-term tobacco users

确定个别烟草使用者的危害和易感性机制可大大有助于减少烟草引起的疾病。要造成危害，烟草烟雾中的致癌物必须被人体吸收和激活。血液中特定烟草致癌物的生物标志物已被确定用于测量有效剂量；其他生物标志物则测量这些致癌物破坏DNA的程度，从而表明个体的表型易感性。这项拟议的研究将评估烟草致癌物质暴露的生物标志物和吸烟者的代谢激活与他们患肺癌的风险之间的关系。这项研究将在前列腺癌、肺癌、结肠直肠癌和卵巢癌筛查试验（PLCO）中进行，这是一项多地点癌症筛查的随机试验，在全国超过15万名男性和女性中进行，其中约7000人目前是吸烟者。PLCO是开展这项活动的理想的流行病学环境，因为它提供了具有严格收集数据的吸烟人群的特征，具有筛查访问时收集的相关广泛的血液样本生物库，并消除了在部分筛查人群中发现的主要偏倚来源。来自PLCO生物资源库参与者的来源队列，他们报告

Identifying mechanisms of harm and susceptibility in individual tobacco users can greatly assist in reducing disease from tobacco. To do harm, the carcinogens in tobacco smoke must be absorbed and activated by the body. Biomarkers in blood for specific tobacco carcinogens have been identified that measure the effective dose; other biomarkers measure the degree to which those carcinogens have become capable of damaging DNA and so indicate the individual phenotypic susceptibility. This proposed study would estimate the association of biomarkers of tobacco carcinogen exposure and metabolic activation in smokers to their risk of developing lung cancer. The study would be nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a randomized trial of multi-site cancer screening in over 150,000 men and women nationwide, about 7,000 of whom are current smokers. The PLCO is an ideal epidemiologic setting for this activity, because it provides a well characterized smoking population with rigorously collected data, has an associated, extensive biorepository of blood samples collected at screening visits, and eliminates a major source of bias found in partially screened populations. From a source cohort of PLCO bio-repository participants who reported smoking on their baseline questionnaire, a sample of 300 incident lung cancer cases and 300 controls will be drawn and their demographic and baseline data obtained. After pooling their blood samples into triplets of similar risk (yielding 100 case and 100 control samples), each pooled sample will be analyzed to measure the specified metabolites. The biomarker levels in lung cancer subjects will be compared to those in non-lung cancer subjects and regression estimates will be made of the odds ratios of developing lung cancer associated with these biomarkers. In order to evaluate the variability of biomarker levels in individual smokers over time, a separate, longitudinal study will recruit 25 men and 25 women who are current smokers to give blood samples every two months for a year. These data will be used to strengthen the results of the case-control study by allowing a sensitivity analysis based on the within subject variance and to provide improved estimates. If successful, these data will improve 1) understanding of lung cancer etiology and 2) predictive models for lung cancer. We project that carcinogen metabolite phenotyping will enhance prevention, early detection, and risk reduction. Moreover, this study will validate the relationship to disease of biomarkers, thus supporting their use in other projects of this TTURC.