胆管癌中异柠檬酸脱氢酶基因突变潜在靶基因的鉴定  

Identification of potential target genesfor isocitrate dehydrogenase mutations in cholangiocarcinoma

作　　者：王迪 李晴 佟伟民[1] 牛亚梅[1] WANG Di;LI Qing;TONG Wei-min;NIU Ya-mei(Department of Pathology, Molecular Pathology Research Center CAMS, Institute of Basic Medical Sciences CAMS,Institute of Basic Medicine PUMC, Beijing 100005, China)

机构地区：[1]中国医学科学院基础医学研究所北京协和医学院基础学院病理学系/中国医学科学院分子病理中心,北京100005

出　　处：《基础医学与临床》2020年第4期512-517,共6页Basic and Clinical Medicine

基　　金：中国医学科学院医学表观中心(2019PT310017)。

摘　　要：目的鉴定胆管癌中异柠檬酸脱氢酶(IDH)基因突变的潜在靶基因。方法下载TCGA胆管癌项目的DNA甲基化、转录组数据。将IDH突变型肿瘤与IDH野生型肿瘤进行比较,分别通过limma和DESeq2进行差异甲基化位点和差异表达分析。对差异表达基因的表达量进行标准化处理并与相应差异甲基化位点的甲基化水平进行Spearman相关性分析。筛选出高甲基化、低表达且两者呈负相关的基因进行富集分析以探究其功能。构建蛋白质互作网络并通过MCODE筛选出核心模块。结果分析得到11605个差异甲基化位点,其中10427个位点高甲基化;而735个差异表达基因中有651个基因下调,其中的143个基因与328个高甲基化位点形成330对强负相关组合。上述143个基因富集于表皮生长因子受体信号通路、细胞外渗及细胞分裂的调控,通过构建蛋白质相互作用(PPI)网络筛选出核心模块的10个基因,分别参与了上皮细胞的分化发育、细胞蛋白质定位等生物学过程。结论本研究通过整合TCGA胆管癌DNA甲基化和转录组数据,得到了IDH突变所影响的潜在靶基因并确定其PPI网络核心模块,为阐明IDH突变在胆管癌发生发展中的作用提供了新的线索。Objective To identify potential target genes for isocitrate dehydrogenase(IDH)mutations in cholangiocarcinoma.Methods DNA methylation 450K data and mRNA expression data of the TCGA CHOL project were downloaded.Probe-wise differential methylation analysis and differential expression analysis were performed through limma and DESeq2 in the IDH-mutant vs IDH-WT comparison.Then,Spearman correlation analysis was performed between the normalized expression levels of differentially expressed genes and the methylation levels of corresponding differentially methylated sites.Genes with high methylation,low expression,and strong negative correlation were screened for enrichment analysis to explore their functions.A protein interaction network was constructed and the core modules were found by MCODE.Results The analysis revealed 11605 differentially methylated sites,of which 10427 were hypermethylated;and 651 of the 735 differentially expressed genes were down-regulated.Among them,143 down-regulated genes and 328 hypermethylation sites formed 330 strongly negatively correlated combinations.The above 143 genes are enriched in the regulation of epidermal growth factor receptor signaling pathway,cell extravasation and cell division.By constructing a protein-protein interaction(PPI)network,10 genes of its core module were identified,which were involved in biological processes such as epithelial cell differentiation and development,and cellular protein localization.Conclusions By integrating the TCGA cholangiocarcinoma transcriptome and DNA methylation data,the potential target genes for IDH mutations are obtained and the core modules of their PPI network are identified,providing new clues for the role of IDH mutations in the development of cholangiocarcinoma.

关 键 词：胆管癌 异柠檬酸脱氢酶突变 靶基因 DNA甲基化 基因表达 

分 类 号：R735.8[医药卫生—肿瘤]