A Novel Prognostic Tool for Glioma Based on Enhancer RNA-Regulated Immune Genes

Background: Gliomas are the most malignant tumors of the nervous system. Even though their survival outcome is closely affected by immune-related genes (IRGs) in the tumor microenvironment (TME), the corresponding regulatory mechanism remains poorly characterized. Methods: Specific enhancer RNAs (eRNAs) can be found in tumors, where they control downstream genes. The present study aimed to identify eRNA-regulated IRGs, evaluate their influence on the TME, and use them to construct a novel prognostic model for gliomas. Results: Thirteen target genes (ADCYAP1R1, BMP2, BMPR1A, CD4, DDX17, ELN, FGF13, MAPT, PDIA2, PSMB8, PTPN6, SEMA6C, and SSTR5) were identified and integrated into a comprehensive risk signature, which distinguished two risk subclasses. Discrepancies between these subclasses were compared to explore potential mechanisms attributed to eRNA-regulated genes, including immune cell infiltration, clinicopathological features, survival outcomes, and chemotherapeutic drug sensitivity. Furthermore, the risk signature was used to construct a prognostic tool that was evaluated by calibration curve, clinical utility, Harrell's concordance index (0.87; 95% CI: 0.84-0.90), and time-dependent receiver operator characteristic curves (AUCs: 0.93 and 0.89 at 3 and 5 years, respectively). The strong reliability and robustness of the established prognostic tool were validated in another independent cohort. Finally, potential subtypes were explored in patients with grade III tumors. Conclusion: Overall, eRNAs were associated with immune-related dysfunctions in the TME. Targeting of IRGs regulated by eRNAs could improve immunotherapeutic/therapeutic outcomes.