Genetics, Epigenetics, and Risk Prediction for Esophageal Adenocarcinoma

项目摘要/摘要 食管腺癌(EAC)是最致命的癌症之一，其5年生存率低于 20%在过去的40年里，EAC在美国和其他西方国家的发病率急剧上升， 这在很大程度上是因为胃食道反流病和肥胖这两个危险因素的患病率不断上升。选管会 起源于Barrett‘s食道(BE)，这是一种癌症前体，由一种特殊的柱状化生定义 远端食道。尽管BE在大多数患者中遵循一个缓慢的过程，但5%-10%的患者最终进展为 癌症，以及相当大一部分BE在人群中仍未被发现。一个关键的未得到满足的需求是确定 高危BE最有可能发展为EAC并因此受益于筛查和 内窥镜检查。相反，找出大多数不太可能取得进展的人将降低风险和 与不必要的频繁监视相关的成本。然而，生物标记物辅助的风险分层， 继续受到我们对支持早期步骤的分子途径的有限了解的阻碍 EAC的发展。近年来，全基因组关联研究(GWAS)已经确定了大约20个新的 遗传易感基因座，但大多数遗传性仍未解释，只有一个SNP与特定的 BE→EAC PROCESS。表观基因组是环境和基因组之间的重要接口，它具有 没有研究它在与基因类型、强烈的环境风险因素和 向EAC进军。为了解决这些差距，克服一种罕见癌症的样本量限制，并 需要现有的研究努力、新的分子和统计方法来系统地整合 已有疾病暴露的多重组学数据。在这个项目中，我们将进行最全面的 关键癌前体BE的多组学研究--500例活检组织的转录组和甲基组分析 来自NCI资助的Barrett‘s和食管腺癌联盟和Roswell Park Complex 癌症中心，并利用已有的基因类型和环境风险因素进行综合分析 可通过对BE/EAC(n≈27,000)进行的最大规模的全球气候变化综合分析获得。目标是识别新的基因 通过eQTL定位和全转录组关联研究(目标1)的风险基因座，新的表观遗传基因座 调解和预测BE进展到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)。统一的主题 三个目标是开发和实施创新的分析战略，利用转录组和 甲基组数据。最终，遗传学、表观遗传学和环境暴露将被结合起来，以识别 为高危人群量身定做的筛查和监测，并防止癌症的发展。

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.