Using functional genomics to inform gene environment interactions for colorectal cancer

项目概要/摘要 结直肠癌（CRC）是一种复杂的疾病，具有遗传（G）和环境（E）危险因素 有助于易感性。全基因组GxE相互作用扫描（GWIS）可以帮助识别新的易感性 基因座和生物学意义的GxE相互作用，指出新的致癌机制。有限的统计 功率仍然是GxE分析中的主要关注点。为了最大限度地提高GWIS的统计能力， 通过汇集研究资源来获得尽可能大的样本量。在这个项目中，我们将联合收割机 现有的三个CRC联盟的资源（约53，600例病例和52，400例欧洲对照） 大肠癌家族登记处（CCFR），大肠癌跨学科（CORECT） 研究和结直肠癌遗传学和流行病学联盟（GECCO）进行相互作用测试 有8个环境和生活方式因素：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。提高统计 功率和增强我们发现真正的GxE协会的能力，我们将作为目标1的一部分， 两种形式的基因组学数据：（1）来自ChIPseq和DNase I超敏的增强子/启动子谱 从Roadmap或我们自己在正常结肠组织中的实验中公开的DHS数据;以及（2） 我们新生成的RNA-Seq结果来自正常结肠活检，具有详细的环境和生活方式风险 因子信息，以及在正常人3D结肠类器官（“小肠”）中测量的基因表达。 应对环境暴露。在目标2中，我们将使用我们的新统计方法， 目的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 罕见和常见的单核苷酸变异（MAF降至0.1%）在多达53，600例病例和52，400例 对照为了缩小任何已确定的新型GxE相互作用的潜在因果变异，我们将 使用跨种族荟萃分析（23，500名非欧洲人和106，000名 欧洲）。为了跟进已确定的重要GxE相互作用，我们将在功能上验证我们最强的 GxE相互作用（包括先前发表的研究结果），为新型GxE相互作用提供支持 例如在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， 将功能基因组学数据整合到我们的新统计方法中， 了解遗传和环境风险因素如何结合在一起，导致CRC的个体风险。 发现GxE相互作用将提供深入了解驱动基因CRC的潜在机制 受既定环境风险因素影响的协会。由于基因图谱是固定的， 环境暴露以改变等位基因的有害作用仍然是重要的预防策略。

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.