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      Expression Profile Analysis Identifies a Novel Five-Gene Signature to Improve Prognosis Prediction of Glioblastoma

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          Abstract

          Glioblastoma multiforme (GBM) is the most aggressive primary central nervous system malignant tumor. The median survival of GBM patients is 12–15 months, and the 5 years survival rate is less than 5%. More novel molecular biomarkers are still urgently required to elucidate the mechanisms or improve the prognosis of GBM. This study aimed to explore novel biomarkers for GBM prognosis prediction. The gene expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets of GBM were downloaded. A total of 2241 overlapping differentially expressed genes (DEGs) were identified from TCGA and GSE7696 datasets. By univariate COX regression survival analysis, 292 survival-related genes were found among these DEGs ( p < 0.05). Functional enrichment analysis was performed based on these survival-related genes. A five-gene signature (PTPRN, RGS14, G6PC3, IGFBP2, and TIMP4) was further selected by multivariable Cox regression analysis and a prognostic model of this five-gene signature was constructed. Based on this risk score system, patients in the high-risk group had significantly poorer survival results than those in the low-risk group. Moreover, with the assistance of GEPIA http://gepia.cancer-pku.cn/, all five genes were found to be differentially expressed in GBM tissues compared with normal brain tissues. Furthermore, the co-expression network of the five genes was constructed based on weighted gene co-expression network analysis (WGCNA). Finally, this five-gene signature was further validated in other datasets. In conclusion, our study identified five novel biomarkers that have potential in the prognosis prediction of GBM.

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          Most cited references33

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          Diagnostic and Therapeutic Biomarkers in Glioblastoma: Current Status and Future Perspectives

          Glioblastoma (GBM) is a primary neuroepithelial tumor of the central nervous system, characterized by an extremely aggressive clinical phenotype. Patients with GBM have a poor prognosis and only 3–5% of them survive for more than 5 years. The current GBM treatment standards include maximal resection followed by radiotherapy with concomitant and adjuvant therapies. Despite these aggressive therapeutic regimens, the majority of patients suffer recurrence due to molecular heterogeneity of GBM. Consequently, a number of potential diagnostic, prognostic, and predictive biomarkers have been investigated. Some of them, such as IDH mutations, 1p19q deletion, MGMT promoter methylation, and EGFRvIII amplification are frequently tested in routine clinical practice. With the development of sequencing technology, detailed characterization of GBM molecular signatures has facilitated a more personalized therapeutic approach and contributed to the development of a new generation of anti-GBM therapies such as molecular inhibitors targeting growth factor receptors, vaccines, antibody-based drug conjugates, and more recently inhibitors blocking the immune checkpoints. In this article, we review the exciting progress towards elucidating the potential of current and novel GBM biomarkers and discuss their implications for clinical practice.
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            The prognostic value of MGMT promoter methylation in glioblastoma: A meta-analysis of clinical trials.

            The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) is suggested to be associated with resistance to alkylating agents such as Temozolomide which is being used in treatment of patients with glioblastoma (GBM). Therefore, we evaluated the associations between MGMT promoter methylation and prognosis of patients with glioblastoma (GBM). Data were extracted from publications in Embase, PubMed, and the Cochrane Library. Data on overall survival (OS), progression-free survival (PFS), and MGMT methylation status were obtained and 4,097 subjects were enrolled. Data from 34 studies showed that MGMT methylated patients had better OS, compared to GBM unmethylated patients (pooled HRs, 0.494; 95%CI 0.412-0.591; p = 0.001). Meta-analysis of 10 eligible studies reporting on PFS, demonstrated that MGMT promoter methylation was not significantly associated with better PFS (pooled HRs, 0.653; 95%CI 0.414-1.030; p = 0.067). GBM patients with MGMT methylation were associated with longer overall survival, although this effect was not detected for PFS. Moreover, we performed further analysis in patients underwent a comprehensive imaging evaluation. This data showed a significant association with better OS and PFS, although further studies are warranted to assess the value of emerging marker in prospective setting in patients with glioblastoma as a risk stratification biomarker in clinical management of the patients.
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              Cancer Stem Cells and Immunosuppressive Microenvironment in Glioma

              Glioma is one of the most common malignant tumors of the central nervous system and is characterized by extensive infiltrative growth, neovascularization, and resistance to various combined therapies. In addition to heterogenous populations of tumor cells, the glioma stem cells (GSCs) and other nontumor cells present in the glioma microenvironment serve as critical regulators of tumor progression and recurrence. In this review, we discuss the role of several resident or peripheral factors with distinct tumor-promoting features and their dynamic interactions in the development of glioma. Localized antitumor factors could be silenced or even converted to suppressive phenotypes, due to stemness-related cell reprogramming and immunosuppressive mediators in glioma-derived microenvironment. Furthermore, we summarize the latest knowledge on GSCs and key microenvironment components, and discuss the emerging immunotherapeutic strategies to cure this disease.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                03 May 2019
                2019
                : 10
                : 419
                Affiliations
                [1] 1Department of Neurosurgery, Xiangya Hospital of Central South University , Changsha, China
                [2] 2Department of Clinical Laboratory, Hunan Provincial People’s Hospital (First Affiliated Hospital of Hunan Normal University) , Changsha, China
                [3] 3Department of Operative Nursing, Xiangya Hospital of Central South University , Changsha, China
                Author notes

                Edited by: Monica Bianchini, University of Siena, Italy

                Reviewed by: Nitish Kumar Mishra, University of Nebraska Medical Center, United States; Sen Peng, Translational Genomics Research Institute, United States; Max Shpak, St David’s Medical Center, United States

                *Correspondence: Xingjun Jiang, jiangxj@ 123456csu.edu.cn ; jxjyjz@ 123456163.com

                This article was submitted to Bioinformatics and Computational Biology, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2019.00419
                6509566
                31130992
                32532bfc-d447-4435-99e9-dfbdb56ef952
                Copyright © 2019 Yin, Tang, Zhou, Cao, Li, Fu, Wu and Jiang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 December 2018
                : 17 April 2019
                Page count
                Figures: 8, Tables: 1, Equations: 2, References: 48, Pages: 12, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Categories
                Genetics
                Original Research

                Genetics
                glioblastoma,differentially expressed genes,gene signature,prognosis,tcga,geo
                Genetics
                glioblastoma, differentially expressed genes, gene signature, prognosis, tcga, geo

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