Abstract
Abstract Background: The incidence of Barrett’s-related esophageal adenocarcinoma (EAC) is rapidly rising in the USA and the Western countries. However, the interaction between genomic and epigenomic alterations in regulating gene expression networks in EAC is poorly understood. Results and Discussion: We carried out an integrative analytical approach to identify DNA copy number, promoter DNA methylation and gene expression in a panel of esophageal adenocarcinomas, using chip-based technologies. Our analysis displayed significant differences between EAC and normal samples in DNA copy numbers, gene expression, and DNA methylation profiles. Our results identified remarkable incidence of DNA copy number (CN) alterations showing that 90% of probes had a copy number aberration (gain or loss) in at least one tumor, suggesting a vast chromosomal instability in EAC. Integrative analysis indicated that altered expression of 1755 genes was associated with changes in CN or methylation. We found that expression alterations in 84 genes (56 overexpressed and 28 down regulated) were associated with changes in both CN and methylation. These data suggest a strong interaction between genetic and epigenetic events to modulate gene expression in EAC. Of note, we detected a prominent K-RAS signature in EAC. Network analysis predicted activation of several important transcription factor networks in EAC, including β-catenin, MYB, TWIST1, SOX7, GATA3 and GATA6. 56 genes were overexpressed in EAC with simultaneous promoter hypomethylation and gene amplification, including CDH17 and GATA6. Notably, several genes associated with inflammation such as COX2, IL8 and IL23R were overexpressed and hypomethylated in EAC, a reaffirmation of the underlying inflammatory process in Barrett’s tumorigenesis and a suggestion of an epigenetic regulation of these genes. Conclusions: In summary, our integrative analysis of genetic and epigenetic alterations in EAC demonstrates a complex interaction between molecular mechanisms in EAC and provides several novel insights for future studies. Citation Format: Dunfa Peng, Yan Guo, Heidi Chen, Shilin Zhao, Kay Washington, Tianling Hu, Yu Shyr, Wael El-Rafai. Complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4375. doi:10.1158/1538-7445.AM2017-4375
