Detection of Colorectal Cancer Susceptibility Loci Using Genome-Wide Sequencing

使用全基因组测序检测结直肠癌易感位点

• 批准号: 8370804
• 负责人: ULRIKE PETERS
• 金额: $ 333.34万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370804
• 关键词: 8q24; Accounting; Affect; Age; Alleles; Biology; Biometry; Cancer Etiology; Case-Control Studies; Cessation of life; Clinical Data; Colorectal Cancer; DNA; Data; Detection; Development; Diagnosis; Diet; Disease; Drug Delivery Systems; Environmental Risk Factor; Family; Family member; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; Heritability; Human; Individual; Knowledge; Logistic Regressions; MADH7 gene; Methods; Mismatch Repair; Mutation; Nucleotides; Obesity; Pathway interactions; Penetrance; Pharmaceutical Preparations; Population; Predisposition; Preventive; Qualifying; Research Personnel; Resources; Risk; Risk Factors; Sampling; Screening procedure; Single Nucleotide Polymorphism; Smoking; Statistical Methods; Syndrome; Technology; Testing; Variant; anticancer research; cancer risk; case control; cohort; colorectal cancer screening; disorder prevention; early onset; epidemiologic data; exome; experience; gene environment interaction; genetic epidemiology; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; high risk; improved; insertion/deletion mutation; multidisciplinary; next generation; novel; prospective; success

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer death in the US. Linkage studies and genome-wide association studies (GWAS) have successfully identified high-penetrance mutations such as those that occur in APC or DNA mismatch-repair genes, as well as low-penetrance variants such as 8q24 and SMAD7. However, these variants explain only a fraction of the heritability of CRC. This is not surprising, as contributions from large classes of genetic variation, specifically less frequent and rare singl nucleotide variants (SNV) with allele frequency of 0.1-5%, insertion/deletions (indels), and copy number variants (CNVs), have not been systematically investigated across the genome. These genetic variants are predicted to have stronger effect sizes than common low-penetrance variants and are postulated to explain a substantial proportion of the heritability of CRC. To comprehensively identify these variants across the genome, we propose to use next generation technology to sequence the whole genome with 12x coverage in 2,123 high-risk CRC cases and 2,123 controls (Aim 1.1). These cases and controls will be selected from our existing Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO; U01CA137088, PI: Peters) of 15 well-characterized prospective cohorts and case-control studies. We demonstrate that combining whole genome sequence data with imputation using existing GWAS data in large sets of case-control studies allows a powerful and efficient screen for CRC susceptibility loci. This method is particularly well suited to identifying less frequent and rare SNVs, indels, and CNVs. Accordingly, in Aim 1.2 we use the sequencing data from Aim 1.1 to impute ~20M variants in an additional 8,958 CRC cases and 10,212 controls with existing GWAS data. We will test the associations between CRC risk and variants (sequenced and imputed) in a total of 11,081 cases and 12,335 controls. In Aim 1.3, we will replicate the most promising loci by genotyping 3,000 variants in 8,827 independent CRC cases and 8,595 controls. In Aim 2, we will investigate gene-environment interactions for directly sequenced and imputed variants, utilizing GECCO studies, which have detailed clinical and epidemiologic data that have already been harmonized across studies. To improve the power for Aim 1 and 2, we will apply novel statistical methods. This project brings together a highly qualified, multidisciplinary team of investigators with expertise in CRC research, biostatistics, population and statistical genetics, epidemiology, and next generation sequencing. We expect to identify several novel CRC susceptibility variants with effect sizes larger than previous GWAS findings. These results will improve our understanding of which genes are impacting CRC. Such knowledge about the underlying biology could have long term impacts on screening, treatment and disease prevention. PUBLIC HEALTH RELEVANCE: This multidisciplinary effort will investigate whether different types of genetic variations, including rare variants and structural variation, influence colorectal cancer risk in humans. Specifically, we will examine genetic variants across the entire genomes of colorectal cancer cases and controls to identify new genetic risk factors for colorectal cancer. Findings from this study will improve our knowledge of the full spectrum of genes that affect the risk of this severe disease.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因。连锁研究和全基因组关联研究（GWAS）成功地鉴定了高渗透突变，例如在APC或DNA失配基因中发生的突变，以及诸如8q24和Smad7之类的低渗透变体。但是，这些变体仅解释了CRC遗传力的一部分。这不足为奇， 由于大量遗传变异的贡献（特定于等位基因频率为0.1-5％），插入/缺失（INDELS）和拷贝数变体（CNV）的贡献尚未在整个基因组中系统地研究。预测这些遗传变异的效应大小比常见的低渗透变量具有更强的效应大小，并被认为可以解释CRC遗传力的很大比例。为了全面地识别整个基因组的这些变体，我们建议使用下一代技术在2,123个高风险CRC病例和2,123个对照组中用12倍覆盖的整个基因组对整个基因组进行测序（AIM 1.1）。这些病例和对照将从我们现有的遗传学和结直肠癌联盟（GECCO; U01CA137088，PI：PETERS）的流行病学中选择，其中15种特征良好的前瞻性人群和病例对照研究。我们证明，在大量病例对照研究中使用现有的GWAS数据将整个基因组序列数据与插补相结合，可以为CRC敏感性基因座提供强大而有效的屏幕。该方法特别适合鉴定较少且稀有的SNV，Indels和CNV。因此，在AIM 1.2中，我们使用AIM 1.1的测序数据在另外8,958个CRC案例和10,212个控件中使用现有GWAS数据中估算约20m的变体。我们将在总共11,081例和12,335个对照中测试CRC风险与变体（测序和估算）之间的关联。在AIM 1.3中，我们将通过在8,827个独立CRC病例和8,595个对照中进行基因分型来复制最有希望的基因座。在AIM 2中，我们将利用GECCO研究研究直接测序和估算变体的基因环境相互作用，这些研究详细介绍了在研究中已经统一的临床和流行病学数据。为了提高目标1和2的功率，我们将采用新颖的统计方法。该项目汇集了一个高素质，多学科的研究人员团队，具有CRC研究，生物统计学，人群和统计遗传学，流行病学和下一代测序方面的专业知识。我们希望鉴定出几种新型的CRC敏感性变体，其效果大小大于以前的GWAS发现。这些结果将提高我们对哪些基因影响CRC的理解。关于潜在生物学的这种知识可能会对筛查，治疗和预防疾病产生长期影响。 公共卫生相关性：这种多学科的工作将调查不同类型的遗传变异（包括罕见变体和结构变化）是否影响结直肠 人类的癌症风险。具体而言，我们将检查结直肠癌病例和对照组的整个基因组中的遗传变异，以鉴定结直肠癌的新遗传危险因素。 这项研究的发现将提高我们对影响这种严重疾病风险的全基因的了解。