Transdisciplinary Studies of Genetic Variation in Colorectal Cancer

结直肠癌遗传变异的跨学科研究（TSGVC）联盟的目标是彻底调查和鉴定结直肠癌的易感基因座，描述遗传易感性的生物学基础，并认识到遗传变异如何被量化和遗传和环境风险因素修饰。这一长期目标将通过一项 综合设计，包括三个高度相关的调查领域和一个行政核心。在区域1内，该计划提出了对五项现有的全基因组关联研究（GWAS）进行综合分析，其中约有7，000例病例和7，000例对照，然后采用加速的综合方法在两个复制阶段表征新的易感基因座。在第一个复制阶段， 进行基因分型，并与来自Welcome Trust Case Control Consortium的约8，000个对照组的公开数据进行比较。第二个复制阶段评估了9,000多例病例和9,000例对照的候选SNP，以确认新的易感基因位点，基因与基因的相互作用，基因与环境 互动和路径分析。在区域2内，该计划将建立一个全面的战略，以研究通过结直肠癌的GWA研究确定的多样化和稳健复制关联的生物学意义，区域3开发了一个框架，用于了解已知的流行病学风险因素如何修改复制关联结直肠癌，估计变异的发病率和人群归因风险，并开发了综合遗传和环境风险因素的复杂风险模型。一个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和财团之间的联合活动。

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.