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: 8241493
• 负责人: Leon Raskin
• 金额: $ 4.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241493
• 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; age related; base; cancer therapy; cancer type; case control; cohort; colon cancer family registry; cost; exome; high throughput technology; mutant; novel; population based; segregation

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.

描述（由申请人提供）：拟议研究的总体目标是鉴定携带罕见突变的新基因，这些突变显著增加结直肠癌（CRC）的风险。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、不完全遗传的孟德尔癌症综合征。本申请所述阶段的第一个目的是使用选择性捕获人类基因组中的蛋白质编码序列（“外显子组”），然后对10名患有FCCTX的患者进行大规模平行重测序，来鉴定与FCCTX患者中的结直肠癌风险相关的新候选基因。这种方法最近在鉴定引起孟德尔疾病的新基因方面取得了成功。将在具有测序的外显子组的个体的家族成员中对鉴定的候选变体进行基因分型以用于分离分析。在独立（R00）期，将在大量结直肠癌病例和对照中对候选基因进行重新测序，以发现散发性结直肠癌中的突变谱及其在一般人群中的存在。此外，候选基因将在一个大的FCCTX家族队列中进行重新测序，以找到携带这些基因突变的其他个体。新的基因和潜在的通路参与结直肠癌的发展可能成为结直肠癌治疗的潜在目标。这项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中新的候选基因和突变。 公共卫生相关性：与遗传性结直肠癌风险相关的新基因和突变的鉴定可能对携带这些突变的家庭的癌症管理和预防产生重大影响。它还可以促进我们对结直肠癌生物学的理解，并有可能导致新的治疗方法。