基于GEO和TCGA数据库筛选恶性胸膜间皮瘤免疫治疗疗效预测关键基因

Identification of candidate genes predicting the response to immunotherapy for malignant pleural mesothelioma based on GEO and TCGA database

目的探索免疫治疗在恶性胸膜间皮瘤(malignant pleural mesothelioma,MPM)中免疫疗效相关关键分子及其可能的机制。方法2018年7月至2020年7月,纳入GEO数据库中GSE117358的表达谱进行分析;首先,根据是否对免疫治疗是否有效分为两组:免疫治疗反应组和免疫治疗无反应组,同时分析两组之间差异有统计学意义基因;其次,分析两组差异有统计学意义基因在基因本体(gene ontology,GO)生物学行为及京都基因与基因组百科全书(Kyoto encyclopedia of genes and ge‐nomes,KEGG)富集信号通路等方面的差异;最后,对差异有统计学意义基因构建蛋白-蛋白互作网络,筛选在生物学行为中的重要模块及关键基因,并对关键基因在TCGA数据库中进行整合分析验证。结果在免疫治疗反应组(12个样本)及免疫治疗无反应组(12个样本)中共筛选出1025个差异基因,相对于免疫治疗无反应组,在免疫治疗反应组中有782个上调和243个下调基因。GO和KEGG分析显示,这些差异基因的功能主要集中在细胞因子受体通路、细胞黏附通路、T细胞受体通路及NFkappa B信号通路等;在蛋白-蛋白互作网络分析中,筛选出节点度最高的10个核心基因包括Tnf,Il6,Ptprc,Csf2,Cd86,Cxcl9,Sell,Cxcr3,Ccl2,Cd40。TCGA数据库整合分析显示,Tnf,Il6,Cd86,Cxcl9,Sell,Cxcr3,Cd40等疗效相关关键基因在肉瘤样胸膜间皮瘤中呈现相对高表达,且差异有统计学意义。结论核心基因Tnf,Il6,Ptprc,Csf2,Cd86,Cxcl9,Sell,Cxcr3,Ccl2,Cd40有望成为预测MPM的分子标志物及治疗的潜在靶点。

Objective To identify the key genes associated with immune efficacy in the treatment of malignant pleural mesothelioma(MPM)and the likely mechansim.Methods The expression profile of GSE117358 obtained from GEO database was analyzed from July 2018 to July 2020.Firstly,according to the response to immunotherapy,patients were assigned into response group and non-response group.Meanwhile,differentially expressed genes(DEGs)were screened.Secondly,Gene Ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)analyses were performed to analyze the differences in biological behavior and enrichment signaling pathways between the two groups.Finally,protein-protein interaction network(PPI)was constructed,and then the important modules and key genes in biological behavior were screened.In addition,the key genes were analyzed and verified in the TCGA database.Results In total,1025 DEGs were screened between the response group(12 samples)and the non-response group(12 samples).There were 782 up-regulated and 243 down-regulated genes in the response group in comparison with the non-response group.GO and KEGG analysis results showed that the functions of these DEGs focused mainly on the cytokine receptor pathway,cell adhesion pathway,T cell receptor pathway and NF-kappa B signaling pathway.In the PPI analysis,the top 10 core genes(Tnf,Il6,Ptprc,Csf2,Cd86,Cxcl9,Sell,Cxcr3,Ccl2,Cd40)with high node degree were screened.TCGA database integration analysis results showed that the expressions of Tnf,Il6,Cd86,Cxcl9,Sell,Cxcr3 and Cd40 genes were higher in the subtype of sarcomatoid mesothelioma than those in other subtypes with statistically significant difference.Conclusion The core genes Tnf,Il6,Ptprc,Csf2,Cd86,Cxcl9,Sell,Cxcr3,Ccl2,Cd40 in these important modules might become novel predictive markers for immunotherapy and potential therapeutic targets in MPM.