儿童肾上腺皮质癌表达谱时序分析用于筛选相关靶点的研究

Time-series analysis of expression profile of adrenocortical carcinoma in children for screening related targets

目的探讨肾上腺皮质癌(ACT)潜在致病机制,并筛选出可能作为相关生物靶标的基因。方法从基因表达数据库Gene Expression Omnibus(GEO)中选取儿童ACT相关RNA芯片数据集(GSE75415),利用R语言的相关函数包对其中的18个ACT组织样本(实验组)以及7个正常肾上腺皮质组织样本(对照组)中的m RNA表达数据进行预处理差异表达分析,对ACT各分级(stage1~4)的差异表达基因(DEGs)和重合差异基因(OLDEGs),采用功能富集分析(GO功能富集和KEGG通路),并筛选出中心基因。同时对TCGA数据库包括79个ACT样本的二代测序数据进行分析,筛选出对ACT患者生存时间有影响的基因。结果 Stage1~4分别有248、334、315和561个基因发生了差异表达,各分级样本组间存在73个重合基因(OLDEGs),中心基因HSPA13、GARS、STXBP1、AKIRIN1、TUBB3在各分级中均表达上调,中心基因ADH1B、DCN、RASSF2、PDGFRA、PLAT、C3、FOS在各分级中均表达下调,它们通过影响免疫反应、细胞周期、磷酸化、凝血及相应的信号通路,对ACT的发生与发展发挥作用。另外,OLDEGs在79个TCGA数据库ACT样本生存期分析发现,基因XPO1、RACGAP1、PDGFD、NR4A2、MXRA5、VPS51、TMED3、NDFIP1和CDKN1C与ACT的生存期密切相关。结论在各级中均差异表达的基因和生存期相关基因可以作为ACT治疗的新靶点,这将有助于进一步理解肾上腺皮质癌的病因和预后治疗。

Objective To explore the potential pathogenic mechanism of adrenocortical carcinoma(ACT),and screen out genes that may be related to biological targets.Methods In this study,the gene expression datasets of ACT were obtained from the Gene Expression Omnibus(GEO)with the accession number of GSE75415.Through R programming software,the microarray preprocessing and differential expression analysis of 18 ACT tissue samples(experimental group)and 7 normal adrenocortical tissue samples(control group)were conducted to identify potential biomarkers for ACT in different stages.Besides,through functional enrichment and Kaplan-Meier analysis,several more reliable biomarkers for ACT were identified.At the same time,the two generation sequencing data of the TCGA database,including 79 ACT samples were analyzed,and the genes that can affect the survival of ACT patients were screened.Results There were 248,334,315 and 561 differentially expressed genes in stage1-4 respectively.There were 73 overlapping genes(OLDEGs)among the different grading samples.Central genes HSPA13,GARS,STXBP1,AKIRIN1 and TUBB3,were up-regulated in all of stages of ACT samples compared with those of normal samples,while,central genes ADH1B,DCN,RASSF2,PDGFRA,PLAT,C3 and FOS were down-regulated in ACT samples.They were found to be significantly associated with pathways of immune response,cell cycle,phosphorylation and cruor,which were all closely related with ACT progression.Besides,Kaplan-Meier analysis of 73 OLDEGs in 79 ACT samples from TCGA database identified several genes,including XPO1,RACGAP1,PDGFD,NR4A2,MXRA5,VPS51,TMED3,NDFIP1 and CDKN1C,which were significantly associated with ACT overall survival.Conclusion Differentially expressed genes and survival related genes in all of stages can serve as new targets for ACT therapy,and which should be helpful for the understanding of its pathogenesis and prognosis.