Genetics, Epigenetics, and Risk Prediction for Esophageal Adenocarcinoma

项目总结/文摘

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.