Genetic Basis of Familial Colorectal Cancer Type X

描述(由申请人提供)：拟议研究的总体目标是识别含有罕见突变的新基因，这些基因极大地增加了结直肠癌(CRC)的风险。这些突变可能是观察到的被称为X型家族性结直肠癌(FCCTX)的林奇综合征样结直肠癌病例的家族聚集的基础。FCCTX是一种孟德尔癌症综合征，具有显性遗传方式和不完全外显。这项应用的指导阶段的第一个目标是通过选择性捕获人类基因组(“外显子”)中的蛋白质编码序列，然后对10名FCCTX患者进行大规模平行重测序，确定与FCCTX患者患结直肠癌风险相关的新候选基因。这种方法最近在识别导致孟德尔疾病的新基因方面取得了成功。已确定的候选变异将在具有外显子序列的个体的家庭成员中进行基因分型，以便进行分离分析。在独立(R00)期，将对大量结直肠癌病例和对照中的候选基因进行重新测序，以发现散发性结直肠癌的突变谱及其在普通人群中的存在。此外，候选基因将在一大群FCCTX家族中进行重新测序，以寻找携带这些基因突变的其他个人。参与结直肠癌发生发展的新基因和潜在途径可能成为结直肠癌治疗的潜在靶点。这项拟议的研究也为外显子组重测序检测癌症易感基因的新策略提供了概念证明。这种低成本、高通量的外显子组重测序技术可能有助于发现新的家族性癌候选基因和突变。

DESCRIPTION (provided by applicant): The overall goal of the proposed study is to identify new genes harboring rare mutations that considerably increase the risk of colorectal cancer (CRC). These mutations can underlie the observed familial aggregation of Lynch syndrome-like colorectal cancer cases called Familial Colorectal Cancer Type X (FCCTX). FCCTX is a Mendelian cancer syndrome with dominant mode of inheritance and incomplete penetrance. The first aim of the mentored-phase of this application is to identify novel candidate genes associated with risk of colorectal cancer in FCCTX patients using selective capture of protein-coding sequences in the human genome ("exome") followed by massively parallel resequencing of 10 patients with FCCTX. This approach has recently been successful in identifying novel genes causing Mendelian diseases. The identified candidate variants will be genotyped in the family members of the individuals with sequenced exomes for segregation analysis. During independent (R00) phase, the candidate genes will be resequenced in a large number of colorectal cancer cases and controls to find the spectrum of mutations in sporadic colorectal cancer and their presence in general population. In addition, the candidate genes will be resequenced in a large cohort of FCCTX families to find other individuals carrying mutations in these genes. The new genes and potentially pathways involved into development of colorectal cancer can become potential targets for colorectal cancer therapy. The proposed study represents also a proof of concept for the new strategy of exome resequencing for detecting of cancer predisposing genes. The low-cost, high throughput technologies for exome resequencing may facilitate the discovery of new candidate genes and mutations in familial cancer.