肾母细胞瘤肿瘤微环境相关预后基因鉴定及免疫浸润模式识别

Identification of tumor microenvironment-related prognostic genes and immune infiltration patterns in Wilms tumor

目的探索肾母细胞瘤(WT)中肿瘤微环境(TME)相关基因、免疫细胞浸润模式及其对预后判断的价值。方法从肿瘤基因组图谱(TCGA)数据库下载WT基因表达及临床数据,通过ESTIMATE算法估计基质评分、免疫评分及总评分,并根据评分中位数分为高、低评分两组,寻找差异表达基因(DEGs)并进行基因本体论(GO)分析和京都基因与基因组百科全书(KEGG)富集分析。单因素及多因素COX回归分析判定DEGs与预后的相关性,构建预后模型。通过MCPcounter算法评估标本免疫浸润模式的特点。结果对124份WT肿瘤组织进行ESTIMATE评分,显示基质评分和总评分与预后相关,评分高的患者生存时间较评分低的患者长(P=1.973×10^(-3)、1.718×10^(-3))。KEGG富集分析显示,DEGs主要集中在磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)信号通路、肾素分泌等通路。构建包含REN/ST6GALNAC1/GABRA5/C10orf71/FMOD共5个基因的预后模型,受试者工作特征(ROC)曲线、校正曲线、决策曲线均显示模型预测能力良好。采用MCPcounter评估肿瘤组织和癌旁正常组织中免疫细胞的浸润数量,发现癌旁正常组织T淋巴细胞、髓样树突状细胞、中性粒细胞、内皮细胞数量高于肿瘤组织,并且Kaplan-Meier(KM)生存曲线显示较高T淋巴细胞浸润预示着更好的预后。不同性别的患者免疫细胞浸润模式无明显差异,低年龄患儿(<3岁)中性粒细胞、单核细胞、内皮细胞数量更多。结论WT中TME相关基因ST6GALNAC1、REN对患儿预后判断有潜在的临床价值,WT组织的免疫细胞浸润模式存在差异,与患者的临床特征和预后相关。这些基因、免疫细胞可能作为预后指标及治疗靶点。

Objective To explore the tumor microenvironment(TME)related genes and the infiltration pattern of immune cells in Wilms tumor(WT)as well as their prognostic value.Methods The gene expression and clinical data of WT were downloaded from the Tumor Cancer Genome Atlas(TCGA)database,and the stromal and immune scores as well as total scores were estimated by the ESTIMATE algorithm.According to the median score,samples were divided into high and low groups.Differentially expressed genes(DEGs)were found,and gene ontology(GO)analysis and enrichment analysis of Kyoto Encyclopedia of Genes and Genomes(KEGG)were carried out.Univariate and multivariate COX regression analysis were used to analyze the correlation between DEGs and prognosis,and a prognostic model was constructed.The characteristics of immune infiltration patterns of the samples were evaluated by MCPcounter algorithm.Results The ESTIMATE scores on 124 tumor samples showed that the stromal and total scores were significantly associated with prognosis.Patients with high scores had a longer survival time than those with low scores(P=1.973×10^(-3),1.718×10^(-3)).KEGG enrichment analysis showed that DEGs were mainly concentrated in the phosphatidylinositol 3-kinase/protein kinase B(PI3K-Akt)signaling pathway,renin secretion and other pathways.A prognostic model with five genes of REN/ST6GALNAC1/GABRA5/C10orf71/FMOD was constructed.The receiver operating characteristic(ROC)curve,calibration curve and decision curve of the subjects showed that the model had good predictive ability.MCPcounter was used to evaluate the infiltration of immune cells in tumor tissues and adjacent normal tissues.It was found that the number of T lymphocytes,myeloid dendritic cells,neutrophils,and endothelial cells in adjacent normal tissues was higher than that in tumor tissues,and the Kaplan-Meier(KM)curve showed that higher T lymphocyte infiltration predicted a better prognosis.There was no significant difference in the infiltration pattern of immune cells between different genders,and the number of neutrophils,monocytes and endothelial cells was more in younger children(less than three years old).Conclusion TME-related genes,ST6GALNAC1 and REN,in WT have potential clinical value in judging the prognosis of children.There are differences in immune cell infiltration patterns in WT tissues,which are related to the clinical features and prognosis of patients.These genes and immune cells may serve as prognostic indicators and therapeutic targets.