基于生物信息学的锌指蛋白492基因突变对卵巢癌转录组的影响及价值

Bioinformatics Based Effect of ZNF492 Mutation on Transcriptome of Ovarian Cancer and Its Clinical Value

目的:探讨锌指蛋白492(zinc finger protein 492,ZNF492)基因突变在卵巢癌的作用机制及其临床价值,为卵巢癌的诊治提供理论依据。方法:通过癌症基因图谱(The Cancer Genome Atlas,TCGA)下载ZNF492突变样本的转录组数据,将样本分成ZNF492突变组和非突变组,使用R包DESeq2分析2组间的差异表达基因,对差异表达基因进行京都基因及基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集分析和基因集富集分析(gene set enrichment analysis,GSEA)。获取卵巢癌患者年龄、肿瘤分期和分化的情况,通过ZNF492表达与卵巢癌患者临床特征的多因素COX回归预测模型进行列线图(Nomogram)模型构建及评价。结果:ZNF492突变组(n=377)与非突变组(n=2)差异基因中有100个上调基因和971个下调基因。2组间的差异基因及ZNF492突变组100个上调基因的通路富集分析均显示富集于转化生长因子-β(transforming growth factor-β,TGF-β)信号通路。多因素COX回归预测模型结果显示卵巢癌患者的年龄大(≥65岁)、肿瘤分期(Ⅲ~Ⅳ期)和分化(G3)高可能与患者较差的总生存期相关(HR>1),而ZNF492高表达(≥0.672)与较好的预后相关(HR<1),其中年龄较大(≥65岁)的患者预后较差(P<0.01)。基于以上4个因素,进一步构建Nomogram预测模型,模型验证结果显示C指数为0.593,3年和5年受试者操作特征曲线下面积(area under the curve,AUC)分别为0.610和0.566,临床决策曲线(decision curve analysis,DCA)提示患者3年或者5年生存率大于18%且小于82%时可采取干预措施。结论:突变的ZNF492可能通过调控TGF-β通路以及抗凋亡的潜在机制影响卵巢癌的发生、发展,并且对预测预后有较强临床实用价值,ZNF492突变有望成为卵巢癌循环肿瘤DNA的标志物和治疗靶点。

Objective:To investigate the mechanism and clinical value of zinc finger protein 492(ZNF492)gene mutation in ovarian cancer,and to provide a theoretical basis for the diagnosis and treatment of ovarian cancer.Methods:The transcriptome data of ZNF492 mutant samples were downloaded by TCGA,and the samples were divided into two groups:ZNF492 mutant and non-mutant groups.The R package DESeq2 was used to analyze the differential genes between the two groups.The differentially expressed genes were analyzed by kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis and gene set enrichment analysis(GSEA).The age,tumor stage and differentiation of ovarian cancer patients were obtained,and the Nomogram model was constructed and evaluated by multivariate COX regression prediction model of ZNF492 expression and clinical characteristics of ovarian cancer patients.Results:There were 100 up-regulated genes and 971 down-regulated genes in the differential genes between the ZNF492 mutant group(n=377)and the non-mutant group(n=2).The pathway enrichment analysis of differential genes between the two groups and 100 up-regulated genes in the ZNF492 mutant group showed that they were enriched transforming growth factor-β(TGF-β)signal path.The results of multivariate COX regression prediction model showed that higher age(≥65 years old),the higher tumor stage(Ⅲ-Ⅳstage)and differentiation(G3)might be related to the poor overall survival(HR>1),while high expression of ZNF492(≥0.672)was related to the better prognosis(HR<1),among which the higher age patients(≥65 years old)had a poor prognosis(P<0.01).Based on the above four factors,further construct the Nomogram prediction model.The model validation results showed that the C index was 0.593,the area under the curve(AUC)(0.610 and 0.566)of three-year and five-year ROC curves,and the clinical decision curve analysis(DCA)suggested that patients can take bold measures when the 3-year or 5-year survival rate was greater than 18%and less than 82%.Conclusions:Mutated ZNF492 may affect the occurrence and development of ovarian cancer by regulating TGF-βpathway and anti-apoptosis potential mechanism,and has strong clinical practical value in predicting prognosis.ZNF492 mutation is expected to be a marker of circulating tumour DNA and therapeutic target for ovarian cancer.