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确定含有显著增加结直肠癌（CRC）风险的罕见突变的新基因。这些突变可能是观察到的Lynch综合征样结直肠癌病例家族聚集的基础，称为家族性结直肠癌X型（FCCTX）。FCCTX是一种显性遗传模式和不完全外显的孟德尔癌症综合征。该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（“外显子组”）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患者结直肠癌风险相关的新的候选基因。这种方法最近在鉴定引起孟德尔病的新基因方面取得了成功。确定的候选变异将在具有测序外显子组的个体的家庭成员中进行基因分型，以进行分离分析。在独立（R00）阶段，候选基因将在大量结直肠癌病例和对照中重新测序，以发现散发性结直肠癌的突变谱及其在一般人群中的存在。此外，候选基因将在FCCTX家族的大队列中重新测序，以寻找携带这些基因突变的其他个体。参与结直肠癌发展的新基因和潜在途径可以成为结直肠癌治疗的潜在靶点。该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。低成本、高通量的外显子组重测序技术可能有助于发现家族性癌症的新候选基因和突变。

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. PUBLIC HEALTH RELEVANCE: The identification of novel genes and mutations associated with risk of hereditary colorectal cancer is likely to have a significant impact on cancer management and prevention in families carrying these mutations. It can also advance our understanding of colorectal cancer biology and has the potential to lead to new treatments.