Biomarkers of NNK in prediction of lung cancer development in smokers

描述（由申请人提供）：肺癌是美国和全世界癌症死亡的主要原因。吸烟导致大约90%的肺癌。然而，大约只有15%的终身吸烟者在其一生中患上肺癌。吸烟者对肺癌易感性的差异不仅取决于他们对烟草致癌物的暴露，还取决于遗传、饮食和其他环境因素。烟草特有的亚硝胺（即，香烟烟雾中的NNK）是导致人类肺癌的最重要的致癌物质之一。该研究旨在评估经验证的尿液生物标志物对NNK的吸收和代谢在预测当前吸烟者肺癌发展中的作用。拟议的研究将利用两个已建立的中国居民队列。上海队列研究于1986年至1989年期间在中国上海招募了18，244名年龄在45-64岁之间的男性。新加坡华人健康研究在1993- 1998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。从所有上海队列成员和约60%的新加坡队列成员中采集血液和尿液标本。通过常规确认方法对队列进行了癌症和死亡发生率的随访。到2012年底，预计这两个队列中将有1317例肺癌病例。将在两个队列中随机选择相同数量的对照组用于拟定研究。我们将测量NNAL和NNAL-葡糖（NNK代谢物）、总尼古丁当量（即，尼古丁、可替宁、反式-32-羟基可替宁及其相应的葡萄糖醛酸苷的总和）和尿液中的总异硫氰酸酯，以及所有研究受试者血清中的β-隐黄素和其他膳食抗氧化剂。还将确定NNK和尼古丁代谢基因的遗传多态性。具体目的是（1）确定诊断前尿液中的总NNAL和NNAL-Glucs：NNAL比值在发生肺癌的患者和未发生癌症的患者之间是否存在差异，但在年龄、性别、研究入组日期、吸烟状态、一生中的强度和持续时间以及尿总尼古丁当量方面是否具有可比性;以及（2）确定NNK和尼古丁代谢基因的遗传多态性和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。拟议研究的最终目标是开发一套有效的非侵入性肺癌发展预测标志物，以便在吸烟者中识别相对较小比例的肺癌高危人群。肺癌高危人群可被密切跟踪，以便及早发现肺癌，并鼓励他们改变生活方式，例如，戒烟。此外，化学预防剂，如果可用的话，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.