基于TCGA和HPA数据库生物学信息分析肝癌组织中YEATS2表达水平与临床预后及治疗价值

Analysis of YEATS2 Expression Level in Hepatocellular Carcinoma Tissues with Clinical Prognosis and Therapeutic Value Based on Biological Information from TCGA and HPA Databases

目的基于肿瘤基因图谱(the cancer genome atlas,TCGA)和人类蛋白质图谱(human protein atlas,HPA)数据库生物学信息,分析肝细胞癌(hepatocellular carcinoma,HCC)中YEATS2表达水平与临床预后及治疗价值。方法从TCGA数据库下载HCC的mRNA表达数据和临床资料,运用R软件分析YEATS2在HCC组织与正常组织间的表达情况,并通过HPA数据库对其蛋白表达差异进行初步验证。比较YEATS2在HCC各临床特征之间的表达差异,然后通过Kaplan-Meier法和COX回归分析评估其对HCC患者生存期的影响,并绘制受试者工作特征(receiveroperating characteristic,ROC)曲线,评价其诊断价值。利用基因本体论(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析,探讨YEATS2在HCC中的生物学功能。通过“ESTIMATE”算法分析YEATS2表达与肿瘤微环境(tumor microenvironment,TME)的关系,并利用CIBERSORT评估其与肿瘤浸润免疫细胞(tumor-infiltrating immune cells,TIICs)的相关性。利用R包分析YEATS2表达水平与免疫检查点及药物敏感度的关系。结果在HCC组织中YEATS2的表达增加(P=4.96e-21),且表达水平与年龄、临床分期、病理分级和T分期相关(均P<0.05)。YEATS2高表达使HCC患者的总生存率(overall survival,OS)(P<0.001)和无进展生存期(progression free survival,FPS)(P=0.016)下降,COX回归结果显示,YEATS2表达水平与HCC患者的不良预后相关(OS:HR=2.167,95%CI:1.441~3.261,P=2.06e-04),其是HCC患者预测不良预后的独立危险因素(OS:HR=1.891,95%CI:1.243~2.877,P=0.003)。ROC曲线提示:1,3,5年AUC分别为0.677,0.622和0.612,具有良好预测能力。TCGA数据库共筛选出YEATS2高、低表达组的差异基因6764个,其中4094个基因在YEATS2高表达组中表达上调,2670个基因表达下调。GO和KEGG富集分析结果显示,YEATS2高表达组差异基因主要富集在免疫调节、细胞周期调控和药物耐药等通路。TME评分结果显示,YEATS2高表达组引起免疫评分减少(P<0.01)。YEATS2与TIICs相关性显示,YEATS2表达与M0型巨噬细胞浸润水平呈正相关(r=0.48,P<0.001),与CD8^(+)T细胞、浆细胞和单核细胞浸润水平呈负相关(r=-0.26,-0.29,-0.30,P=0.021,0.011,0.008),并与23种免疫检查点基因呈正相关(r=0.20~0.46,均P<0.05)。药物敏感度分析显示,YEATS2高表达组患者中卡博替尼、林西替尼、多柔比星和环巴胺的半抑制浓度(half maximal inhibitory concentration,IC50)高于低表达组患者(均P<0.01)。结论YEATS2在HCC中高表达,且表达水平与HCC患者的预后不良有关。YEATS2可作为HCC临床早期诊断、预后和免疫治疗的生物标志物,为临床诊疗提供新的思路。

Objective To analyze the expression level of YEATS2 in hepatocellular carcinoma(HCC)about its clinical prognosis and therapeutic value based on biological information from the cancer genome atlas(TCGA)and human protein atlas(HPA)databases.Methods The mRNA expression data and clinical information of HCC were downloaded from the TCGA database,the expression of YEATS2 between HCC tissues and normal tissues was analyzed by using the R software,and the protein expression differences were preliminary verified by the HPA database.The expression differences of YEATS2 between various clinical features of HCC were compared,and their effects on the survival of HCC patients by Kaplan-Meier method and COX regression analysis were then evaluated.Receiver operating characteristic(ROC)curves were plotted to evaluate their diagnostic values.The biological functions of YEATS2 in HCC were analyzed using gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analysis.The relationship between YEATS2 expression and tumor microenvironment(TME)was analyzed by the“ESTIMATE”algorithm,and its relationship with tumor-infiltrating immune cells(TIICs)was assessed by CIBERSORT.Analysis of YEATS2 expression levels to immune checkpoints and drug sensitivity was performed using the R package.Results The expression of YEATS2 was increased in HCC tissues(P=4.96e-21),and its expression level was correlated with age,clinical stage,pathological grade and T stage(all P<0.05).Overall survival(OS)(P<0.001)and progression-free survival(FPS)(P=0.016)were decreased in HCC patients with high expression of YEATS2,COX regression results showed that the expression level of YEATS2 was associated with poor prognosis in HCC patients(OS:HR=2.167,95%CI:1.441~3.261,P=2.06e-04),and it was an independent risk factor for predicting poor prognosis in HCC patients(OS:HR=1.891,95%CI:1.243~2.877,P=0.003).The ROC curve suggested the AUCs for 1,3 and 5 years were 0.677,0.622 and 0.612,respectively,indicating good predictive ability.The TCGA database screened a total of 6764 differential genes in the YEATS2 high and low expression groups,of which 4094 genes were up-regulated and 2670 genes were down-regulated in the YEATS2 high expression group.The results of GO and KEGG enrichment analyses showed that the differentially differentiated genes in the YEATS2 high expression group were mainly enriched in immunoregulation,and cell cycle regulation drug resistance pathway.The results of the TME score showed that the YEATS2 high expression group caused a decrease in immunity score(P<0.01).The correlation between YEATS2 and TIICs showed that YEATS2 expression was positively correlated with the level of M0-type macrophage infiltration levels(r=0.48,P<0.001)and 23 immune checkpoint genes(r=0.20~0.46,all P<0.05),and was negatively correlated with the CD8^(+)T-cells,plasma cells and monocyte(r=-0.26,-0.29,-0.30,P=0.021,0.011,0.008).Drug sensitivity analysis showed that the half maximal inhibitory concentration(IC50)of cabozantinib,lincitinib,doxorubicin,and cyclobenzaprine in patients with high expression of YEATS2 was higher than those in patients with low expression(all P<0.01).Conclusion YEATS2 was highly expressed in HCC,and the expression level was associated with poor prognosis in HCC patients.YEATS2 can be used as a biomarker for the clinical early diagnosis,prognosis and immunotherapy of HCC,which may provide new ideas for clinical diagnosis and treatment.