Using functional genomics to inform gene environment interactions for colorectal cancer

项目摘要/摘要 结直肠癌是一种既有遗传(G)危险因素，又有环境(E)危险因素的复杂疾病 增加了易感性。全基因组GxE相互作用扫描(GWI)可帮助识别新的易感性 基因座和具有生物学意义的GxE相互作用指向新的致癌机制。有限统计 电力仍然是GxE分析中的主要关注点。为了最大限度地发挥gwis的统计能力，它是必不可少的。 通过汇集不同研究的资源来获得尽可能大的样本量。在这个项目中，我们将结合 现有的三个儿童权利保护财团的资源(约53 600起案件和52 400起欧洲控制 下降)：结直肠癌家族登记(CCFR)，结直肠癌跨学科(CORECT) 结直肠癌联合会(GECCO)相互作用检验的遗传学和流行病学研究 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(NSAIDs)、红肉、加工肉类和吸烟。提高统计水平 增强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 两种形式的基因组数据：(1)来自ChIPseq和DNase I超敏的增强子/启动子图谱 从Roadmap或我们自己的正常结肠组织实验中公开获得的站点(DHS)数据；以及(2) 我们新产生的RNA-Seq结果来自正常的结肠活组织检查，具有详细的环境和生活方式风险 在正常人体3D结肠器官(“迷你肠道”)中测量的因子信息和基因表达 对环境暴露的反应。在目标2中，我们将使用我们的新统计方法，这些方法可以将 目标1中生成的CR和E特定的功能基因组数据，以发现结直肠癌新的GxE相互作用 在多达53,600个病例和52,400个病例中发现罕见和常见的单核苷酸变异(MAF 0.1%) 控制。为了缩小到任何已发现的新的GxE相互作用的潜在因果变量(S)，我们将 使用跨种族元分析进行精细映射分析(23,500名非欧洲人和106,000名 欧洲)。为了跟进已确定的重要GxE交互，我们将从功能上验证我们最强的 GxE相互作用(包括之前发表的发现)，为新的GxE相互作用提供支持 例如在结直肠癌细胞系和正常人3D结肠上皮器官中被击倒。 我们庞大而有特色的研究人群，加上我们经验丰富的研究团队，以及 将功能基因组学数据集成到我们的新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结合在一起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 受既定环境风险因素影响的关联。由于基因图谱是固定的，因此修改 环境暴露以改变等位基因的有害影响仍然是一项重要的预防策略。

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.