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%，或许多达三分之一的结直肠癌可归因于遗传因素。识别遗传变异对于阐明结直肠癌的潜在机制非常重要，结直肠癌是美国癌症死亡的第二大原因。全基因组关联研究 (GWAS) 的初步结果表明，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相当大的成功。鉴于整体关联性较弱，大样本量（无论是初始全基因组扫描还是在独立研究群体中的复制）对于识别和建立真正的关联性都变得至关重要。为了加速结直肠癌相关变异的发现，我们成立了结直肠癌 GWAS 联盟。该联盟的目标是对所有五种现有结直肠癌 GWAS 进行汇总分析，并在大规模复制研究中验证该汇总分析的结果（具体目标 1）。作为第一步，我们将对五个 GWAS 进行联合汇总分析，其中包括 6,500 多个结直肠癌病例和 9,000 多个对照。这一初步分析将为选择最有希望的遗传变异提供强大的手段，随后将进行独立的复制研究。对于这项复制研究，该联盟提供了约 8,500 个结直肠癌病例和约 11,500 个匹配对照，这些对照来自 11 个描述良好且大部分是前瞻性研究人群，这些人群不受回忆和生存偏差的影响。我们将在复制研究中对 7,600 个变异进行基因分型，以尽量减少假阴性结果的数量。基于其他常见复杂疾病的最新结果，我们期望鉴定出几个高度显着的新型结直肠癌易感基因/位点。为了确定这些真实遗传区域中潜在因果变异的身份，我们将进一步对这些区域进行测序，并随后在整个复制研究中对新识别的遗传标记进行基因分型（具体目标 2）。由于这个联盟汇集了来自多个学科的专家，我们完全有能力充分探索这个独特的数据集及其详细的暴露评估，并调查遗传变异和环境因素之间潜在的重要相互作用（具体目标 3）。该联盟提供了前所未有的机会来研究结直肠癌的潜在遗传易感性，而目前这在很大程度上尚无法解释。研究人群中的大样本量以及详细的暴露和结果确定提供了独特的资源来进行强有力的复制，以确定几个新的 CRC 易感性基因/位点，如果团体单独进行这项研究，则可能会错过这些基因/位点。我们期望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，从而改进预防策略。公共健康相关性：这项大型合作项目将全面调查基因的常见变异是否会影响人类结直肠癌的风险。此外，该研究还将检查环境因素（包括吸烟、药物、酒精、体力活动或饮食）是否会改变与这些基因变异相关的结直肠癌风险。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风险的理解，从而制定更好的策略来预防这种严重疾病并在其发生时及早发现。