Genetic Basis of Familial Colorectal Cancer Type X

摘要 这项研究的总体目标是确定携带罕见突变的新基因， 大大增加了患结直肠癌（CRC）的风险。这些突变可能是 观察到Lynch综合征样结直肠癌病例的家族聚集性，称为家族性 结肠直肠癌X型（FCCTX）。FCCTX是一种孟德尔癌症综合征， 遗传方式和不完全遗传。该指导阶段的第一个目标是 本发明的应用是鉴定与结肠直肠癌风险相关的新的候选基因， 使用选择性捕获人类基因组中的蛋白质编码序列的FCCTX患者 （“外显子组”），随后对10名具有FCCTX的患者进行大规模平行重测序。这 最近，一种方法成功地鉴定了引起孟德尔疾病的新基因。 将在具有以下特征的个体的家庭成员中对鉴定的候选变体进行基因分型： 测序外显子以进行分离分析。在独立（R00）阶段，候选人 将在大量的结直肠癌病例和对照中对基因进行重新测序，以发现 散发性结直肠癌的突变谱及其在一般人群中的存在。在 此外，候选基因将在一个大的FCCTX家族队列中重新测序， 其他携带这些基因突变的个体。新的基因和潜在的途径 参与结直肠癌的发展可能成为结直肠癌的潜在靶点 癌症治疗拟议的研究也代表了新战略的概念证明， 外显子组重测序用于检测癌症易感基因。低成本、高吞吐量 外显子组重测序技术可能有助于发现新的候选基因， 家族性癌症的突变

Abstract 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.