Molecular and Clinicopathological Characterization of a Prognostic Immune Gene Signature Associated With MGMT Methylation in Glioblastoma

Abstract

Background: O6-methylguanine-DNA methyltransferase (MGMT) methylation status affects tumor chemo-resistance and the prognosis of glioblastoma (GBM) patients. We aimed to investigate the role of MGMT methylation in the regulation of GBM immunophenotype and discover an effective biomarker to improve prognosis prediction of GBM patients.Methods: A total of 769 GBM patients with clinical information from five independent cohorts were enrolled in the present study. Samples from the Cancer Genome Atlas (TCGA) dataset were used as the training set, whereas transcriptome data from the Chinese Glioma Genome Atlas (CGGA) RNA-seq, CGGA microarray, GSE16011, and the Repository for Molecular Brain Neoplasia (REMBRANDT) cohort were used for validation. A series of bioinformatics approaches were carried out to construct a prognostic signature based on immune-related genes, which were tightly related to the MGMT methylation status. In silico analyses were performed to investigate the influence of the signature on immunosuppression and remodeling of the tumor microenvironment. Then, the utility of this immune gene signature was analyzed by the development and evaluation of a nomogram. In vitro experiments were further used to verify the immunologic function of the genes in the signature.Results: We found that MGMT unmethylation was closely associated with immune-related biological processes in GBM. Sixty-five immune genes were more highly expressed in the MGMT unmethylated than the MGMT-methylated group. An immune gene-based risk model was further established to divide patients into high and low-risk groups, and the prognostic value of this signature was validated in several GBM cohorts. Functional analyses manifested a universal up-regulation of immune-related pathways in the high-risk group. Furthermore, the risk score was highly correlated to the immune cell infiltration, immunosuppression, inflammatory activities, as well as the expression levels of immune checkpoints. A nomogram was developed for clinical application. Knockdown of the five genes in the signature remodeled the immunosuppressive microenvironment by restraining M2 macrophage polarization and suppressing immunosuppressive cytokines production.Conclusions:MGMT methylation is strongly related to the immune responses in GBM. The immune gene-based signature we identified may have potential implications in predicting the prognosis of GBM patients and mechanisms underlying the role of MGMT methylation.

Elevated TAF12 Expression Predicts Poor Prognosis in Glioma Patients: Evidence from Bioinformatic and Immunohistochemical Analyses

“…Additionally, although higher TAF12 expression was observed in patients older than 40 years in the CGGA and TCGA, this difference was not confirmed in the GEO datasets ( Supplementary Figure S1A ). Moreover, although previous studies reported that MGMT methylation was associated with a better prognosis and better response to chemotherapy in GBM patients [ 23 ], lower TAF12 expression was observed in samples with MGMT methylation in the CGGA ( Supplementary Figure S1B ). Furthermore, because of an update to the classification system, we also evaluated the expression level of TAF12 according to the grading of adult diffuse gliomas in the 2021 5th edition of the WHO classification of tumors of the CNS.…”

Integrated MRI–Immune–Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma

“…It should be pointed out that, while several reports have documented a correlation between IDH status and tumor infiltrating lymphocytes [17,49], the literature is scant about the identification of specific immunophenotypic characteristics associated with MGMT status and so far inconsistent results have been described [50,51]. On a large-scale RNAseq profiling of 769 GBM patients from five independent datasets, the score evaluation, defined as GBM-associated TIME immune cell infiltration (GTMEI) score, of more than 20 immune cell marker genes, including Thy-1 CD4, were analyzed in patients with different MGMT methylation status to define prognostic classes [52] and/or response to treatment [53]. While immune gene signatures were able to discriminate high-vs low-risk groups and to predict the response to chemo-or immuno-therapy, no differences were observed in the GTMEI score according to MGMT methylation status.…”

Glioma: molecular signature and crossroads with tumor microenvironment

“…Dysfunction of tumor suppressor p53 is widely known to protect tumor cells from apoptosis, and accelerating evidence reveals that dysfunction also leads to inflammatory states and tumor-immune evasion [ 48 ]. However, the critical clinical biomarker MGMT is associated with an increased immune response [ 44 ], as analyses revealed an upregulation of immune genes in unmethylated glioma. Furthermore, there are further indications that inflammatory pathways influence the molecular properties and can represent biomarkers accordingly.…”