Development and Validation of a Novel Prognostic Model for Lower-Grade Glioma Based on Enhancer RNA-Regulated Prognostic Genes

Abstract

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.

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors

“…Some seRNA-regulated immunerelated genes (IRGs) relevant in the tumor microenvironment were identified in glioma 154 , and they were used to construct a prognostic model that can predict the survival outcomes of patients with glioma. These glioma-specific seRNAs that regulate IRGs are located in adjacent sites and coexpressed in tumors, suggesting that they have potential as therapeutic targets 154,155 .…”

Exploring the relationship between abnormally high expression of NUP205 and the clinicopathological characteristics, immune microenvironment, and prognostic value of lower-grade glioma

“…According to the World Health Organization (WHO) 2016 classification system, gliomas are generally divided into two types: WHO Grade I to III, considered as lower-grade gliomas (LGGs), and WHO Grade IV, considered as glioblastomas (GBMs) ( 2 ). LGG accounts for approximately 43.2% of all gliomas and has a median survival rate of 7 years ( 3 , 4 ). However, due to the invasive growth characteristic of LGG cells, LGGs exhibit a high recurrence rate, and 70% of LGGs eventually progress to high-grade malignancies within 5–10 years ( 5 ).…”