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

查明个人烟草使用者的危害和易感性机制可以极大地帮助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并激活。血液中特定烟草致癌物的生物标记物已经被确定，用于测量有效剂量；其他生物标记物测量这些致癌物对DNA的破坏程度，从而表明个体的表型易感性。这项拟议的研究将评估吸烟者暴露于烟草致癌物质和代谢激活的生物标记物与其患肺癌风险的关系。这项研究将嵌套在前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验(PLCO)中，这是一项对全国超过15万名男性和女性进行多部位癌症筛查的随机试验，其中约7000人目前是吸烟者。PLCO是这项活动的理想流行病学环境，因为它为吸烟人群提供了严格收集的数据，拥有相关的、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见来源。来自PLCO生物信息库参与者的来源队列，他们报告 在他们的基线调查问卷上，将抽取300例肺癌病例和300名对照的样本，并获得他们的人口统计学和基线数据。在将他们的血液样本混合成三个相似风险的样本(产生100个病例样本和100个对照样本)后，将对每个混合样本进行分析，以测量指定的代谢物。肺癌患者的生物标记物水平将与非肺癌患者的水平进行比较，并将对与这些生物标记物相关的发生肺癌的优势比进行回归估计。为了评估个体吸烟者体内生物标记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，他们将在一年内每两个月采集一次血液样本。这些数据将用于加强 病例对照研究的结果，允许根据受试者内差异进行敏感性分析，并提供改进的估计。如果成功，这些数据将提高1)对肺癌病因的理解和2)肺癌的预测模型。我们预计致癌物代谢物表型将加强预防、早期发现和降低风险。此外，这项研究将验证生物标志物与疾病的关系，从而支持它们在本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.