Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
Sci Rep. 2017 Jan 19;7:40729. doi: 10.1038/srep40729.
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.
食管腺癌（EAC）在美国和西方国家的发病率正在迅速上升。在这项研究中，我们进行了综合的分子分析，以确定基因组和表观遗传改变之间的相互作用，从而调节 EAC 中的基因表达网络。我们检测到 DNA 拷贝数（CN）、基因表达水平和 DNA 甲基化谱的显著改变。综合分析表明，1755 个基因的表达改变与 CN 或甲基化的改变有关。我们发现，84 个基因的表达改变与 CN 和甲基化的改变都有关。这些数据表明遗传和表观遗传事件之间存在强烈的相互作用，以调节 EAC 中的基因表达。值得注意的是，生物信息学分析检测到一个突出的 K-RAS 特征，并预测了几个重要转录因子网络的激活，包括β-catenin、MYB、TWIST1、SOX7、GATA3 和 GATA6。值得注意的是，我们检测到几个促炎基因（如 COX2、IL8 和 IL23R）的低甲基化和过表达，表明这些基因的表观遗传调控在与 EAC 相关的炎症级联反应中具有重要作用。总之，这项综合分析表明遗传和表观遗传机制之间存在复杂的相互作用，为我们理解 EAC 中的分子事件提供了一些新的见解。
