Using functional genomics to inform gene environment interactions for colorectal cancer

使用功能基因组学来了解结直肠癌的基因环境相互作用

基本信息

批准号：
9763541
负责人：
GRAHAM CASEY
金额：
$ 170.25万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763541
关键词：
3-Dimensional African Alcohols Alleles Asians Aspirin Biological Biological Assay Biopsy CRISPR/Cas technology Calcium Cancer Etiology Cessation of life Clinical Colon Colorectal Colorectal Cancer Complex Data Data Set Deoxyribonuclease I Development Diet Disease Enhancers Environmental Exposure Environmental Risk Factor Epigenetic Process Epithelial European Exposure to Family-Based Registry Folic Acid Future Gene Expression Gene Frequency Gene Targeting Genes Genetic Genetic Risk Genome Genotype Hispanics Hormone replacement therapy Hormone use Human Hypersensitivity In Vitro Individual Intervention Interview Life Style Link Luciferases Maps Measures Meat Meta-Analysis Methodology Minor Non-Steroidal Anti-Inflammatory Agents Nucleotides Organoids Participant Patient Self-Report Population Predisposition Prevention strategy Preventive Processed Meats Publishing Research Resources Risk Factors Sample Size Scanning Site Site-Directed Mutagenesis Smoking Statistical Methods Subgroup Susceptibility Gene Testing Tissues Validation Variant Weight Work base carcinogenicity causal variant colon cancer cell line colorectal cancer prevention colorectal cancer risk environmental agent experience experimental study follow-up functional genomics gene environment interaction genetic epidemiology genetic profiling genetic risk factor genetic variant genome editing genome wide association study genome-wide genomic data improved innovation insight knock-down lifestyle factors novel promoter rare variant response study population success transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a complex disease with both genetic (G) and environmental (E) risk factors contributing to susceptibility. Genome-wide GxE interaction scans (GWIS) can help identify novel susceptibility loci and biologically meaningful GxE interactions that point to new carcinogenic mechanisms. Limited statistical power remains a primary concern in GxE analyses. To maximize the statistical power in a GWIS, it is essential to have the largest possible sample size by pooling resources across studies. In this project, we will combine the resources of three existing CRC consortia (approximately 53,600 cases and 52,400 controls of European descent): the Colorectal Cancer Family Registry (CCFR), the Colorectal Cancer Transdisciplinary (CORECT) Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) for interaction testing with 8 environmental and lifestyle factors: alcohol, calcium, folate, hormone replacement therapy (HRT), non- steroidal anti-inflammatory drugs (NSAIDs), red meat, processed meat, and smoking. To improve statistical power and enhance our ability to discover true GxE associations, we will as part of Aim 1 incorporate functional genomics data in two forms: (1) enhancer/promoter profiles derived from ChIPseq and DNase I hypersensitive sites (DHS) data publicly available from Roadmap or from our own experiments in normal colon tissue; and (2) our newly generated RNA-Seq results from normal colon biopsies with detailed environmental and lifestyle risk factor information, and gene expression measured in normal human 3D colon organoids (“mini guts”) in response to environmental exposures. In Aim 2 we will use our novel statistical methods that can incorporate the CR and E-specific functional genomics data generated in Aim 1 to discover new GxE interaction for CRC with rare and common single nucleotide variants (down to MAF 0.1%) in up to 53,600 cases and 52,400 controls. To narrow in on the underlying causal variant(s) for any identified novel GxE interaction, we will conduct fine-mapping analyses using a trans-ethnic meta-analysis (23,500 non-European and 106,000 European). To follow-up on identified significant GxE interactions, we will functionally validate our strongest GxE interactions (including previously published findings) to provide support for the novel GxE interactions such as knock down in CRC cell lines and normal human 3D colon epithelial organoids. Our large and well-characterized study population, combined with our experienced research team, and integration of functional genomics data into our novel statistical methods provide opportunities to better understand how genetic and environmental risk factors, combined, contribute to individual risk of CRC. Discovering GxE interactions will provide insight into the underlying mechanisms that drive gene-CRC associations impacted by established environmental risk factors. Since genetic profiles are fixed, modifying environmental exposures to alter deleterious effects of alleles remains an important preventive strategy.

项目概要/摘要结直肠癌 (CRC) 是一种复杂的疾病，同时具有遗传 (G) 和环境 (E) 危险因素全基因组 GxE 相互作用扫描 (GWIS) 有助于识别新的易感性。位点和具有生物学意义的 GxE 相互作用表明新的致癌机制有限的统计数据。功效仍然是 GxE 分析中的主要关注点，为了最大限度地提高 GWIS 中的统计功效，这一点至关重要。在这个项目中，我们将结合不同研究的资源来获得尽可能大的样本量。三个现有 CRC 联盟的资源（欧洲大约 53,600 个病例和 52,400 个对照）血统）：结直肠癌家族登记处 (CCFR)、结直肠癌跨学科 (CORECT) 研究与结直肠癌遗传学和流行病学联盟 (GECCO) 进行相互作用测试与 8 种环境和生活方式因素有关：酒精、钙、叶酸、激素替代疗法 (HRT)、非类固醇抗炎药 (NSAID)、红肉、加工肉类和吸烟改善统计。权力并增强我们发现真正的 GxE 关联的能力，作为目标 1 的一部分，我们将整合功能基因组学数据有两种形式：(1) 来自 ChIPseq 和 DNase I 超敏感的增强子/启动子图谱站点（DHS）数据可从路线图或我们自己的正常结肠组织实验中公开获得；以及（2）我们新生成的 RNA 测序结果来自正常结肠活检，其中包含详细的环境和生活方式风险正常人 3D 结肠类器官（“迷你肠道”）中测量的因子信息和基因表达在目标 2 中，我们将使用新的统计方法来应对环境暴露。目标 1 中生成的 CR 和 E 特定功能基因组学数据，以发现 CRC 的新 GxE 相互作用多达 53,600 例和 52,400 例中存在罕见和常见的单核苷酸变异（低至 MAF 0.1%）为了缩小任何已识别的新型 GxE 相互作用的潜在因果变异的范围，我们将使用跨种族荟萃分析（23,500 个非欧洲人和 106,000 个为了跟进已确定的重要 GxE 交互，我们将在功能上验证我们最强大的功能。 GxE 交互（包括之前发表的研究结果）为新颖的 GxE 交互提供支持例如 CRC 细胞系和正常人 3D 结肠上皮类器官中的敲低。我们庞大且特征鲜明的研究人群，加上我们经验丰富的研究团队，以及将功能基因组学数据整合到我们新颖的统计方法中提供了更好的机会了解遗传和环境风险因素如何共同导致结直肠癌的个体风险。发现 GxE 相互作用将有助于深入了解驱动基因-CRC 的潜在机制由于遗传图谱是固定的，因此受既定环境风险因素影响的关联。环境暴露以改变等位基因的有害影响仍然是重要的预防策略。