AUTHOR=Tan Shichuan , Spear Ryan , Zhao Juan , Sun Xiulian , Wang Pin 

TITLE=Comprehensive Characterization of a Novel E3-Related Gene Signature With Implications in Prognosis and Immunotherapy of Low-Grade Gliomas

JOURNAL=Frontiers in Genetics

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.905047

DOI=10.3389/fgene.2022.905047

ISSN=1664-8021

ABSTRACT=Gliomas, a type of primary brain tumor, have emerged as a threat to global mortality due to their high heterogeneity and mortality. A low-grade glioma (LGG), although less aggressive compared with glioblastoma, still exhibits high recurrence and malignant progression. Ubiquitination is one of the most important post-translational modifications that contribute to carcinogenesis and cancer recurrence. E3-related genes (E3RGs) play essential roles in the process of ubiquitination. Yet, the biological function and clinical significance of E3RGs in LGG need further exploration. In this study, differentially expressed genes (DEGs) were screened by three differential expression analyses of LGG samples from The Cancer Genome Atlas (TCGA) database. DEGs with prognostic significance were selected by univariate Cox regression analysis and log-rank statistical test. LASSO-COX method was performed to identify an E3-related prognostic signature consisting of seven genes including AURKA, PCGF2, MAP3K1, TRIM34, PRKN, TLE3, and TRIM17. The Chinese Glioma Genome Atlas (CGGA) dataset was used as the validation cohort. Kaplan-Meier survival analysis showed that LGG patients in the low-risk group had significantly higher overall survival time than those in the high-risk group in both TCGA and CGGA cohorts. Further, multivariate Cox regression analysis revealed that the E3RGs signature could be used as an independent prognostic factor. A nomogram based on the E3RGs signature was then established and provided the prediction of the 1-, 3-, 5-year survival probability of patients with LGG. Moreover, DEGs were analyzed based on the risk signature, on which function analyses were performed. GO analysis and KEGG analysis uncovered gene enrichment in extracellular matrix-related functions and immune-related biological processes in the high-risk group. GSEA revealed high enrichment in pathways that promote tumorigenesis and progression in the high-risk group. Furthermore, ESTIMATE algorithm analysis showed a significant difference in immune and stroma activity between high- and low-risk groups. Positive correlations between the risk signature and the tumor microenvironment immune cells infiltration as well as immune checkpoint molecules were also observed, implying patients with the high-risk score may have better responses to immunotherapy. Overall, our findings might provide potential diagnostic and prognostic markers for LGG patients and offer meaningful insight for individualized treatment.