Biological Studies

结直肠癌（CRC）的几项全基因组关联（GWA）研究已经发表，并报告了许多显著相关的命中，这些命中在欧洲血统人群中得到了强有力的复制。预计已确定的CRC协会的数量将通过诸如本提案领域1和3中所述的国际努力而增加。迄今为止，对与这些发现相关的假定的因果变异特征的强调并不多，对其生物学相关性的全面理解的努力就更少了。如果我们要充分利用全球水环境研究的潜力，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域或基因贫乏区域内的变异，这使得确定其功能后果更加困难。因此，本提案的目标是建立一个全面的战略，以研究通过GWA研究确定的CRC的各种关联的生物学意义。我们将通过本研究区域1和3中所述的拟议研究来选择经过验证的靶点和新靶点。我们将利用最先进的ChlP-seq和RNA-seq方法的信息，并结合计算机方法来识别基因或调控区域的候选因果变异。假定的因果变异的功能影响将通过全面的基因特异性分子和生化分析进行验证。成功完成我们的目标应该导致更好地理解与结直肠癌风险遗传关联的生物学机制。

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