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)联盟的目标是彻底调查和确定结直肠癌的易感基因，确定遗传易感性的生物学基础，并认识到遗传和环境风险因素如何量化和修改基因变异。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内，该计划建议对现有的五项全基因组关联研究(GWAS)进行组合分析，包括大约7,000个病例和7,000个对照，然后采用一种加速的综合方法来表征两个复制阶段的新易感基因座。在第一个复制阶段，将对8,000个病例进行基因分型，并将其与欢迎信托病例控制联盟提供的约8,000个对照的公开数据进行比较。第二个复制阶段评估9000多个病例和9000个对照中的候选SNPs，以确认新的易感基因位点、基因与基因的相互作用、基因与环境的相互作用以及基于途径的分析。在区域2内，该计划将制定一项全面的战略，以研究通过GWA对结直肠癌的研究确定的各种和强有力的重复关联的生物学影响。区域3开发了一个框架，用于了解已知的结直肠癌流行病学风险因素如何改变重复关联，估计变异的外显性和人群归因风险，并开发包含遗传和环境风险因素的复杂风险模型。行政核心协调调查团队的研究和生物信息工作，与其他跨主动调查人员互动，并促进NCI和财团之间的联合活动。 这项拟议的研究将确定易患结直肠癌的新基因。详细的研究将揭示为什么这些基因易患癌症。利用这一新的遗传信息和已知的结直肠癌环境因素的复杂模型将加快将这些发现转化为临床实践，并将减轻结直肠癌的公共健康负担。

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.