Discovery and validation of DNA methylation markers for overall survival prognosis in patients with thymic epithelial tumors
Discovery and validation of DNA methylation markers for overall survival prognosis in patients with thymic epithelial tumors
复制标题
胸腺上皮肿瘤患者总体生存预后的 DNA 甲基化标记物的发现和验证
DOI：
10.1186/s13148-019-0619-z
复制
发表时间：
2019-03-04
影响因子：
5.7
通讯作者：
Wang, Ge
中科院分区：
文献类型：
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作者：
Li, Songlin;Yuan, Yuan;Wang, Ge
背景胸腺上皮肿瘤（Thymic epithelial tumors，THTs）的预后主要依据世界卫生组织（WHO）的组织学分类和Masaoka分期系统。这些预后判断方法在临床应用中有一定的局限性，需要寻求新的判断TBI患者预后的方法。到目前为止，还没有关于使用DNA甲基化生物标志物预测THBG的研究。因此，进行本研究以鉴定可以确定TcDNA 450 K甲基化阵列数据、转录组测序数据、采用WHO组织学分类和Masaoka分期系统鉴定胸腺瘤和胸腺癌之间差异表达的甲基化位点，以及与胸腺癌相关的不同DNA甲基化位点。总生存率。采用焦磷酸测序法，对100例中国人甲状腺癌组织中4个不同甲基化位点（cg 05784862、cg 07154254、cg 02543462和cg 06288355）进行测序。使用这四个甲基化sites.ResultsThe TCGA数据集显示5155和6967高甲基化和低甲基化的CpG位点，分别在A-B3型组和C型组，其中3600位于基因启动子区域内。134个基因被沉默的启动子高甲基化和174个mRNA的上调。单因素和多因素考克斯回归分析显示，187个位点的甲基化水平与TCRs患者的总生存率显著相关。cg 05784862（KSR 1）、cg 07154254（ELF 3）、cg 02543462（ILRN）和cg 06288355（RAG 1）被确定为100例中国患者中调整Masaoka分期后的总生存期的独立预后因素。与Masaoka临床分期相比，由上述四个基因组成的预后模型预测THBV 5年总生存率的准确性更高。结论cg 05784862（KSR 1）、cg 07154254（ELF 3）、cg 02543462（ILRN）和cg 06288355（RAG 1）位点甲基化水平与TcR进展相关，可能作为预测TcR患者总生存期的新生物标志物。
BackgroundThe current prognosis of thymic epithelial tumors (TETs) is according to the World Health Organization (WHO) histologic classification and the Masaoka staging system. These methods of prognosis have certain limitations in clinical application and there is a need to seek new method for determining the prognosis of patients with TETs. To date, there have been no studies done on the use of DNA methylation biomarkers for prognosis of TETs. The present study was therefore carried out to identify DNA methylation biomarkers that can determine the overall survival in patients with TETs.MethodsBioinformatic analysis of TCGA 450 K methylation array data, transcriptome sequencing data, WHO histologic classification and Masaoka staging system was performed to identify differentially expressed methylation sites between thymoma and thymic carcinoma as well as the different DNA methylation sites associated with the overall survival in patients with TETs. Using pyrosequencing, 4 different methylation sites (cg05784862, cg07154254, cg02543462, and cg06288355) were sequenced from tumor tissues of 100 Chinese patients with TETs. A prognostic model for TETs was constructed using these four methylation sites.ResultsThe TCGA dataset showed 5155 and 6967 hyper- and hypomethylated CpG sites in type A–B3 group and type C group, respectively, of which 3600 were located within the gene promoter regions. One hundred thirty-four genes were silenced by promoter hypermethylation and 174 mRNAs were upregulated. Analysis of univariate and multivariate Cox regression showed significant association between the methylation levels of 187 sites and the overall survival in patients with TETs. cg05784862(KSR1), cg07154254(ELF3), cg02543462(ILRN), and cg06288355(RAG1) were identified as independent prognostic factors for overall survival in patients with TETs after adjusting for Masaoka staging in 100 Chinese patients. The prognostic model which consists of the four abovementioned genes had higher accuracy for predicting the 5-year overall survival in patients with TETs as compared to the Masaoka clinical staging. (Time-dependent ROC analysis AUC 1.000 vs 0.742,P= 2.7 × 10−6).ConclusionsThe methylation levels of cg05784862(KSR1), cg07154254(ELF3), cg02543462(ILRN), and cg06288355(RAG1) sites are associated with the progression of TETs and may serve as new biomarkers for predicting the overall survival in patients with TETs.