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

确定烟草使用者个人的危害和易感性机制可以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质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经被确定，可以测量有效剂量;其他生物标志物测量这些致癌物能够破坏DNA的程度，从而表明个体的表型易感性。这项拟议的研究将估计吸烟者中烟草致癌物暴露和代谢活化的生物标志物与其患肺癌风险的关联。该研究将嵌套在前列腺，肺，结直肠和卵巢癌筛查试验（PLCO）中，这是一项在全国超过15万名男性和女性中进行多部位癌症筛查的随机试验，其中约7，000人是目前的吸烟者。PLCO是这项活动的理想流行病学环境，因为它提供了一个特征明确的吸烟人群与严格收集的数据，有一个相关的，广泛的生物储存库的血液样本收集在筛选访视，并消除了主要来源的偏见，发现在部分筛选的人群。来自PLCO生物储存库参与者的源队列， 吸烟的基线调查问卷，将抽取300例肺癌病例和300例对照样本，并获得他们的人口统计学和基线数据。在将其血液样本合并为具有相似风险的三份样本（产生100份病例样本和100份对照样本）后，将对每份合并样本进行分析，以测定特定代谢物。将肺癌受试者中的生物标志物水平与非肺癌受试者中的生物标志物水平进行比较，并对发生与这些生物标志物相关的肺癌的比值比进行回归估计。为了评估个体吸烟者生物标志物水平随时间的变化，一项单独的纵向研究将招募25名男性和25名女性吸烟者，每两个月提供一次血液样本，持续一年。这些数据将用于加强 通过允许基于受试者内方差的敏感性分析，并提供改进的估计值，来评估病例对照研究的结果。如果成功，这些数据将提高1）肺癌病因学的理解和2）肺癌的预测模型。我们预计，致癌物质代谢物表型将加强预防，早期发现和风险降低。此外，本研究将验证生物标志物与疾病的关系，从而支持其在本TTURC的其他项目中的使用。

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.