Genetics, Epigenetics, and Risk Prediction for Esophageal Adenocarcinoma

食管腺癌的遗传学、表观遗传学和风险预测

• 批准号: 10703461
• 负责人: Matthew Frank Buas
• 金额: $ 71.02万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703461
• 关键词: Address; Age; American; Barrett Esophagus; Biological Markers; Biometry; Biopsy; Cancer Center; Clinical; Columnar Metaplasia; Comprehensive Cancer Center; Computing Methodologies; Country; Data; Development; Diagnosis; Disease; Distal; Dysplasia; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Esophageal Adenocarcinoma; Esophageal Tissue; Esophagus; Etiology; Funding; Gastroenterology; Gastroesophageal reflux disease; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genome; Genotype; Genotype-Tissue Expression Project; Goals; Guidelines; Heritability; Incidence; Individual; Indolent; Leadership; Length; Lesion; Life Style; Link; Malignant Neoplasms; Maps; Mediating; Mediation; Mediator; Meta-Analysis; Methodology; Methods; Modeling; Molecular; Molecular Abnormality; Molecular Probes; Multiomic Data; Non-Steroidal Anti-Inflammatory Agents; Obesity; Pathway interactions; Patients; Population; Predisposition; Prevalence; Prevention; Public Health; Publishing; Reflux; Research; Resources; Risk; Risk Factors; Risk Reduction; Role; Sample Size; Smoking; Specimen; Survival Rate; Susceptibility Gene; Tissues; analytical method; bead chip; biobank; cancer prevention; candidate validation; cohort; college; cost; deep neural network; epidemiologic data; epigenetic marker; epigenome; epigenome-wide association studies; epigenomics; genetic association; genetic risk factor; genome wide association study; genome-wide; high risk; high risk population; improved; innovation; methylome; multiple omics; novel; polygenic risk score; predictive marker; predictive modeling; prevent; preventive intervention; progression marker; rare cancer; risk prediction; risk prediction model; risk stratification; risk variant; screening; sex; trait; transcriptome; transcriptome sequencing; transcriptomic profiling; tumor progression

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.

项目摘要/摘要 食道腺癌（EAC）是最致命的癌症之一，生存率少于5年 20％。在过去的四十年中，EAC的发病率在美国和其他西方国家急剧上升， 很大程度上是由于两个危险因素的患病率上升 - 胃食管反应疾病和肥胖症。 EAC 由Barrett的食道（BE）发展，这是一种由专门的柱状替代品的癌症前体 食管远端。尽管在大多数患者中都遵循懒惰的过程，但最终有5-10％的进展 癌症和相当大的部分在人群中仍未发现。一个关键的未满足需要是确定 具有高风险的人最有可能发展EAC，因此受益于筛查和 内窥镜监视。相反，确定大多数不太可能进步的人将降低风险，并且 与不必要的频繁监视相关的成本。但是，生物标志物辅助风险分层 我们对我们对早期步骤的分子途径的有限理解继续阻碍 EAC的开发。近年来，全基因组关联研究（GWAS）已经确定了约20本小说 遗传敏感性局部，但大多数遗传力仍然未知，只有一个SNP专门链接 是→EAC进展。表观基因组是环境与基因组之间的重要接口，具有 没有研究与基因型，强烈的环境风险因素和 向EAC的发展。要解决这些差距，请克服稀有癌症的样本量限制，并激发 现有的研究工作，需要新的分子和统计方法来系统整合 具有既定疾病暴露的多态数据。在这个项目中，我们将进行最全面的 BE的多词研究，关键癌症前体，分析500活检的转录组和甲基甲基 来自NCI资助的Barrett和食管腺癌财团和Roswell Park综合 癌症中心，并进行综合分析，利用基因型和环境风险因素 可通过最大的GWAS荟萃分析提供BE/EAC（N≈27,000）。目标是确定新的通用 通过EQTL映射和全转录组协会研究（AIM 1），新表观遗传基因座的风险位点 调解和预测向EAC发展的风险（AIM 2），并开发风险预测模型 整合全基因组的多基因风险评分和环境暴露（AIM 3）。统一主题的主题 三个目的是制定和实施创新分析策略，利用转录组和 甲基团数据。最终，将纳入遗传学，表观遗传学和环境暴露以识别 高危人群，用于量身定制的筛查和监视，并防止癌症发展。