权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9357531
负责人：
GRAHAM CASEY
金额：
$ 210.32万
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/9357531
关键词：
African Alcohols Alleles Anti-Inflammatory Agents Anti-inflammatory 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 Nucleotides Organoids Participant Patient Self-Report Pharmaceutical Preparations Population Predisposition Prevention strategy Preventive Processed Meats Publishing Research Resources Risk Risk Factors Sample Size Scanning Site Site-Directed Mutagenesis Smoking Statistical Methods Subgroup Susceptibility Gene Testing Tissues Validation Variant Weight Work base cancer risk carcinogenicity colon cancer cell line 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 prevent 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.

项目总结/文摘