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.

项目摘要/摘要结直肠癌（CRC）是一种复杂的疾病，均具有遗传（G）和环境（E）风险因素有助于易感性。全基因组GXE相互作用扫描（GWIS）可以帮助识别新的敏感性基因座和生物学上有意义的GXE相互作用，指向新的致癌机制。有限的统计数据在GXE分析中，功率仍然是主要问题。为了最大化gwis中的统计能力，这是必不可少的通过在研究中汇总资源，具有最大的样本量。在这个项目中，我们将结合三个现有CRC财团的资源（大约53,600例和52,400个欧洲控制血统）：大肠癌家族登记处（CCFR），大肠癌跨学科（CORECT）研究，结直肠癌联盟（GECCO）的遗传学和流行病学用于相互作用测试具有8种环境和生活方式因素：酒精，钙，叶酸，马酮替代疗法（HRT），非 - 类固醇抗炎药（NSAIDS），红肉，加工肉和吸烟。改善统计数据权力并增强我们发现真正GXE关联的能力，我们将作为AIM 1的一部分。基因组学数据有两种形式：（1）源自Chipseq和DNase I超敏的增强子/启动子曲线从路线图或我们自己在正常结肠组织中的实验中公开获得的站点（DHS）数据；（2）我们新产生的RNA序列是由正常的结肠活检带来的，具有详细的环境和生活方式风险因子信息和基因表达在正常人3D结肠机体（“迷你胆”）中测得的基因表达对环境暴露的反应。在AIM 2中，我们将使用我们的新颖统计方法，可以合并在AIM 1中生成的CR和E特异性功能基因组学数据，以发现CRC的新GXE相互作用在多达53,600例和52,400例中，具有罕见和常见的单核苷酸变体（降至MAF 0.1％）控件。为了在任何已确定的新型GXE相互作用的基本因果变体上缩小范围，我们将使用跨种族荟萃分析进行精细图分析（23,500个非欧洲和106,000 欧洲的）。为了跟进确定的显着GXE相互作用，我们将在功能上验证我们的strongst GXE相互作用（包括先前发表的发现），为新型GXE相互作用提供支持例如在CRC细胞系和正常的人类3D结肠上皮器官中撞倒。我们大型且符合特点的研究人群，以及我们经验丰富的研究团队，以及功能基因组学数据集成到我们的新统计方法中，为更好的机会提供了机会了解遗传和环境风险因素如何加在一起，导致个人CRC的个人风险。发现GXE相互作用将提供对驱动基因-CRC的基本机制的见解由既定的环境风险因素影响的协会。由于遗传概况是固定的，请修改环境暴露改变等位基因的有害影响仍然是一个重要的预防策略。