Lifestyle, genetics and colonoscopy for colorectal cancer prevention

预防结直肠癌的生活方式、遗传学和结肠镜检查

• 批准号: 9397635
• 负责人: Reiko Nishihara
• 金额: $ 10.14万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397635
• 关键词: Lifestyle; genetics; colonoscopy; colorectal; cancer

 DESCRIPTION (provided by applicant): The candidate's long-term career goal is to become an independent investigator with interdisciplinary expertise in statistical genetics, bioinformatic, and cost-effectiveness analysis to advance individualized colorectal cancer (CRC) prevention in the context of precision medicine. Current guidelines endorse the initiation of screening colonoscopy at age 50 with a 10-year colonoscopy-screening interval for the average-risk population. Although lifestyle, a family history of CRC, and genetic susceptibility influence risk f developing CRC, those factors are not currently incorporated in colonoscopy-screening recommendations. Building on her prior work in colonoscopy screening, the candidate seeks to fill this knowledge gap by optimizing colonoscopy screening according to an individual's lifestyle, family history, and genetic susceptibility. Specifically, the candidate proposes to: 1) develop and validate a risk prediction model for CRC incidence based on lifestyle, family history, and known genetic susceptibility loci; 2) determine optimal age of initiation and interval of colonoscopy screening for individuals characterized as high-risk according to this prediction model; 3) evaluate the cost- effectiveness of a colonoscopy-screening program tailored according to individual's risk; and 4) identify biological pathways and networks that underlie CRCs that arise despite a negative colonoscopy within 5 years ("interval CRCs"). To achieve these goals, the candidate and her mentors have designed a career development plan for research and educational training to obtain: 1) advanced didactic training in statistical genetics, bioinformatis, and cost-effectiveness analysis; 2) practical experience to synthesize data from multiple sources including epidemiological, bioinformatics, and economic data; 3) enhanced understanding of CRC etiology and genomics; and 4) extensive analytical skills using pooled data from large consortia. To achieve the proposed research aims, the candidate will utilize two large prospective cohort studies, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), in which data on endoscopy- screening status have biennially collected among 88,902 participants over the last 26 years. Within these cohorts, a substantial number of participants have been characterized for genetic susceptibility to CRC and cases of CRC have been molecularly profiled. The candidate will also validate findings within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which includes a large independent cohort of men and women. The interdisciplinary mentorship and advisory team comprised of national leaders in epidemiology, statistical genetics, bioinformatics, and decision science will provide the requisite expertise to ensure the success of this proposal and the candidate in her critical transition towards an independent investigator. This integrated examination of lifestyle factors, family history, genetic variation, and the molecular interdependency network of interval CRC may lead to the development of more efficacious and cost-effective CRC screening guidelines that can substantially reduce the U.S.'s overall burden of CRC.

 候选人的长期职业目标是成为一名独立的研究者，在统计遗传学，生物信息学和成本效益分析方面具有跨学科的专业知识，以推进个性化的结直肠癌（CRC）预防在精准医学的背景下。目前的指南支持在50岁时开始筛查结肠镜检查，平均风险人群的结肠镜检查筛查间隔为10年。尽管生活方式、CRC家族史和遗传易感性影响CRC的发生风险，但这些因素目前尚未纳入结肠镜筛查建议。在她之前在结肠镜检查筛查方面的工作的基础上，候选人试图通过根据个人的生活方式优化结肠镜检查筛查来填补这一知识空白， 家族史和遗传易感性具体而言，候选人建议：1）发展和 基于生活方式、家族史和已知的遗传易感基因座验证CRC发病率的风险预测模型; 2）根据该预测模型确定被表征为高风险的个体的结肠镜检查筛查的最佳开始年龄和间隔时间; 3）评估根据个体风险定制的结肠镜检查筛查程序的成本效益;和4）鉴定尽管在5年内结肠镜检查阴性仍出现CRC（“间隔CRC”）的生物学途径和网络。为了实现这些目标，候选人和她的导师设计了一个研究和教育培训的职业发展计划，以获得：1）统计遗传学，生物信息学和成本效益分析的高级教学培训; 2）综合来自多个来源的数据的实践经验，包括流行病学，生物信息学和经济数据; 3）增强对CRC病因学和基因组学的理解;以及4）使用来自大型财团的汇集数据的广泛分析技能。为了实现拟议的研究目标，候选人将利用两项大型前瞻性队列研究，护士健康研究（NHS）和卫生专业人员随访研究（HPFS），其中在过去26年中每两年收集88，902名参与者的内镜检查状态数据。在这些队列中，相当数量的参与者已被表征为CRC的遗传易感性，并且CRC病例已被分子分析。候选人还将验证结直肠癌遗传学和流行病学联盟（GECCO）的研究结果，该联盟包括一个大型的独立男性和女性队列。由流行病学、统计遗传学、生物信息学和决策科学领域的国家领导人组成的跨学科指导和咨询小组将提供必要的专业知识，以确保这一提议的成功，并确保候选人在向独立调查员的关键过渡中取得成功。这种对生活方式因素、家族史、遗传变异和间隔期CRC的分子相互依赖网络的综合检查可能会导致更有效和更具成本效益的CRC筛查指南的发展，从而大大降低美国癌症的发病率。CRC的总体负担。