基于高通量RNA测序的肾母细胞瘤关键基因鉴定及其对预后和免疫反应的影响
[Identification of key genes in Wilms tumor based on high-throughput RNA sequencing and their impacts on prognosis and immune responses].
作者信息
Gao Z, Lin J, Hong P, Hu Z, Dong J, Shi Q, Tian X, Liu F, Wei G
机构信息
Department of Urological Surgery, Children's Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing 400014, China.
出版信息
Nan Fang Yi Ke Da Xue Xue Bao. 2024 Apr 20;44(4):727-738. doi: 10.12122/j.issn.1673-4254.2024.04.15.
OBJECTIVE
To identify the key genes differentially expressed in Wilms tumor and analyze their potential impacts on prognosis and immune responses of the patients.
METHODS
High-throughput RNA sequencing was used to identify the differentially expressed mRNAs in clinical samples of Wilms tumor and paired normal tissues, and their biological functions were analyzed using GO, KEGG and GSEA enrichment analyses. The hub genes were identified using STRING database, based on which a prognostic model was constructed using LASSO regression. The mutations of the key hub genes were analyzed and their impacts on immunotherapy efficacy was predicted using the cBioPortal platform. RT-qPCR was used to verify the differential expressions of the key hub genes in Wilms tumor.
RESULTS
Of the 1612 differentially expressed genes identified in Wilms tumor, 1030 were up-regulated and 582 were down-regulated, involving mainly cell cycle processes and immune responses. Ten hub genes were identified, among which 4 genes (, , and ) were closely related to the survival of children with Wilms tumor. A 3-gene prognostic signature was constructed through LASSO regression analysis, and the patients stratified into with high- and low-risk groups based on this signature had significantly different survival outcomes (HR=1.814, log-rank =0.002). The AUCs of the 3-, 5- and 7-year survival ROC curves of this model were all greater than 0.7. The overall mutations in the key hub genes or the individual mutations in / were strongly correlated with a lower survival rates, and a high TP53 expression was correlated with a poor immunotherapy efficacy. RT-qPCR confirmed that the key hub genes had significant differential expressions in Wilms tumor tissues and cells.
CONCLUSION
gene plays an important role in the Wilms tumor and may potentially serve as a new immunotherapeutic biomarker as well as a therapeutic target.
目的
鉴定肾母细胞瘤中差异表达的关键基因，并分析其对患者预后和免疫反应的潜在影响。
方法
采用高通量RNA测序鉴定肾母细胞瘤临床样本及配对正常组织中差异表达的mRNA，并通过GO、KEGG和GSEA富集分析对其生物学功能进行分析。利用STRING数据库鉴定枢纽基因，并基于此使用LASSO回归构建预后模型。分析关键枢纽基因的突变情况，并使用cBioPortal平台预测其对免疫治疗疗效的影响。采用RT-qPCR验证关键枢纽基因在肾母细胞瘤中的差异表达。
结果
在肾母细胞瘤中鉴定出1612个差异表达基因，其中1030个上调，582个下调，主要涉及细胞周期进程和免疫反应。鉴定出10个枢纽基因，其中4个基因（……）与肾母细胞瘤患儿的生存密切相关。通过LASSO回归分析构建了一个3基因预后特征，根据该特征分层的高风险组和低风险组患者的生存结果有显著差异（HR=1.814，log-rank=0.002）。该模型3年、5年和7年生存ROC曲线的AUC均大于0.7。关键枢纽基因的总体突变或……的个别突变与较低的生存率密切相关，而高TP53表达与较差的免疫治疗疗效相关。RT-qPCR证实关键枢纽基因在肾母细胞瘤组织和细胞中存在显著差异表达。
结论
……基因在肾母细胞瘤中起重要作用，可能作为一种新的免疫治疗生物标志物及治疗靶点。
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