Prospective Studies of Colorectal Adenoma

描述（由申请人提供）：本提案旨在丰富Andrew T.陈博士的职业发展在癌症预防流行病学通过整合的指导研究经验与正式课程在哈佛公共卫生学院。 该研究旨在利用三个大型前瞻性队列的资源来改善结直肠癌的预防-护士健康研究（NHS），卫生专业人员随访研究（HPFS）和塞来昔布腺瘤预防（APC）试验。 这些分析将集中在三个有希望的预防领域，这些领域补充了目前在腺瘤筛查和切除方面的努力，腺瘤是绝大多数结直肠癌的前驱病变。 首先，该研究计划旨在阐明阿司匹林，非甾体抗炎药和环氧合酶-2选择性抑制剂在化学预防中的作用。 特别是，这些分析将提供迫切需要的数据，这些药物的最佳剂量和使用持续时间，以预防平均风险人群中的初始腺瘤。 此外，将研究这些药物代谢中的遗传变异在调节其潜在益处中的作用。 其次，该提案将检查可改变的危险因素，这些因素在冠心病（CHD）和结直肠腺瘤中很常见，并研究当前CHD生物标志物在结直肠肿瘤预测中的应用。 最后，计划中的研究旨在阐明增生性息肉在后续腺瘤风险分层中的作用。 为了实现这些目标，陈博士将使用多变量模型设计前瞻性研究。 总体方法学优势是纳入了三个具有互补特征的大型队列：NHS和HPFS允许分析初始结直肠腺瘤，延长随访和重复暴露措施; APC试验允许分析复发性腺瘤，对受试者进行统一监测。 这项研究计划将为腺瘤预防和风险评估提供重要信息，以改善基于人群的监测和筛查。 此外，陈博士将获得几项研究设计的经验-包括观察性队列，病例对照和临床试验-以及问卷调查，生物标志物和遗传多态性等数据。 这一总体建议将确保陈博士成为一名公认的独立研究者和癌症预防领域的领导者。

DESCRIPTION (provided by applicant): This proposal is designed to enrich Andrew T. Chan, MD's career development in cancer prevention epidemiology through an integration of mentored research experience with formal coursework at the Harvard School of Public Health. The proposed research aims to improve prevention of colorectal cancer using the resources of three large, prospectively followed cohorts -- the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Adenoma Prevention with Celecoxib (APC) Trial. The analyses will focus on three promising areas of prevention which complement existing efforts in screening and removal of adenomas, the precursor lesions for the vast majority of colorectal cancer. First, the research plan seeks to clarify the role of aspirin, non-steroidal anti-inflammatory drugs, and cyclooxygenase-2 selective inhibitors in chemoprevention. In particular, the analyses will provide urgently needed data on the optimal dose and duration of use of such agents for the prevention of initial adenoma in an average risk population. Moreover, the role of genetic variation in metabolism of these drugs in modulating their potential benefit will be investigated. Second, the proposal will examine modifiable risk factors, which are common to coronary heart disease (CHD) and colorectal adenoma and investigate the application of current CHD biomarkers in the prediction of colorectal neoplasia. Finally, the planned research aims to clarify the role of hyperplastic polyps in risk stratification for subsequent adenoma. To pursue these aims, Dr. Chan will design prospective studies using multivariable models. The overarching methodological strength is the inclusion of three large cohorts with complementary features: the NHS and HPFS allow analysis of initial colorectal adenoma, with extended follow-up and repeated exposure measures; the APC trial permits analysis of recurrent adenoma, with uniform surveillance of subjects. This research plan will provide important information on adenoma prevention and risk assessment for improved population-based surveillance and screening. Moreover, Dr. Chan will obtain experience in several study designs -- including observational cohort, case-control, and clinical trials -- and data ranging from questionnaires, biomarkers, and genetic polymorphisms. This overall proposal will ensure that Dr. Chan will become an established independent investigator and a leader in cancer prevention.