基于生物学信息分析筛选晚期肝细胞癌患者接受PD-1抑制剂治疗后糖酵解相关基因差异表达并构建生存获益模型与验证  

Differential Expression of Glycolysis-related Genes in Patients with Advanced Hepatocellular Carcinoma Treated with PD-1 Inhibitors Screened Based on Biological Information Analysis,and Survival Benefit Model Constructed and Verified

作　　者：吴翠婷 周雪辉 张婉馨 WU Cuiting;ZHOU Xuehui;ZHANG Wanxin(Department of Pharmacy,Zhujiang Hospital of Southern Medical University,Guangzhou 510280,China)

机构地区：[1]南方医科大学珠江医院药剂科,广州510280

出　　处：《现代检验医学杂志》2023年第5期34-39,共6页Journal of Modern Laboratory Medicine

摘　　要：目的 基于糖酵解基因构建风险评分模型,对经程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)抑制剂治疗后的晚期肝细胞癌(hepatocellular carcinoma,HCC)患者的生存获益状况进行预测分析。方法 从癌症基因组图谱(the cancer genome atlas,TCGA)选取369例接受PD-1抑制剂治疗的HCC患者和50例正常肝组织的临床数据和高通量测序数据,患者年龄53~72(69.23±6.61)岁;使用“limma” R包进行差异分析,筛选出肝细胞癌组织中异常表达的糖酵解相关基因,将获得的基因进行多因素COX回归分析;利用LASSO分析筛选关键预测因子,以验证以上糖酵解相关基因是否与生存获益相关;以数据库的中值风险评分作为阈值,将患者分为高风险和低风险组,构建风险模型,利用Kaplan-Meier法绘制生存曲线评估基因特征对总体生存的预测价值;构建列线图模型来预测患者生存获益情况并进行模型验证。结果 鉴定HCC中差异表达的糖酵解相关基因发现,与正常肝组织相比,前10个上调基因中S100P和SPP1在HCC组织中高表达,而PLA2G2A和APOA4在HCC组织中表达下调;在前10个下调基因中,SPP2,LECT2,SLC10A1,CYP2A6,CYP3A4,HSD17B13,CYP2A7和IYD表达显著下调,而CYP7A1表达在肿瘤组织中相对于正常肝组织明显上调;多因素分析结果发现高表达的SPP1,TMEM92和EGLN3预示着HCC患者的不良预后,而SPP2,LECT2,SLC10A1,CYP3A4,HSD17B13和IYD的高表达预测HCC患者的预后更佳(均P <0.05);利用LASSO筛选确定了与HCC糖酵解相关的6个差异表达基因(SPP2,LECT2,SLC10A1,CYP3A4,HSD17B13和IYD);风险模型显示,随着风险评分的升高,患者生存时间呈逐渐下降趋势,随访结果为死亡的患者比例逐渐升高,两组患者中6个基因的表达水平存在显著差异,表明它们与风险评分密切相关,是预后模型中的关键分子;生存曲线结果显示低危组患者总生存时间显著高于高危组患者,Log-Rankχ2=4.933,P <0.001;列线图预测模Objective To construct a risk scoring model based on glycolytic genes and predict the survival benefits of advanced hepatocellular carcinoma(HCC)patients treated with programmed cell death protein 1(PD-1)inhibitors.Methods Clinical data and high-throughput sequencing data of 369 HCC patients receiving PD-1 inhibitor and 50 normal liver tissues were selected from the cancer genome atlas(TCGA).The patients were 53~72(69.23±6.61)years old.“limma”R package was used for differential analysis,and the abnormal expression of glycolytis-related genes in hepatocellular carcinoma tissues was screened out,and the obtained genes were analyzed by COX multivariate regression.LASSO analysis was used to screen key predictors to verify whether the above glycolytis-related genes were associated with survival benefits.With the median risk score of the database as the threshold,patients were divided into high risk and low risk groups.A risk model was constructed,and Kaplan-Meier method was used to draw a survival curve to evaluate the predictive value of genetic characteristics on overall survival.A line graph model was constructed to predict the survival benefits of patients and the model was verified.Results Compared with normal liver tissues,thefirst 10 up-regulated genes S100P and SPP1 were highly expressed in HCC tissues,while PLA2G2A and APOA4 were down-regulated in HCC tissues.Among the top 10 down-regulated genes,the expressions of SPP2,LECT2,SLC10A1,CYP2A6,CYP3A4,HSD17B13,CYP2A7 and IYD were significantly down-regulated,while the expression of CYP7A1 was significantly up-regulated in tumor tissues compared with normal liver tissues.Multivariate analysis showed that high expression of SPP1,TMEM92 and EGLN3 predicted poor prognosis of HCC patients,while high expression of SPP2,LECT2,SLC10A1,CYP3A4,HSD17B13 and IYD predicted better prognosis of HCC patients(all P<0.05).Six differentially ex-pressed genes(SPP2,LECT2,SLC10A1,CYP3A4,HSD17B13 and IYD)related to HCC glycolysis were identified by LASSO screening.The risk

关 键 词：肝细胞癌 糖酵解相关基因 程序性细胞死亡蛋白-1抑制剂 

分 类 号：R735.7[医药卫生—肿瘤] R730.43[医药卫生—临床医学]