Genetic Basis of Familial Colorectal Cancer Type X

家族性结直肠癌 X 型的遗传基础

• 批准号: 8550528
• 负责人: Leon Raskin
• 金额: $ 23.41万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550528
• 关键词: Americas; Applications Grants; Australia; Bioinformatics; Cancer Biology; Cancer Patient; Cancer-Predisposing Gene; Candidate Disease Gene; Cells; Code; Colon; Colorectal Cancer; Complementary DNA; Computer software; Custom; DNA; DNA Resequencing; Data; Development; Disease; Etiology; Family; Family member; Founder Generation; Frequencies; Future; Gene Mutation; General Population; Genes; Genetic; Genome; Genomics; Genotype; Goals; Hereditary Malignant Neoplasm; Hereditary Nonpolyposis Colorectal Neoplasms; Heritability; Human Genome; Individual; Inherited; Intestines; Lead; Malignant Neoplasms; Mentors; Micellar Electrokinetic Capillary Chromatography; Mutation; Mutation Analysis; Mutation Spectra; Pathway interactions; Patients; Penetrance; Phase; Phenotype; Prevention; Proteins; Quality Control; RNA Interference; Reading; Risk; Sampling; Sequence Analysis; Series; Source; Syndrome; Variant; abstracting; age related; base; cancer therapy; cancer type; case control; cohort; colon cancer family registry; cost; exome; exome sequencing; high throughput technology; mutant; novel; population based; segregation

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.

摘要 这项拟议研究的总体目标是确定含有罕见突变的新基因 显著增加患结直肠癌(CRC)的风险。这些突变可能是 家族性Lynch综合征样结直肠癌的家族聚集性观察 结直肠癌X型(FCCTX)。FCCTX是一种孟德尔癌症综合征，以 遗传方式和不完全外显。指导阶段的第一个目标是 应用是寻找与结直肠癌风险相关的新候选基因 选择性捕获人类基因组中蛋白质编码序列的FCCTX患者 (“外显子组”)，随后对10名FCCTX患者进行大规模平行重测序。这 该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患有 用于分离分析的测序外显子。在独立(R00)阶段，候选人 将对大量结直肠癌病例和对照中的基因进行重新测序，以找到 散发性结直肠癌基因突变谱及其在普通人群中的存在。在……里面 此外，候选基因将在一大群FCCTX家族中重新测序，以找到 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。拟议的研究也是对#年新战略的概念证明。 外显子组重测序用于癌症易感基因的检测。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和 家族性癌症的突变。