Next generation sequencing to identify novel colorectal cancer genes

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驱动下，全基因组关联研究仅确定了一些常见的易感基因座，这些基因座解释了CRC遗传性的一小部分。该项目的目标是识别罕见的遗传 具有中等效应大小的变异，通过下一代测序方法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患者人群的丰富资源和犹他州大学基于人群的资源基础上。有四个具体目标。第一个目标是确定新的易感性 通过对MD安德森的500例病例和500例对照进行全外显子组测序，极端表型研究设计将用于通过CRC家族史和/或早期发病年龄丰富病例。这种病例中遗传成分的富集将使我们有足够的能力以当前的样本量识别潜在的致病罕见变异。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。第二个目标是在MD安德森的另外4,400个样本中通过靶向测序对前1,000个基因进行内部验证。第三个目的是在来自犹他州大学的另外1，500个样本中外部验证前100个基因，并通过靶向测序在来自MD安德森的400个非洲裔美国人（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对照中进一步检查这100个基因。第四个目标是建立定量风险预测模型，将流行病学因素，暴露因素和遗传因素的CRC的风险。这项研究将提供重要的洞察力的病因， CRC和提高我们对CRC的遗传基础的理解。该预测模型将使我们能够识别出遗传易感个体，这些个体具有发展CRC的高风险，并将受益于强化筛查和/或化学预防干预。它具有巨大的临床和公共卫生效益。

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.