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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要食管腺癌 (EAC) 是最致命的癌症之一，其 5 年生存率低于过去四十年，美国和其他西方国家的 EAC 发病率急剧上升，这主要是由于两种危险因素——胃食管反流病和肥胖——的患病率上升。由巴雷特食管 (BE) 发展而来，巴雷特食管是一种癌症前体，由特殊的柱状化生定义尽管大多数患者的 BE 病程呈惰性，但 5-10% 的患者最终会进展为远端食管。癌症，并且在人群中仍有相当大一部分 BE 未被检测到，一个关键的未满足需求是识别。患有高风险 BE 的个体最有可能发展为 EAC，因此可以从筛查和治疗中受益离线内窥镜监测，识别出大多数不太可能取得进展的人将降低风险和然而，生物标志物辅助的风险分层我们对早期步骤背后的分子途径的了解有限，这仍然阻碍着我们的研究。近年来，全基因组关联研究 (GWAS) 已鉴定出约 20 种新发现。遗传易感性位点，但大多数遗传性仍然无法解释，并且只有一个 SNP 与 BE→EAC 进程，是环境和基因组之间的重要界面。尚未研究其与基因型、强环境风险因素和为了解决这些差距，克服罕见癌症的样本量限制，并激发活力。需要现有的研究工作、更新的分子和统计方法来系统地整合在这个项目中，我们将进行最全面的具有已确定疾病暴露的多组学数据。 BE（关键癌症前体）的多组学研究，分析 500 个活检组织的转录组和甲基化组来自 NCI 资助的巴雷特和食管腺癌联盟和罗斯威尔公园综合中心癌症中心，并利用基因型和环境风险因素进行综合分析可通过最大的 BE/EAC GWAS 荟萃分析（n≈27,000）获得。目标是识别新的遗传。通过 eQTL 作图和全转录组关联研究（目标 1）发现风险位点，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基因组整合多基因风险评分和环境暴露（目标 3）。三个目标是开发和实施创新分析策略，利用转录组和最终，将结合遗传学、表观遗传学和环境暴露来识别。对高危人群进行量身定制的筛查和监测，并预防癌症的发展。