Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas

Abstract

The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. In this study, we carried out an integrative molecular analysis to identify interactions between genomic and epigenomic alterations in regulating gene expression networks in EAC. We detected significant alterations in DNA copy numbers (CN), gene expression levels, and DNA methylation profiles. The integrative analysis demonstrated that altered expression of 1,755 genes was associated with changes in CN or methylation. We found that expression alterations in 84 genes 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, bioinformatics analysis detected a prominent K-RAS signature and predicted activation of several important transcription factor networks, including β-catenin, MYB, TWIST1, SOX7, GATA3 and GATA6. Notably, we detected hypomethylation and overexpression of several pro-inflammatory genes such as COX2, IL8 and IL23R, suggesting an important role of epigenetic regulation of these genes in the inflammatory cascade associated with EAC. In summary, this integrative analysis demonstrates a complex interaction between genetic and epigenetic mechanisms providing several novel insights for our understanding of molecular events in EAC.

The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

“…Lastly, we focused on those TFs that had been previously linked to RAS signaling (Cebpα, Cebpβ, Cmyb, Evi1, Meis1, The similar expression pattern of Gata3 and miR181a/miR181b, and the presence of regulatory elements in the Mir181ab1 promoter suggested that miR181a1 and miR181b1 could be regulated by Gata3. To substantiate this potential association, further analysis of GATA3 expression was done in immortalized lung epithelial cells expressing Gata2, Gata3, and Foxa2) (51)(52)(53)(54)(55)(56)(57)(58). Quantitative PCR (qPCR) analysis of the TFs revealed upregulation of Gata3 in both mouse lung and pancreatic cancer cell lines after TGF-β treatment for 3 hours ( Figure 9C), while no consistent upregulation in the 2 cell lines was found for the remaining TFs (Supplemental Figure 6, C and D).…”

Integrated Analysis of Hub Genes and Pathways In Esophageal Carcinoma Based on NCBI’s Gene Expression Omnibus (GEO) Database: A Bioinformatics Analysis

“…More crucially, it can provide novel insight leading to early diagnosis, definitive treatment, and survival prediction [ 12 ]. Previous research in the bioinformatics field has yielded some achievements in ESCA knowledge, such as identification of associated genes and pathways and altered methylation associated with ESCA pathology [ 13 , 14 ]. However, analytical ability for ESCA has been limited due to insufficient sample size and a lack of in-depth evaluation of key genes which play a dominant role in the malignant development of ESCA.…”

Identification of genes and pathways in esophageal adenocarcinoma using bioinformatics analysis

“…The gene expression profiles of GSE92396, contributed by Peng et al ( 11 ), were downloaded from the Gene Expression Omnibus (GEO) database ( ). The platform was GPL6244, HuGene-1_0-st Affymetrix Human Gene 1.0 ST Array.…”