Next generation sequencing to identify novel colorectal cancer genes

描述(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。在常见疾病共同变异假说的推动下，全基因组关联研究只确定了一些共同的易感基因，解释了一小部分结直肠癌的遗传性。这个项目的目标是识别稀有的基因 通过下一代测序方法使个体易患结直肠癌的中等效应大小的变异。这项建议建立在MD Anderson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基础上。有四个具体目标。第一个目标是确定新的易感性 对来自MD Anderson的500例患者和500名对照进行了全外显子组测序，以确定结直肠癌的基因。极端表型研究设计将用于通过结直肠癌家族史和/或发病早期来丰富病例。病例中遗传成分的这种丰富将使我们有足够的能力识别潜在的疾病，以目前的样本量引起罕见的变异。对于罕见变异(MAF&lt；5%)，我们将使用基于基因的方法来促进与结直肠癌风险相关的罕见变异的识别。第二个目标是通过对MD Anderson另外4400个样本进行定向测序，在内部验证前1000个基因。第三个目标是从外部验证犹他大学另外1,500个样本中的前100个基因，并通过定向测序在MD Anderson的400个非裔美国人(AA)CRC病例和400个AA对照、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。第四个目标是将流行病学因素、暴露因素和遗传因素结合起来，建立结直肠癌风险的定量预测模型。这项研究将为本病的病因学提供重要的见解。 提高我们对结直肠癌遗传基础的认识。该预测模型将使我们能够识别那些将受益于密集筛查和/或化学预防干预的高风险结直肠癌遗传易感个体。它对临床和公共卫生都有巨大的好处。

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.