摘要
目的探讨肺腺癌免疫微环境特征基因以及相关基因对患者生存时间及免疫检查点抑制剂(ICB)疗效的预测价值。方法使用非负矩阵分解(NMF)聚类分析在癌症基因图谱(TCGA)数据库肺腺癌患者测序数据集(TCGA-LUAD)中鉴定不同的免疫亚型,并对免疫亚型进行肿瘤纯度评估、免疫应答评分(TIDE评分)、肿瘤突变负荷(TMB)分析以及基因组DNA拷贝数变异(CNV)分析。对GSE136961数据集和TCGA-LUAD数据集中的基因表达进行加权基因共表达网络分析(WGCNA)。使用R语言中ClusterProfiler包对获得的基因进行基因本体论(GO)富集分析和京都基因与基因组数据库(KEGG)通路分析;利用Cytoscape的regulon模块进行转录调控网络分析;使用SPSS 25.0统计软件绘制Kaplan-Meier曲线进行生存分析。结果TCGA-LUAD数据集中鉴定出C1、C22种免疫亚型。2种免疫亚型中,C2免疫亚型的免疫应答评分显著高于C1免疫亚型(P<0.05);C2免疫亚型TIDE评分、TMB低于C1免疫亚型(均P<0.05)。对GSE136961数据集和TCGA-LUAD数据集进行WGCNA分析共获得10种与免疫耐受以及生存相关的基因。GO富集分析和KEGG通路分析结果显示10种基因主要与DNA损伤以及细胞周期通路相关。转录调控网络分析结果显示E2F4是与免疫耐受相关5个基因(BRCA1、BRCA2、FOXM1、MELK、TUBB)的转录调控因子。2种免疫亚型中进行E2F4及与免疫耐受相关5种基因的表达及生存分析结果显示,E2F4、BRCA1、BRCA2、FOXM1、MELK、TUBB在免疫活性低以及免疫应答差的C1亚型显著高表达。结论转录调控因子E2F4及与免疫耐受相关5个基因(BRCA1、BRCA2、FOXM1、MELK、TUBB)高表达预测肺腺癌患者具有较短的生存时间和较差的免疫疗效。
Objective To investigate the predictive value of the characteristic genes of tumor immune microenvironment and related genes on the survival time and immune checkpoint inhibitor(ICB)response in patients with lung adenocarcinoma.Methods Different immune subtypes in the Cancer Gene Atlas(TCGA)lung adenocarcinoma patient sequencing dataset(TCGA-LUAD)were identified using non-negative matrix factorization(NMF)clustering analysis.Tumor purity,TIDE score,tumor mutation burden(TMB)analysis,and genomic DNA copy number variation(CNV)analysis were performed for immune subtypes.The weighted gene co-expression network analysis(WGCNA)was performed on the gene expression in GSE136961 dataset and TCGA-LUAD dataset.Gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis of the obtained genes were performed using ClusterProfiler package in R language.Transcriptional regulatory network analysis was performed using the regulon module of Cytoscape.The Kaplan-Meier curve for survival analysis was drawn using the SPSS 25.0 statistical software.Results Two immune subtypes,C1 and C2,were identified in TCGA-LUAD dataset.The immune response score of the C2 immune subtype was significantly higher than that of the C1 immune subtype(P<0.05).The TIDE score and TMB of the C2 subtype were lower than those of the C1 subtype(all P<0.05).Ten genes related to immune tolerance and survival were obtained using WGCNA analysis on the GSE136961 and TCGA-LUAD datasets.The results of GO enrichment analysis and KEGG pathway analysis showed that 10 genes were mainly related to DNA damage and cell cycle pathways.Transcription regulatory network analysis results showed that E2F4 was a transcriptional regulator of five genes related to immune tolerance(BRCA1,BRCA2,FOXM1,MELK,and TUBB).E2F4,BRCA1,BRCA2,FOXM1,MELK,and TUBB were highly expressed in the C1 subtype with low immune activity and poor immune response.Conclusion Overexpression of E2F4 and five immune tolerance-related genes(BRCA1,BRCA2,FOXM1,MELK,and TUBB)
作者
刘烨妹
李梦玲
吴胜男
李思宇
赵闯
LIU Yemei;LI Mengling;WU Shengnan;LI Siyu;ZHAO Chuang(Department of Pharmacy,Shengjing Hospital of China Medical University,Shenyang 110004,China;Department of Clinical Epidemiology and Evidence-based Medicine,The First Hospital of China Medical University,Shenyang 110001,China;Department of Oncology,The First Hospital of China Medical University,Shenyang 110001,China;Department of General Medicine,The First Hospital of China Medical University,Shenyang 110001,China;Department of General Surgery,Shengjing Hospital of China Medical University,Shenyang 110004,China)
出处
《中国医科大学学报》
CAS
北大核心
2023年第5期438-446,共9页
Journal of China Medical University
基金
沈阳市科学技术计划(17-231-1-51)。
关键词
肺腺癌
肿瘤免疫微环境
免疫亚型
免疫微环境特征基因
生物信息学分析
lung adenocarcinoma
tumor immune microenvironment
immune subtype
immune efficacy-associated genes
bioinformatics analysis
