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.
Highlights
The central nervous system’s primary tumors are dominated by gliomas with histologic characteristics of normal glial cells and are often named after these similarities
Genes would be identified as prognostic genes when the gene met specific criteria, and the criteria were listed as the following: (a) gene expression level was significantly different in normal brain samples and lower grade gliomas; (b) gene was significantly associated with overall survival of LGG; (c) gene was significantly associated with disease-free survival of LGG
Five genes were differentially expressed in normal brain tissue and LGG, including CD44, HYAL2, MMP2, SPP1, RHOA; seven genes were significantly associated with overall survival (OS) of LGG, including CD44, HYAL2, MMP2, SPP1, ERBB2, MMP7, HMMR; eight genes were significantly associated with disease-free survival (DFS) of LGG, including CD44, HYAL2, MMP2, SPP1, ERBB2, MMP7, NANOG, HMMR
Summary
The central nervous system’s primary tumors are dominated by gliomas with histologic characteristics of normal glial cells and are often named after these similarities. According to the classification criteria for the central nervous system's tumors, gliomas were divided into four grades according to the pathological characteristics of gliomas, in which grade I/II is the low grade and grade III/IV is the high grade [1, 2]. The criteria for diagnosing and classifying brain tumors have been microscopic or histopathological features, and the WHO grade system is commonly used for prognostic prediction in glioma patients [1, 2]. To the best of our knowledge, surveys for the classification and prognosis prediction of gliomas are mainly focused on highgrade gliomas or glioblastoma; biomarkers associated with stratification of prognosis in patients with LGG are still limited
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