Tian Wei, Yan Guangcan, Chen Kegong, Han Xinhao, Zhang Wei, Sun Lin, Zhang Qi, Zhang Yafeng, Li Yan, Liu Meina, Zhang Qiuju
Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin, China.
Department of Cardio-Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Front Oncol. 2022 Mar 1;12:714338. doi: 10.3389/fonc.2022.714338. eCollection 2022.
Enhancer RNAs (eRNAs) are present specifically in tumors, where they affect the expression of eRNA-regulated genes (ERGs). Owing to this characteristic, ERGs were hypothesized to improve prognosis of overall survival in heterogeneous low-grade and intermediate-grade gliomas. This study aimed to construct and validate an ERG prognostic tool to facilitate clinical management, and offer more effective diagnostic and therapeutic biomarkers for glioma. Survival-related eRNAs were identified, and their ERGs were selected based on eRNA and target gene information. The ERG prognostic model was constructed and validated using internal and external validation cohorts. Finally, biological differences related to the ERG signature were analysed to explore the potential mechanisms influencing survival outcomes. Thirteen ERGs were identified and used to build an ERG risk signature, which included five super-enhancer RNA (seRNA)-regulated genes and five LGG-specific eRNA-regulated genes. The prognostic nomogram established based on combining the ERG score, age, and sex was evaluated by calibration curves, clinical utility, Harrell's concordance index (0.86; 95% CI: 0.83-0.90), and time-dependent receiver operator characteristic curves. We also explored potential immune-related mechanisms that might cause variation in survival. The established prognostic model displayed high validity and robustness. Several immune-related genes regulated by seRNAs or specific eRNAs were identified, indicating that these transcripts or their genes were potential targets for improving immunotherapeutic/therapeutic outcomes. The functions of an important specific eRNA-regulated gene (USP28) were validated in robust vitro experiments. In addition, the ERG risk signature was significantly associated with the immune microenvironment and other immune-related features.
增强子RNA（eRNAs）特异性存在于肿瘤中，在肿瘤中它们会影响由eRNA调控的基因（ERGs）的表达。由于这一特性，有人推测ERGs可改善异质性低级别和中级别胶质瘤的总生存预后。本研究旨在构建并验证一种ERG预后工具，以促进临床管理，并为胶质瘤提供更有效的诊断和治疗生物标志物。我们鉴定了与生存相关的eRNAs，并根据eRNA和靶基因信息选择了它们的ERGs。使用内部和外部验证队列构建并验证了ERG预后模型。最后，分析了与ERG特征相关的生物学差异，以探索影响生存结果的潜在机制。我们鉴定出13个ERGs，并用于构建一个ERG风险特征，其中包括5个超级增强子RNA（seRNA）调控的基因和5个低级别胶质瘤特异性eRNA调控的基因。通过校准曲线、临床实用性、Harrell一致性指数（0.86；95%置信区间：0.83 - 0.90）和时间依赖性受试者工作特征曲线，对基于ERG评分、年龄和性别的预后列线图进行了评估。我们还探索了可能导致生存差异的潜在免疫相关机制。所建立的预后模型显示出高有效性和稳健性。我们鉴定出了一些由seRNAs或特异性eRNAs调控的免疫相关基因，表明这些转录本或其基因是改善免疫治疗/治疗结果的潜在靶点。在可靠的体外实验中验证了一个重要的特异性eRNA调控基因（USP28）的功能。此外，ERG风险特征与免疫微环境和其他免疫相关特征显著相关。
