Biomarkers of NNK in prediction of lung cancer development in smokers

描述(申请人提供)：肺癌是美国和世界范围内癌症死亡的主要原因。吸烟导致了大约90%的肺癌。然而，大约只有15%的终身吸烟者在他们的一生中患上肺癌。吸烟者对肺癌的易感性的差异不仅取决于他们接触烟草致癌物，还取决于遗传、饮食和其他环境因素。香烟烟雾中的烟草特有亚硝胺(NNK)是导致人类肺癌的最重要的致癌物质之一。这项拟议的研究旨在评估有效的尿NNK摄取和代谢生物标志物在预测当前吸烟者肺癌发展中的作用。这项拟议的研究将利用两个既定的中国人居住队列。上海队列研究招募了18,244名年龄在45岁-之间的男性，1986年至1989年在上海的中国。新加坡华人健康研究在1993-98年间招募了27,959名男性和35,298名女性，年龄在45-74岁之间。在招募时，所有队列成员都提供了详细的饮食和病史。血液和尿液样本来自所有上海队列成员和大约60%的新加坡队列成员。通过常规的确定方法，对癌症和死亡的发生情况进行了队列跟踪。到2012年底，预计这两个队列的肺癌病例总数将达到1317例。对于拟议的研究，将在两个队列中随机选择相同数量的对照。我们将测量所有研究对象的血清中NNAL和NNAL-GLucs(NNK代谢物)、总尼古丁当量(即尼古丁、可替宁、反式-32-羟基可替宁和它们对应的葡萄糖醛酸化物的总和)、总异硫氰酸酯、β-隐黄素和其他饮食抗氧化剂的浓度。NNK和尼古丁代谢基因的遗传多态也将被确定。具体目的是(1)确定诊断前尿液中的总NNAL和NNAL-GLucs：NNAL比率是否在患肺癌和未患肺癌的患者之间存在差异，但在年龄、性别、研究登记日期、吸烟状况、一生中的强度和持续时间以及尿总尼古丁当量方面具有可比性；以及(2)确定NNK和尼古丁代谢基因的遗传多态以及饮食因素是否改变了NNK生物标志物与肺癌发生之间的关联。这项拟议研究的最终目标是开发一套有效的非侵入性、可预测的肺癌发展标志物，以便在吸烟者中识别出相对较少的肺癌高危个体。可密切跟踪肺癌高危人群及早发现肺癌，并鼓励他们改变生活方式，例如戒烟。此外，化学预防药物，如果有的话，可以开给高危人群，以防止肺癌的发展。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States and worldwide. Cigarette smoking causes approximately 90 percent of lung cancer. However, approximately only 15 percent of lifelong smokers develop lung cancer over their lifetimes. The variation in the susceptibility to lung cancer among smokers not only depends on their exposure to tobacco carcinogens, but also upon genetic, dietary, and other environmental factors. Tobacco- specific nitrosamines (i.e., NNK) in cigarette smoke is among the most important carcinogens that cause lung cancer in humans. The proposed study is to assess the role of validated urinary biomarkers for the uptake and metabolism of NNK in prediction of lung cancer development among current smokers. The proposed study will utilize two established residential cohorts of Chinese. The Shanghai Cohort Study enrolled 18,244 men aged 45-64 years in Shanghai, China, during 1986-89. The Singapore Chinese Health Study enrolled 27,959 men and 35,298 women aged 45-74 years during 1993-98. At recruitment, all cohort members provided detailed dietary and medical histories. Blood and urine specimens were collected from all Shanghai cohort members and about 60 percent of Singapore cohort members. The cohorts have been followed for the occurrence of cancer and death through routine ascertainment approaches. By the end of 2012, a total of 1317 incident lung cancer cases will be expected in the two cohorts. An equal number of controls will be randomly chosen among the two cohorts for proposed studies. We will measure the concentrations of NNAL and NNAL-Glucs (NNK metabolites), total nicotine equivalents (i.e., the sum of nicotine, cotinine, trans-32-hydroxycotinine and their corresponding glucuronides), and total isothiocyanates in urine, and beta-cryptoxanthin and other dietary antioxidants in serum on all study subjects. Genetic polymorphisms in NNK- and nicotine-metabolizing genes also will be determined. The specific aims are (1) to determine if total NNAL and NNAL-Glucs:NNAL ratio in prediagnostic urines differ between those who develop lung cancer and those who remain free of cancer, but are otherwise comparable in terms of age, gender, date of study enrollment, smoking status, intensity and duration over lifetime, and urinary total nicotine equivalents; and (2) to determine if genetic polymorphisms in NNK- and nicotine-metabolizing genes and dietary factors modify the association between NNK biomarkers and development of lung cancer. The ultimate goal of the proposed research is the development of an effective set of non-invasive, predictive markers of lung cancer development that allow for the identification, among smokers, of the relatively small fraction of individuals who are at very high risk for lung cancer. People with high risk for lung cancer could be closely followed for early detection of lung cancer and encouraged to change their lifestyles, e.g., quitting smoking. In addition, chemopreventive agents, if available, could be prescribed to high-risk people for protection against lung cancer development.