Prospective studies of cancer etiology and prevention in Shanghai and Singapore

描述（申请人提供）：该提案寻求资金，以继续对上海和新加坡队列研究的81，501名中老年中国男性和女性参与者进行为期5年的观察性随访，以积累和验证数量大幅增加的癌症终点，从而评估与生活方式、生化标志物、遗传标志物、以及基因与环境的相互作用对癌症风险的影响。上海队列于1986 - 1989年组建，新加坡队列于1993 - 1998年组建。除了基线和随访访视时收集的数据外，基线时还采集了5万多名受试者的血液和尿液样本，并自采集后在超低温条件下储存。有力和有效的随访程序使失访保持在最低限度;迄今为止，在过去20年中，仅约880（1%）例原始队列参与者失访。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。 在未来5年内，我们还计划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生中的作用。主要科学目的是：（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PAH、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-腺苷甲硫氨酸、S-腺苷高半胱氨酸、甲硫氨酸、胆碱、高半胱氨酸、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中的作用，以及它们对甲基与肝癌风险之间的关联的修饰作用;和（5）评估整体DNA低甲基化在肝癌发展中的作用。拟议的研究具有前瞻性研究设计、可用的诊断前血液和尿液样本以及大样本量，将为实现这些科学目标提供新颖且明确的数据。此外，拟议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。拟议研究的最终目标是开发一套有效的非侵入性预测标记物，以识别相对较小比例的肺癌或肝癌风险非常高的个体。高危人群可采取一级预防措施降低风险，或在临床治疗更有效时定期筛查，以早期发现恶性肿瘤。 公共卫生相关性：上海和新加坡队列研究是分别于1986年和1993年开始的对81，501名中年和老年中国男性和女性进行的环境和遗传因素对人类癌症的观察性随访研究。这两个队列中的拟议研究将确定一组肺癌和肝癌发展的非侵入性预测标志物。高危人群可采取一级预防措施降低风险，或在临床治疗更有效时定期筛查，以早期发现恶性肿瘤。拟议研究的结果将对降低人类肺癌和肝癌的发病率和死亡率产生重大影响。

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.