Next generation sequencing to identify novel colorectal cancer genes

下一代测序鉴定新的结直肠癌基因

基本信息

批准号：
8697393
负责人：
Chad Daniel Huff
金额：
$ 66.36万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-05 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697393
关键词：
APC gene Accounting Adenomatous Polyposis Coli African American Age Age of Onset Area Under Curve Cancer Center Cancer Etiology Cancer Patient Candidate Disease Gene Caucasians Caucasoid Race Cessation of life Chemopreventive Agent Clinical Collaborations Colorectal Cancer Complex DNA Development Disease Epidemiologic Factors Ethnic Origin Etiology Family Family history of Frequencies Gender Gene Frequency Gene Targeting Genes Genetic Genetic Predisposition to Disease Genome Goals Health Benefit Hereditary Nonpolyposis Colorectal Neoplasms Heritability Hispanic Americans Individual Intervention MLH1 gene MSH2 gene MSH6 gene Malignant Neoplasms Measures Minor Mismatch Repair Modeling Mutation Not Hispanic or Latino Nucleotides Oncogenes Open Reading Frames PMS2 gene Penetrance Performance Phenotype Physicians Play Population Predisposition Prevention strategy Public Health Recording of previous events Research Design Resources Risk Sample Size Sampling Signal Transduction Staging Susceptibility Gene Syndrome Targeted Resequencing Testing United States Universities Utah Validation Variant Woman base cancer risk cancer type design exome exome sequencing genetic risk factor genetic variant genome wide association study genotyping technology high risk improved insight lifetime risk men next generation sequencing novel novel diagnostics patient population population based prognostic public health relevance rare variant risk variant screening tool

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Driven by common disease common variants hypothesis, genome-wide association studies only identified a number of common susceptibility loci that explained a small portion of CRC heritability. The goal of this project is to identify rare genetic variants with intermediate effect size that predispose individuals to colorectal cancer through a next generation sequencing approach. This proposal builds upon a rich resource of the large CRC patient population at MD Anderson Cancer Center and a population-based resource at University of Utah. There are four specific aims. The first aim is to identify novel susceptibility genes for CRC by conducting whole exome sequencing in 500 cases and 500 controls from MD Anderson. The extreme phenotype study design will be used to enrich the cases by family history of CRC and/or early age of onset. This enrichment of genetic component in the cases will enable us to have sufficient power to identify potential disease causing rare variants with th current sample size. For rare variants (MAF < 5%), we will employ the gene-based approach to facilitate identification of rare variants associated with the risk of CRC. The second aim is to internally validate the top 1,000 genes by targeted sequencing in an additional 4,400 samples from MD Anderson. The third aim is to externally validate the top 100 genes in an additional 1,500 samples from University of Utah and further examine these 100 genes in 400 African American (AA) CRC cases and 400 AA Controls and 400 Hispanic American (HA) cases and 400 HA controls from MD Anderson by targeted sequencing. The fourth aim is to build quantitative risk prediction model by incorporating epidemiologic factors, exposure factors, and genetic factors for the risk of CRC. This study will provide significant insight in the etiology of CRC and improve our understandings of the genetic basis of CRC. The prediction model will enable us to identify genetically susceptible individuals at high-risk of developing CRC who would benefit from intensive screening and/or chemopreventive interventions. It is of immense clinical and public health benefit.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症相关死亡的第二大原因。在常见疾病常见变异假说的推动下，全基因组关联研究仅发现了一些常见的易感性位点，这些位点解释了一小部分结直肠癌的遗传性。该项目的目标是鉴定稀有基因通过下一代测序方法，具有中等效应大小的变异使个体易患结直肠癌。该提案建立在 MD 安德森癌症中心大量 CRC 患者群体的丰富资源和犹他大学基于人群的资源的基础上。有四个具体目标。第一个目标是确定新的易感性通过对 MD 安德森癌症中心的 500 例病例和 500 例对照进行全外显子组测序，研究了 CRC 基因。极端表型研究设计将用于根据 CRC 家族史和/或发病年龄早来丰富病例。病例中遗传成分的丰富将使我们有足够的能力以当前的样本量识别导致罕见变异的潜在疾病。对于罕见变异（MAF < 5%），我们将采用基于基因的方法来促进与 CRC 风险相关的罕见变异的识别。第二个目标是通过对来自 MD 安德森的另外 4,400 个样本进行靶向测序，在内部验证前 1,000 个基因。第三个目标是从外部验证来自犹他大学的另外 1,500 个样本中的前 100 个基因，并进一步检查 400 个非裔美国人 (AA) CRC 病例和 400 个 AA 对照以及 400 个西班牙裔美国人 (HA) 病例和 400 个 HA 中的这 100 个基因。 MD Anderson 通过靶向测序进行控制。第四个目标是结合流行病学因素、暴露因素和遗传因素建立CRC风险的定量风险预测模型。这项研究将为该病的病因学提供重要的见解 CRC 并提高我们对 CRC 遗传基础的理解。该预测模型将使我们能够识别出患有结直肠癌高风险的遗传易感个体，这些个体将受益于强化筛查和/或化学预防干预措施。它具有巨大的临床和公共卫生益处。