Prospective studies of cancer etiology and prevention in Shanghai and Singapore

描述（由申请人提供）：本申请寻求资金，继续对上海和新加坡队列研究的81501名中老年中国男性和女性参与者进行5年的观察性随访，以积累和验证大量增加的癌症终点，以评估与生活方式、生化标志物、遗传标志物和基因-环境相互作用有关的癌症风险的重要问题。上海组于1986-1989年组建，新加坡组于1993-1998年组建。除了在基线和随访访谈时收集的数据外，在基线时收集了50,000多名受试者的血液和尿液样本，并在收集后保存在超低温条件下。积极有效的随访程序使随访损失降到最低；到目前为止，在过去的20年里，只有大约880名（1%）原始队列参与者失去了随访。这些数据库为大量癌症病因学和预防研究项目提供了独特的资源。在接下来的5 - 5年里，我们还建议在这两个队列中进行一系列巢式病例对照研究，以阐明环境暴露、遗传变异和DNA甲基化在肺癌或肝癌发展中的作用。主要的科学目的是：(1)评估多环芳烃（PAH）、1,3-丁二烯、丙烯醛、苯和环氧乙烷在吸烟者肺癌发生中的独立作用；(2)评估多环芳烃、1,3-丁二烯、丙烯醛、苯和环氧乙烷在终身不吸烟者肺癌发生中的独立作用；(3)评估甲基- s -腺苷蛋氨酸、s -腺苷同型半胱氨酸、蛋氨酸、胆碱、同型半胱氨酸、叶酸、维生素B6和B12在肝癌发生中的作用；(4)评估影响甲基代谢的遗传多态性在肝癌发生发展中的作用，及其对甲基与肝癌风险相关性的调节作用；(5)评估整体DNA低甲基化在肝癌发展中的作用。前瞻性研究设计、可获得的诊断前血液和尿液样本以及大样本量的拟议研究将为实现这些科学目标提供新颖和明确的数据。此外，所提出的研究结果将为理解甲基（DNA甲基化的供体）在人类肝癌发生中的作用提供见解。这项研究的最终目标是开发一套有效的、非侵入性的、可预测的标志物，从而识别出相对较小比例的肺癌或肝癌高危人群。高风险人群可以采取初级预防措施以降低风险，或者在临床治疗更有效时定期进行恶性肿瘤早期检测。

DESCRIPTION (provided by applicant): This proposal seeks funding to continue the observational follow-up of the 81,501 middle-aged and older Chinese men and women participants of the Shanghai and Singapore cohort studies for another 5 five years, to accrue and validate a substantially increased number of cancer endpoints in order to evaluate important questions related to lifestyle, biochemical markers, genetic markers, and gene-environment interactions on cancer risk. The Shanghai cohort was assembled in 1986-1989 and the Singapore cohort in 1993-1998. In addition to data collected at baseline and follow-up interviews, blood and urine samples were collected from more than 50,000 subjects at baseline and stored in ultra-low temperature condition since their collection. The vigorous and effective follow-up procedures kept the loss of follow-up to be minimal; to date, only approximately 880 (1%) original cohort participants have been lost to follow-up over the past 20 years. These databases have been serving unique resources for a large number of projects for research on cancer etiology and prevention. In the next 5 five years, we also propose to conduct a series of nested case-control studies within the two cohorts to elucidate the role of environmental exposure, genetic variants and DNA methylation in the development of lung or liver cancer. The primary scientific aims are: (1) to assess the independent role of polycyclic aromatic hydrocarbons (PAH), 1,3-butadiene, acrolein, benzene, and ethylene oxide in the development of lung cancer among smokers; (2) to assess independent role of PAH, 1,3-butadiene, acrolein, benzene, and ethylene oxide in the development of lung cancer among lifelong nonsmokers; (3) to assess the role of methyl groups - S-adenosylmethionine, S-adenosylhomocysteine, methionine, choline, homocysteine, folate, vitamins B6 and B12 in the development of liver cancer; (4) to assess the role of genetic polymorphisms influencing methyl group metabolism in the development of liver cancer, and their modifying effect on the associations between methyl groups and liver cancer risk; and (5) to assess the role of global DNA hypomethylation in the development of liver cancer. The proposed studies with prospective study design, available pre-diagnostic blood and urine samples, and large sample sizes will provide novel and definitive data to accomplish these scientific aims. Furthermore, findings of the proposed studies will provide insights for the understanding of the role of methyl groups, the donor of DNA methylation, in human hepatocarcinogenesis. The ultimate goal of the proposed research is the development of an effective set of non-invasive, predictive markers that allow for the identification of the relatively small fraction of individuals who are at very high risk for lung or liver cancer. People with high risk could take primary preventive measures to reduce their risk, or undergo regular screening for early detection of the malignancies when clinical treatment is more effective. PUBLIC HEALTH RELEVANCE: The Shanghai and Singapore cohort studies are ongoing observational follow-up investigation of environmental and genetic factors on human cancers in 81,501 middle-aged and older Chinese men and women beginning in 1986 and 1993, respectively. The proposed studies within these two cohorts will identify a set of non-invasive, predictive markers of lung and liver cancer development. People with high risk could take primary preventive measures to reduce their risk, or undergo regular screening for early detection of the malignancies when clinical treatment is more effective. The findings of the proposed study will have great impact on reducing incidence and mortality of lung and liver cancers in humans.