基于转录组学的肝内胆管癌预后相关基因分析

Analysis of genes associated with prognosis of intrahepatic cholangiocarcinoma based on transcriptomics

目的从转录组学层面研究肝内胆管癌(ICC)发生异常的生物学通路并发现与ICC预后相关的基因。方法通过t检验和倍数变化法筛选差异表达基因并对相关基因进行KEGG功能富集分析;利用STRING数据库构建蛋白质互作网络,通过计算每个节点的度、介数和接近中心性来寻找网络的Hub节点;采用log-rank检验进行Kaplan-Meier生存分析,识别ICC预后相关基因。结果在3个数据集中重复的ICC相关的差异表达基因共1134个,主要参与15条通路,包括参与DNA复制、细胞周期、药物代谢、RNA转运等信号通路和氨基酸合成等生物学过程。通过蛋白质互作网络分析发现TAF1、GRB2、E2F4、HNF4A、MYC和TP53基因是Hub节点。因GRB2和TP53既是蛋白质互作网络的Hub节点也是ICC死亡相关基因,因此分析其高低表达发现,GRB2基因低表达者较其高表达者总生存情况更好(P=0.0409),而TP53是低表达者较其高表达者总生存情况更差(P=0.0273),且在TCGA数据库中也得到验证。结论ICC的发生与细胞代谢异常息息相关,且TAF1、GRB2、E2F4、HNF4A、MYC和TP53这些差异表达基因是ICC发生发展的重要基因,尤其是GRB2和TP53基因的表达与ICC预后有关。

Objective To study the abnormal biological pathways of intrahepatic cholangiocarcinoma(ICC)from the transcriptomics level and identify genes associated with the prognosis of ICC.Methods The differentially expressed genes were screened by t test and fold change method,then KEGG functional enrichment analysis was performed on related genes.The STRING database was applied to construct protein interaction network and find the hub nodes of the network by calculating the degree,betweenness,and closeness of each node.Kaplan-Meier survival analysis was performed using log-rank test to identify prognostic genes related to ICC.Results All of 1134 differentially expressed genes were overlapped in 3 datasets,which were mainly involved in 15 pathways,including DNA replication,cell cycle,drug metabolism,RNA transport,etc.signaling pathways and amino acid synthesis.According to protein interaction network analysis,TAF1,GRB2,E2F4,HNF4A,MYC,and TP53 genes were hub nodes.As GRB2 and TP53 genes were also the death related genes of ICC,it was found that patients with lower GRB2 gene expression had a better overall survival than those with higher GRB2 gene expression(P=0.0409),while patients with lower TP53 had a worse overall survival than those with higher TP53 gene expression(P=0.0273),which were also verified in the TCGA database.Conclusions The abnormal cell metabolism is notably related to the tumorigenesis of ICC.TAF1,GRB2,E2F4,HNF4A,MYC,and TP53 are the key genes in the carcinogenesis and progression of ICC.Expressions of GRB2 and TP53 genes are associated with the prognosis of ICC.