Abstract
Glioma is one of the most typical intracranial tumors, comprising about 80% of all brain malignancies. Several key molecular signatures have emerged as prognostic biomarkers, which indicate room for improvement in the current approach to glioma classification. In order to construct a more veracious prediction model and identify the potential prognosis-biomarker, we explore the differential expressed m6A RNA methylation regulators in 665 gliomas from TCGA-GBM and TCGA-LGG. Consensus clustering was applied to the m6A RNA methylation regulators, and two glioma subgroups were identified with a poorer prognosis and a higher grade of WHO classification in cluster 1. The further chi-squared test indicated that the immune infiltration was significantly enriched in cluster 1, indicating a close relation between m6A regulators and immune infiltration. In order to explore the potential biomarkers, the weighted gene co-expression network analysis (WGCNA), along with Least absolute shrinkage and selection operator (LASSO), between high/low immune infiltration and m6A cluster 1/2 groups were utilized for the hub genes, and four genes (TAGLN2, PDPN, TIMP1, EMP3) were identified as prognostic biomarkers. Besides, a prognostic model was constructed based on the four genes with a good prediction and applicability for the overall survival (OS) of glioma patients (the area under the curve of ROC achieved 0.80 (0.76–0.83) and 0.72 (0.68–0.76) in TCGA and Chinese Glioma Genome Atlas (CGGA), respectively). Moreover, we also found PDPN and TIMP1 were highly expressed in high-grade glioma from The Human Protein Atlas database and both of them were correlated with m6A and immune cell marker in glioma tissue samples. In conclusion, we construct a novel prognostic model which provides new insights into glioma prognosis. The PDPN and TIMP1 may serve as potential biomarkers for prognosis of glioma.
Highlights
Glioma is a common primary tumor in the central nervous system (CNS), accounting for about 80% of brain malignancies [1, 2]
Based on biological functions of each m6A RNA methylation regulator in clinical prognosis, we performed consensus clustering based on gene expression of 12 key m6A RNA
We explored the relationship between the expression levels of five hub genes and m6A RNA methylation regulators to elucidate the underlying mechanisms of abnormal up-regulation in glioma
Summary
Glioma is a common primary tumor in the central nervous system (CNS), accounting for about 80% of brain malignancies [1, 2]. The lower-grade gliomas (LGGs) has a relatively favorable prognosis, consisting of the diffuse low-grade and intermediate-grade gliomas (World Health Organization [WHO] grades II and III), whereas glioblastoma (GBM) are generally high-grade gliomas (grade IV) [3, 4]. N6-Methyladenosine (m6A) is the most popular internal mRNA modification in diverse cell types and consists of the m6A methyltransferases, reverted by the demethylases and identified by m6A binding proteins [5,6,7,8,9,10]. M6A modification has various regulatory functions in tumorigenesis, progression and immunity modulation [11,12,13,14,15]. Immune classification of cancers is crucial in therapeutic strategy establishing and prognosis assessment of patients with tumors [19, 20]
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