VAVs基因家族在肝癌中的表达及临床意义

Expression of VAV gene family in hepatocellular carcinoma and its clinical significance

目的探究VAVs家族基因在肝细胞癌(HCC)患者中的表达水平及其在预后中的临床价值,并基于阳性作用基因建立肝癌的预后预测模型。方法从肿瘤基因组图谱(TCGA)数据库中下载并提取342例HCC癌组织和50例癌旁组织中VAVs家族基因mRNA测序表达数据及其临床信息。比较TCGA中VAVs mRNA在HCC癌组织和癌旁组织中的表达差异,并比较温州医科大学附属第一医院20例HCC患者的癌组织及癌旁组织中VAVs蛋白的表达差异。根据VAVs mRNA表达量中位值分为高表达组(n=171)和低表达组(n=171),比较两组的临床病理特征差异,采用Kaplan-Meier法分析比较两组的生存差异。采用单因素和多因素Cox分析筛选HCC患者预后的危险因素。基于VAV2 mRNA构建HCC生存预后列线图模型,采用受试者工作特征(ROC)曲线及校正曲线来评估模型的预测准确性。结果对TCGA数据库分析显示,VAV2 mRNA在HCC癌组织中的表达量高于癌旁组织(P<0.05);本中心免疫组化结果表明,VAV2蛋白在HCC癌组织中的表达量高于癌旁组织(P<0.05)。TCGA数据库分析结果显示,VAV2 mRNA表达水平与HCC患者的性别、肝癌临床分期显著相关(P<0.05),在女性、肝癌临床分期中的Ⅲ期、T分期中的T3期的患者中表达上调(P<0.05)。VAV2 mRNA高表达组的生存时间显著短于VAV2低表达组(P<0.05)。Cox分析显示,VAV2 mRNA表达水平(HR=1.031,95%CI 1.009-1.054,P<0.05)和肝癌临床分期(HR=1.626,95%CI 1.083-2.442,P<0.05)是HCC患者预后的独立危险因素。基于VAV2 mRNA和肝癌临床分期建立的HCC患者生存预后列线图,C指数为0.731。患者1、2、3年ROC曲线下面积(AUC)分别为0.772、0.683、0.650,校准曲线图表明第1年实际观测值与预测值具有较好的一致性。结论VAV2 mRNA的高表达与HCC患者疾病发展及不良预后相关。基于VAV2和肝癌临床分期建立的列线图具有一定的区分度和准确度。

Objective To investigate the expression level VAVs gene family in hepatocellular carcinoma(HCC)and its clinical significance,and establish a prognostic model for HCC based on the positive gene.Methods The mRNA sequencing expression data of VAVs family genes in 342 cases of HCC tissues and 50 case of paracancer tissues and corresponding clinical indicators were extracted from The Cancer Genome Atlas(TCGA)database.The expression difference of VAVs mRNA in HCC tissues and para-cancer tissues from TCGA,and the expression difference of VAVs protein in 20 cases of HCC and corresponding para-cancer tissues in the First Affiliated Hospital of Wenzhou Medical University were compared.According to the median expression value of VAVs mRNA,342 HCC patients were divided into high expression group(n=171)and low expression group(n=171).The difference in clinic-pathologic characteristics and survival between the two groups were analyzed by Chi-square test and Kaplan-Meier method.Univariate and multivariate Cox analysis was used to screen the prognostic risk factors of HCC.The survival prognosis profile model of HCC was constructed mainly based on VAV2 gene and clinical stage.The predictive accuracy of the model was evaluated by receiver operating characteristic(ROC)curve and calibration curve.Results TCGA database showed that the mRNA expression level of VAV2 in HCC tissues was higher than that in para-cancer tissues(P<0.05),and the immunohistochemical results in our center showed that the protein expression level of VAV2 in HCC tissues was higher than that in para-cancer tissues(P<0.05).For TCGA database,there were significantly correlation between VAV2 mRNA expression and gender,clinical stage of HCC patients(P<0.05).The expression of VAV2 mRNA was upregulated in clinical stage Ⅲ,female stage and T stage T3.The survival time of HCC patients in the high VAV2 expression group was significantly lower than that in the low VAV2 expression group(P<0.05).Cox analysis showed that the expression level of VAV2 mRNA(HR=1.031,95%CI 1.009-1.054,P<0.05)and the clinical stage of HCC(HR=1.626,95%CI 1.083-2.442,P<0.05)were independent risk factors for prognosis of HCC patients.The survival prognosis histogram of HCC patients was established based on VAV2 gene and clinical stage,and the C index of the model was 0.731.The area under ROC curve(AUC)in 1-,2-and 3-year were 0.772,0.683 and 0.650,respectively.The calibration curve showed that the actual observed values in the first year were in good agreement with the predicted values.Conclusion The high expression of VAV2 in HCC is related to the development of HCC,and the poor prognosis of HCC patients.The histogram established based on VAV2 gene and clinical stage has certain differentiation and accuracy.