Biological Studies

已经发表了几项结直肠癌（CRC）的全基因组关联（GWA）研究，并报告了许多在欧洲血统人群中稳健复制的显著相关命中。预计通过本提案领域1和领域3所述的国际努力，已确定的儿童权利委员会协会的数量将增加。到目前为止，只有适度的强调，与这些发现相关的推定的因果变异的特点，甚至更少的努力，发展一个全面的了解其生物学相关性。如果我们要充分利用GWA研究的潜力，这种功能研究将是必要的。应对这一挑战并不简单，因为迄今为止通过GWA研究确定的大多数关联并不针对基因的编码外显子，而是针对位于基因附近的非编码区或基因贫乏区域内的变异，这使得确定其功能后果变得更加困难。因此，本提案的目标是制定一项综合战略，研究通过全球妇女协会对CRC的研究确定的各种关联的生物学影响。我们将通过本研究领域1和3中描述的拟议研究，对选定的经验证的命中和新命中进行追踪。我们将利用来自最先进的ChIP-seq和RNA-seq方法的信息，并采用计算机模拟方法来识别基因或调控区域中的候选致病变体。将使用全面的基因特异性分子和生物化学分析来验证推定的致病变体的功能效应。我们的目标的成功完成，应导致更好地了解与结直肠癌风险的遗传关联的生物学机制。 这项拟议中的研究将在功能上表征易患结直肠癌的新基因。新基因的功能特征将为了解结直肠癌遗传风险的生物学机制提供重要的见解，并应揭示癌症预防和治疗的重要靶点

Several genome wide association (GWA) studies of colorectal cancer (CRC) have been published and have reported a number of significantly associated hits that have been robustly replicated in populations of European ancestry. It is expected that the number of identified CRC associations will increase through International efforts such as those described in Areas 1 and 3 of this proposal. To date there has been only modest emphasis on characterizing the putative causal variant(s) associated with these findings and even less effort directed towards developing a comprehensive understanding of their biological relevance. Such functional studies will be necessary if we are to fully exploit the potential of GWA studies. Meeting this challenge will not be simple, as the majority of the associations identified to date through GWA studies do not target coding exons of genes, but instead target variants that lie in non-coding regions near genes or within gene-poor regions making it more difficult to determine their functional consequences. The goal of this proposal is therefore to establish a comprehensive strategy to study the biological implications of the diverse associations identified through GWA studies of CRC. We will pursue selected validated hits and novel hits identified through the proposed studies described in Areas 1 and 3 of this study. We will leverage information from state-of-the-art ChlP-seq and RNA-seq approaches and incorporate in silico methods to identify candidate causal variants in genie or regulatory regions. The functional effects of putative causal variants will be validated using comprehensive gene-specific molecular and biochemical analyses. Successful completion of our Aims should lead to a better understanding of biological mechanisms underiying genetic associations with colorectal cancer risk. The proposed study will functionally characterize new genes that predispose to colorectal cancer. This functional characterization of new genes will provide important insight into the biological mechanisms underiying genetic risk for colorectal cancer and should reveal important targets for cancer prevention and treatment