基于铜死亡基因识别脑膜瘤亚型并筛选脑膜瘤-免疫相关的关键基因

Identification of meningioma subtypes and screening of meningioma-immune related hub-genes based on cuproptosis gene

目的筛选铜死亡相关的脑膜瘤亚型并识别与疾病-免疫相关的关键基因。方法利用公共数据库中脑膜瘤相关的基因表达数据筛选差异表达的铜死亡基因,并基于其在肿瘤样本中的表达值识别脑膜瘤亚型。分析亚型间的差异表达基因以及亚型与肿瘤免疫微环境的关联。以亚型间显著差异的免疫细胞为表型,利用加权基因共表达网络分析(WGCNA)筛选疾病-免疫相关的模块并提取模块基因。通过交集分析筛选出差异表达的疾病-免疫相关基因,进行后续蛋白-蛋白相互作用(PPI)网络分析、功能富集分析、Friends分析、基因表达验证以及关键基因与临床因素关联分析。结果在脑膜瘤和正常样本中检测到6个铜死亡基因的差异表达,如CDKN2A和GLS,并鉴定了2个相关的铜死亡亚型。两个亚型间涵盖397个差异表达基因,包括8种免疫细胞,其浸润丰度在亚型间存在显著差异。通过WGCNA筛选到282个疾病-免疫相关基因,交集分析得到74个差异表达的疾病-免疫相关基因。PPI和Friends分析最终确认了5个关键基因,包括LTBP1、LTBP2和MFAP5等。其中,LTBP2和MFAP5在脑膜瘤不同级别中表达存在显著差异。Western Blot和免疫组化实验证实,MFAP5在WHOⅠ级和WHOⅢ级之间以及WHOⅠ级和WHOⅡ级之间存在显著差异。结论本研究筛选到2个铜死亡相关的脑膜瘤亚型,这两个亚型在免疫细胞浸润和免疫反应方面存在差异。两个亚型间的免疫相关关键基因,如LTBP2和MFAP5,可能是铜死亡调控脑膜瘤发生和发展的关键机制,有望成为脑膜瘤诊断生物标志物或免疫治疗靶点。

Objective To identify copper induced death-related subtypes of meningiomas and recognize key genes associated with disease-immune interactions.Methods Utilizing publicly available gene expression data related to meningiomas,differentially expressed acproptosis genes were screened.Subsequently,meningioma subtypes based on the expression values of these genes in tumor samples were identified.The differentially expressed genes between subtypes and their association with the tumor immune microenvironment were analyzed.Using immune cells with significant differences between subtypes as a phenotype,Weighted Gene Co-expression Network Analysis(WGCNA)was employed to screen disease-immune-related modules and extract module genes.Through intersection analysis,differentially expressed disease-immune-related genes were selected.Further analyses included protein-protein interaction(PPI)network analysis,functional enrichment analysis,Friends analysis,gene expression validation and correlation analysis between key genes and clinical factors.Results Differential expression of six copper death genes were detected,such as CDKN2A and GLS,in meningiomas compared to normal samples,identifying two associated copper induced death subtypes.These subtypes encompassed 397 differentially expressed genes,including eight immune cell types.There were significant differences in immune cell infiltration between subtypes.WGCNA identified 282 disease-immune-related genes,and intersection analysis revealed 74 differentially expressed disease-immune-related genes.PPI and Friends analyses ultimately confirmed five key genes:LTBP1,LTBP2,and MFAP5,etc.Among these,LTBP2 and MFAP5 exhibited significant expression differences in meningioma grades.Western blot and immunohistochemistry validation demonstrated significant differences in MFAP5 expression between WHO GradeⅠand WHO GradeⅢ,as well as WHO GradeⅠand WHO GradeⅡ.Conclusions This study identifies two copper death-related meningioma subtypes characterized by differences in immune cell infiltration and immune responses.Key immune-related genes between these subtypes,such as LTBP2 and MFAP5,may represent critical mechanisms in the regulation of copper death in the occurrence and development of meningiomas,potentially serving as diagnostic biomarkers or immunotherapeutic targets for meningiomas.