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Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide-resistant glioblastoma

ABSTRACT: Glioblastoma(GBM), an aggressive brain cancer, occurs frequently compared to other brain tumors. This study aimed to reveal the novel mechanism of temozolomide (TMZ) resistance (chemotherapeutic drug) Meta-Z analysis, Kaplan–Meier (KM) survival analysis, protein-protein interaction (PPI) network establishment, cluster analysis of co-expressed gene networks, and hierarchical clustering of all upregulated and downregulated genes were used. Next-generation sequencing (NGS) and quantitative polymerase chain reaction (q-PCR) analysis revealed the downregulated (TIE1, CACNA2D1, CAPN6, and ADAMTS6) and upregulated (SAA1, SAA2, GDF15, and USP26) genes. Different statistical models were developed for these genes using the Z-score and the KM plot was depicted using a cohort of patient with brain tumors. The maximum number of nodes was observed in the PPI-network for ADAMTS6 and TIE1. The PPI network model of all genes showed 35 nodes and 241 edges. Immunohistochemical staining was performed using GBM with isocitrate dehydrogenase (IDH)-wild-type or IDH-mutant samples and significant upregulation of TIE1 (p<0.001) and CAPN 6 (p<0.05) protein expression was found in IDH-mutant GBM. Structural analysis revealed the IDH-mutant model using mutant residues (R132, R140, and R172). The result of this study will aid the development of novel biomarkers and new therapeutics for brain tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234762 | GEO | 2023/06/30

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTS) may provide important insight into the biology of GBM. We identified 7 patients with GBM treated at Memorial Sloan-Kettering Cancer Center (MSKCC) with survival greater than 48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTS in two independent cohorts (TCGA and REMBRANDT) and analyzed the transcriptomal characteristics of these LTS. The median overall survival of our cohort was 62.5 months. LTS were distributed between the proneural (n=2), neural (n=2), classical (n=2) and mesenchymal (n=1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identity. The majority of the MSKCC LTS (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutations, and IDH mutation occurred in a minority of the TCGA LTS as well. A set of 42 genes was found to be differentially expressed in the MSKCC and TCGA LTS. While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression. All tumors (n = 7) were obtained following surgical resection at the MSKCC as part of routine clinical care, and snap frozen. Tumors were obtained in accordance with Institutional Review Board policies at the MSKCC. Each sample was examined histologically by 3 independent neuropathologists and confirmed to be World Health Organization (WHO) grade IV glioma (GBM). Before analysis, tumors were sectioned and microdissected. Genomic DNA or RNA was extracted using the DNeasy kit (Qiagen) or RNeasy Lipid Tissue Mini Kit (Qiagen) as per the manufacturer’s instructions. Expression analysis of tumors was performed using the Affymetrics U133 2.0 microarray (Affymetrix). Affymetrix CEL files were imported into the Partek Genomics Suite (Partek). The TCGA gene expression data (HT-HG-U133A) was accessed from the TCGA data repositories (http://cancergenome.nih.gov, date of download 12/2013).

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Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide-resistant glioblastoma

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