A Novel Four-Gene Signature Associated With Immune Checkpoint for Predicting Prognosis in Lower-Grade Glioma

Abstract

The overall survival of patients with lower grade glioma (LGG) varies greatly, but the current histopathological classification has limitations in predicting patients’ prognosis. Therefore, this study aims to find potential therapeutic target genes and establish a gene signature for predicting the prognosis of LGG. CD44 is a marker of tumor stem cells and has prognostic value in various tumors, but its role in LGG is unclear. By analyzing three glioma datasets from Gene Expression Omnibus (GEO) database, CD44 was upregulated in LGG. We screened 10 CD44-related genes via protein–protein interaction (PPI) network; function enrichment analysis demonstrated that these genes were associated with biological processes and signaling pathways of the tumor; survival analysis showed that four genes (CD44, HYAL2, SPP1, MMP2) were associated with the overall survival (OS) and disease-free survival (DFS)of LGG; a novel four-gene signature was constructed. The prediction model showed good predictive value over 2-, 5-, 8-, and 10-year survival probability in both the development and validation sets. The risk score effectively divided patients into high- and low- risk groups with a distinct outcome. Multivariate analysis confirmed that the risk score and status of IDH were independent prognostic predictors of LGG. Among three LGG subgroups based on the presence of molecular parameters, IDH-mutant gliomas have a favorable OS, especially if combined with 1p/19q codeletion, which further confirmed the distinct biological pattern between three LGG subgroups, and the gene signature is able to divide LGG patients with the same IDH status into high- and low- risk groups. The high-risk group possessed a higher expression of immune checkpoints and was related to the activation of immunosuppressive pathways. Finally, this study provided a convenient tool for predicting patient survival. In summary, the four prognostic genes may be therapeutic targets and prognostic predictors for LGG; this four-gene signature has good prognostic prediction ability and can effectively distinguish high- and low-risk patients. High-risk patients are associated with higher immune checkpoint expression and activation of the immunosuppressive pathway, providing help for screening immunotherapy-sensitive patients.

CKS2 (CDC28 protein kinase regulatory subunit 2) is a prognostic biomarker in lower grade glioma: a study based on bioinformatic analysis and immunohistochemistry

“…The classification combined molecular characteristics and histology, which then categorized grade II and grade III gliomas as well as grade IV glioblastomas (GBMs) as diffuse gliomas [1]. Because of convergence of many features of the grade II and grade III gliomas, they are collectively referred to as lower grade gliomas (LGGs) [2].…”

Novel Immune-Related Gene-Based Signature Characterizing an Inflamed Microenvironment Predicts Prognosis and Radiotherapy Efficacy in Glioblastoma

“…It has been shown that the expression of IFNG gene signature (including IDO1, CXCL10, CXCL9, HLA-DRA, STAT1, and IFNG), as well as expanded IFNG gene signature (including 18 genes involved in the IFNG response and major downstream pathways), characterizes the T-cell inflamed phenotype well, acts as an effective indicator for screen potential responders to ICB therapy, and is a marker of improved prognosis for most tumors, except for gliomas ( Danaher et al, 2018 ; Qian et al, 2018 ). Besides, another four-gene signature associated with immune pathways and the expression of immune checkpoints also predicts a poor prognosis for patients with lower-grade glioma ( Xiao et al, 2020 ). These results may suggest that excessive immune responses do not benefit glioma patients, even if more tumor cells can be eliminated, in line with our IRG-based gene signature to characterize immune activation while being associated with poor prognosis.…”

Construction of an immune infiltration-associated ceRNA network and prognostic model for low-grade gliomas

“…In recent years, prognostic factors (IDH status, WHO Grade, 1p/19q co-deletion) have been found to correlate with immune checkpoint expression. Xiao et al suggested that higher immune checkpoint expression in the high-risk group of LGG patients with the same IDH status may be associated with activation of immunosuppressive pathways (30). In a study by Lei Lv et al, it was noted that 1p/ 19q co-deletion could lead to reduced expression levels of several immune checkpoints, including PD1 and PD-L1/2, and suggested that both IDH mutations and 1p/19q co-deletion are markers of better prognosis in LGG patients (31).…”