title: 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.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: DunFa
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Shilin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Kay
authors.initials: K
authors.lastname: Washington
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: TianLing
authors.initials: T
authors.lastname: Hu
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.|Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics; D004938:Esophageal Neoplasms / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D023281:Genomics; D006801:Humans