Transdisciplinary Studies of Genetic Variation in Colorectal Cancer

描述（由申请人提供）：结直肠癌遗传变异跨学科研究（TSGVC）联盟的目标是深入研究和鉴定结直肠癌的易感性位点，表征遗传易感性的生物学基础，并认识遗传变异如何被遗传和环境风险因素量化和修饰。这一长期目标将通过三个高度相关的调查领域和一个行政核心的综合设计来实现。在区域1中，该项目建议对现有的五项全基因组关联研究（GWAS）进行综合分析，其中包括大约7000例病例和7000例对照，然后采用一种加速的综合方法，在两个复制阶段表征新的易感位点。在第一个复制阶段，将对8000例病例进行基因分型，并与来自Welcome Trust病例控制联盟的约8000例对照的公开数据进行比较。第二个复制阶段评估了9000多个病例和9000个对照的候选snp，以确认新的易感位点、基因间相互作用、基因间环境相互作用和基于通路的分析。在区域2中，该项目将建立一个全面的战略，研究通过GWA研究确定的结直肠癌的多种和强大的复制关联的生物学含义；区域3开发一个框架，了解如何通过已知的结直肠癌流行病学风险因素修改复制关联，估计外显率和人口归因风险变异；并开发了包含遗传和环境风险因素的复杂风险模型。行政核心协调调查小组的研究和生物信息学工作，与其他跨倡议调查人员互动，并促进NCI和联盟之间的联合活动。

DESCRIPTION (provided by applicant): The objectives of the Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (TSGVC) consortium are to thoroughly investigate and identify susceptibility loci for colorectal cancer, to characterize the biologic basis of inherited susceptibility, and to recognize how genetic variation may be quantified and modified by genetic and environmental risk factors. This long-term goal will be achieved through an integrated design with three highly-related Areas of investigation and an Administrative Core. Within Area 1, the program proposes a combined analysis of five existing genome-wide association studies (GWAS) with approximately 7,000 cases and 7,000 controls, followed by an accelerated, integrated approach to characterize new susceptibility loci in two replication phases. In the first replication phase, 8,000 cases will be genotyped and compared to publicly available data on ~8,000 controls from the Welcome Trust Case Control Consortium. A second replication phase evaluates candidate SNPs in more than 9,000 cases and 9,000 controls to confirm new susceptibility loci, gene by gene interactions, gene by environment interactions, and pathway-based analyses. Within Area 2, the program will establish a comprehensive strategy to study the biological implications of the diverse and robustly replicated associations identified through GWA studies of colorectal cancer, Area 3 develops a framework for understanding how replicated associations are modified by known epidemiologic risk factors for colorectal cancer, estimates the penetrance and population attributable risk of variants, and develops complex risk models that incorporate genetic and environmental risk factors. An Administrative Core coordinates the research and bioinformatic efforts of the investigative team, interacts with other trans-initiative investigators, and facilitates joint activities between NCI and the consortium. The proposed study will identify new genes that predispose to colorectal cancer. Detailed studies will show why these genes predispose to cancer. Complex models that take advantage of this new genetic information together with known environmental factors for colorectal cancer will expedite the translation of these findings into clinical practice and will reduce the public health burden of colorectal cancer.