Colorectal Cancer Genome-Wide Association Studies Consortium

结直肠癌全基因组协会研究联盟

• 批准号: 8318557
• 负责人: ULRIKE PETERS
• 金额: $ 189.58万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318557
• 关键词: Accounting; Adenomatous Polyposis Coli; Age; Alcohols; All-Trans-Retinol; Anti-Inflammatory Agents; Anti-inflammatory; Calcium; Cancer Etiology; Cancer-Predisposing Gene; Carotene; Case-Control Studies; Cessation of life; Cohort Studies; Colorectal; Colorectal Cancer; Complex; Data; Data Set; Diet; Discipline; Disease; Environment; Environmental Risk Factor; Folate; Foundations; Funding; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genotype; Goals; Health; Health Professional; Hereditary Nonpolyposis Colorectal Neoplasms; Hormones; Human; Individual; Left; Life Style; Malignant Neoplasms; Meat; Molecular; Mutation; Negative Finding; Nurses' Health Study; Obesity; Outcome; Pharmaceutical Preparations; Physical activity; Physicians; Population; Population Study; Postmenopause; Predisposition; Prevention strategy; Prospective Studies; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Research; Research Design; Resources; Risk; Risk Factors; Sample Size; Smoking; Syndrome; Variant; Vitamins; Women' s Health; base; cancer genome; cancer risk; carcinogenesis; cohort; efficacy trial; follow-up; gene environment interaction; genetic risk factor; genetic variant; genome wide association study; improved; novel; population based; prevent; sex; success

DESCRIPTION (provided by applicant): At least 20%, perhaps as much as one-third, of colorectal cancer is attributable to inherited factors. Identifying genetic variants is important to elucidate underlying mechanisms of colorectal cancer, the second leading cause of cancer death in the US. First results from genome-wide association studies (GWAS) have demonstrated considerable success in identifying genetic variants associated with various common complex diseases, including colorectal cancer. Given the overall weak associations, large sample sizes, both for the initial genome- wide scan, as well as for the replication in independent study populations, have become crucial in identifying and establishing true associations. To accelerate the discovery of colorectal cancer-related variants, we have formed the Colorectal Cancer GWAS Consortium. The goal of this Consortium is to conduct a pooled analysis of all five existing colorectal cancer GWAS and validate findings from this pooled analysis in a large-scale replication study (specific aim 1). As a first step, we will conduct a combined pooled analysis of five GWAS, including more than 6,500 colorectal cancer cases and more than 9,000 controls. This initial analysis will provide a powerful means to select the most promising genetic variants, which will be followed up in an independent replication study. For this replication study, the Consortium provides about 8,500 colorectal cancer cases and about 11,500 matched controls from eleven well described and mostly prospective study populations, which are protected against recall and survival bias. We will genotype 7,600 variants in the replication study to minimize the number of false- negative findings. Based on recent results of other common complex diseases, we expect to identify several highly significant novel colorectal cancer susceptibility genes/loci. To establish the identity of the underlying causal variants in these true genetic regions, we will further sequence these regions and subsequently genotype newly identified genetic markers in the entire replication study (specific aim 2). As this consortium brings together experts from multiple disciplines, we are well placed to explore fully this unique data set with its detailed exposure assessment and also to investigate potentially important interactions between genetic variants and environmental factors (specific aim 3). This Consortium provides an unprecedented opportunity to investigate the underlying genetic susceptibility to colorectal cancer, which is, at this point, largely unexplained. The large sample size and detailed exposure and outcome ascertainment in the study populations provide a unique resource to conduct a well-powered replication to identify several new CRC susceptibility genes/loci, which could be missed if groups pursued this research individually. We expect that our findings will enhance our understanding of the genetic susceptibility and molecular mechanisms of colorectal carcinogenesis, thus leading to improved preventive strategies. PUBLIC HEALTH RELEVANCE: This large collaborative effort will investigate comprehensively whether common variations in genes influence colorectal cancer risk in humans. Furthermore, the study will examine whether environmental factors, including smoking, medications, alcohol, physical activity, or diet change the risk of colorectal cancer related to these genetic variants. Findings from this study will improve our understanding of how genes and environment modify risk of colorectal cancer, leading to better strategies to prevent this serious disease and to detect it early when it does occur.

描述（由申请人提供）：至少20％，也许是三分之一的大肠癌归因于遗传因素。识别遗传变异对于阐明结直肠癌的潜在机制很重要，这是美国癌症死亡的第二大原因。全基因组关联研究（GWAS）的首先结果在识别与各种常见复杂疾病（包括结直肠癌）相关的遗传变异方面取得了很大的成功。鉴于总体弱关联，对于初始基因组扫描以及独立研究人群的复制，大型样本量对于识别和建立真正的关联至关重要。为了加速结直肠癌相关的变体，我们形成了大肠癌GWAS联盟。该财团的目的是对所有五个现有的结直肠癌GWAS进行合并分析，并在一项大规模复制研究中验证该汇总分析的发现（特定目标1）。作为第一步，我们将对五个GWAS进行合并的合并分析，包括6,500多个结直肠癌病例和9,000多个对照。该初始分析将提供一种有力的手段来选择最有希望的遗传变异，这将在独立的复制研究中进行跟进。在这项复制研究中，该财团提供了约8,500例结直肠癌病例，并提供了11,500个匹配的对照，来自11个良好描述，主要是前瞻性研究人群，这些人受到保护和生存偏见的保护。在复制研究中，我们将基因型7,600种变体，以最大程度地减少假阴性发现的数量。根据其他常见复杂疾病的最新结果，我们希望鉴定出几种高度重要的新型大肠癌易感基因/基因座。为了确定这些真实遗传区域中基本因果变异的认同，我们将进一步对这些区域进行进一步测序，并随后在整个复制研究中新鉴定出新鉴定的遗传标记物（特定目的2）。由于该联盟将来自多个学科的专家汇集在一起​​，因此我们可以很好地探索此独特的数据集，其详细的暴露评估以及研究遗传变异和环境因素之间的潜在重要相互作用（特定目的3）。该财团提供了一个前所未有的机会，可以调查对大肠癌的潜在遗传敏感性，这在这一点上基本上无法解释。研究人群中大型样本量和详细的暴露和结果确定提供了一种独特的资源，可以进行良好的复制，以识别几个新的CRC敏感性基因/基因座/基因座，如果小组单独进行这项研究，则可能会错过。我们预计我们的发现将增强我们对结直肠癌发生的遗传易感性和分子机制的理解，从而改善预防策略。公共卫生相关性：这项巨大的合作努力将全面研究基因的常见变异是否影响人类大肠癌的风险。此外，该研究将检查包括吸烟，药物，酒精，体育锻炼或饮食在内的环境因素是否改变了与这些遗传变异有关的大肠癌的风险。这项研究的结果将提高我们对基因和环境如何改变结直肠癌的风险的理解，从而为预防这种严重疾病的更好的策略提供了更好的策略，并在发生这种情况时会尽早发现它。