Genetics, Epigenetics, and Risk Prediction for Esophageal Adenocarcinoma

项目总结/摘要 食管腺癌（EAC）是最致命的癌症之一，其5年生存率低于10%。 百分之二十在过去的四十年里，EAC的发病率在美国和其他西方国家急剧上升， 这主要是由于两个危险因素-胃食管反流病和肥胖-的流行率上升。EAC 从巴雷特食管（BE）发展而来，这是一种由特化柱状化生定义的癌症前兆， 远端食道虽然BE在大多数患者中遵循无痛过程，但5-10%最终进展为 癌症和相当大一部分BE在人群中仍未被检测到。一个未得到满足的关键需求是确定 最有可能发展为EAC并因此从筛查中获益的高风险BE个体， 内窥镜监视。相反，确定大多数不太可能取得进展的人将减少风险， 与不必要的频繁监控相关的成本。然而，生物标志物辅助的风险分层， 由于我们对早期阶段的分子途径的理解有限， EAC的发展。近年来，全基因组关联研究（GWAS）已经确定了约20个新的 遗传易感性位点，但大多数遗传性仍然无法解释，只有一个SNP是专门联系到 BE→EAC进展。表观基因组是环境和基因组之间的重要界面， 尚未研究其与基因型、强环境风险因素和 发展到EAC。为了解决这些差距，克服罕见癌症的样本量限制， 现有的研究成果，更新的分子和统计方法，需要系统地整合 多组学数据与已确定的疾病暴露。在这个项目中，我们将进行最全面的 BE的多组学研究，关键的癌症前体，分析500个活检的转录组和甲基化组 来自国家癌症研究所资助的巴雷特食管腺癌联合会和罗斯威尔公园综合医院 癌症中心，并进行综合分析，利用基因型和环境风险因素已经 通过BE/EAC的最大GWAS荟萃分析获得（n = 27，000）。目标是识别新的基因 通过eQTL定位和全转录组关联研究（Aim 1），新的表观遗传位点 调解和预测BE进展为EAC的风险（目标2），并开发风险预测模型 整合全基因组多基因风险评分和环境暴露（目标3）。的统一主题 三个目标是开发和实施创新的分析策略，利用转录组， 甲基化数据。最终，遗传学，表观遗传学和环境暴露将被纳入，以确定 对高危人群进行量身定制的筛查和监测，并预防癌症发展。

PROJECT SUMMARY/ABSTRACT Esophageal adenocarcinoma (EAC) is one of the most lethal cancers, with a 5-year survival rate less than 20%. Incidence of EAC has risen sharply in the U.S. and other Western countries over the past four decades, largely due to rising prevalence of two risk factors – gastroesophageal reflux disease and obesity. EAC develops from Barrett’s esophagus (BE), a cancer precursor defined by a specialized columnar metaplasia of the distal esophagus. Although BE follows an indolent course in most patients, 5-10% eventually progress to cancer, and a sizable fraction of BE remain undetected in the population. A critical unmet need is to identify individuals with high-risk BE who are most likely to develop EAC and thus benefit from screening and endoscopic surveillance. Conversely, identifying the majority who are unlikely to progress will reduce risks and costs associated with unnecessarily frequent surveillance. Biomarker-assisted risk stratification, however, continues to be hindered by our limited understanding of the molecular pathways underlying early steps in the development of EAC. In recent years, genome-wide association studies (GWAS) have identified ~20 novel genetic susceptibility loci, yet most heritability remains unexplained, and only one SNP is linked specifically to BE→EAC progression. The epigenome, an important interface between the environment and the genome, has not been studied for its potential mediating roles in relation to genotypes, strong environmental risk factors and progression to EAC. To address these gaps, overcome sample size limitations for a rare cancer, and invigorate existing research efforts, newer molecular and statistical approaches are needed to systematically integrate multi-omics data with established disease exposures. In this project we will conduct the most comprehensive multi-omics study of BE, the key cancer precursor, profiling the transcriptome and methylome of 500 biopsies from the NCI-funded Barrett’s and Esophageal Adenocarcinoma Consortium and Roswell Park Comprehensive Cancer Center, and perform integrative analyses leveraging genotypes and environmental risk factors already available through the largest GWAS meta-analysis for BE/EAC (n≈27,000). The goal is to identify new genetic risk loci through eQTL mapping and transcriptome-wide association study (Aim 1), new epigenetic loci mediating and predicting the risk of BE progression to EAC (Aim 2), and develop risk prediction models integrating genome-wide polygenic risk score and environmental exposures (Aim 3). The unifying theme of the three aims is development and implementation of innovative analytical strategies, leveraging transcriptome and methylome data. Ultimately, genetics, epigenetics, and environmental exposures will be incorporated to identify high-risk populations for tailored screening and surveillance, and prevent cancer development.