Abstract
Melanoma associated antigen (MAGE) is an extensively studied family of tumor-associated genes that share a common MAGE homology domain (MHD). Based upon their expression pattern, MAGE genes have been broadly classified into type 1 MAGEs (T1Ms) and type 2 MAGEs (T2Ms) categories. Interestingly, several T2Ms are highly expressed in the brain and involved in the regulation of neuronal development, differentiation, and survival. Available literature suggests possible tumor suppressor functions of a few T2Ms, while information available about their expression, regulation, and clinical significance in glioma is scanty. This prompted us to perform a comprehensive analysis of T2M expression in glioma. Gene expression data from glioma datasets: Oncomine, TCGA, and REMBRANDT study, were used to assess the mRNA expression of T2M genes (MAGED1, MAGED2, MAGED3, MAGED4, MAGED4B, MAGEE1, MAGEE2, MAGEF1, MAGEH1, MAGEL2, NSMCE3, and NDN), and their association with clinical characteristics and composition of the tumor microenvironment. Further, mutation, copy number alteration, and DNA methylation data from TCGA were assessed for determining potential mechanisms of T2Ms expression in glioma. Expression analysis revealed overexpression of MAGED subfamily genes in glioma, while other genes of this family exhibited reduced expression in advanced grades of this malignancy. Further, the expression of T2Ms exhibited varying extent of positive correlations with each other. Amongst downregulated T2Ms, MAGEH1 expression exhibited negative correlations with DNA methylation. Additionally, genes associated with MAGEH1 were enriched in Myc and Hedgehog signaling. Furthermore, T2Ms downregulation was associated with immune infiltration in glioma tissues and poor overall survival of glioma patients. In multivariate Cox regression analysis, MAGEH1 emerged as an independent prognosticator in lower grade glioma. Conclusively, these results suggest that expression of T2Ms is associated with important clinical and molecular features in glioma. Mechanistic studies may further provide novel insights into their role in glioma progression.
Highlights
Gliomas are a group of heterogeneous primary malignant brain tumors with a dismal outcome [1]
An opposite pattern was observed for TRO (MAGED3), MAGEE1, MAGEE2, MAGEH1, MAGEL2, and NDN, which exhibited reduced expression in tumors compared to normal brain tissues
In view of the reported overexpression of MAGED4 in glioma [18], we focused our further analysis on downregulated type 2 MAGEs (T2Ms) using MAGEH1 as a representative member of this highly co-expressed T2M subgroup
Summary
Gliomas are a group of heterogeneous primary malignant brain tumors with a dismal outcome [1]. Aberrant MAGEH1 expression has been linked to dementia [22] These studies suggest crucial roles of T2Ms in neuronal growth, survival and possibly in the pathogenesis of central nervous system diseases, including glioma. Wide variations in the nucleotide sequences of regulatory regions of T1Ms enables their differential expression [9], epigenetic alterations including DNA methylation and histone modification underlie the co-expression of several T1Ms and other tumor associated antigens in cancers [23]. While current evidence suggests crucial roles of T2Ms in normal brain functions and neurological disorders, no systematic study has been done to investigate the expression, regulation, cellular function, and clinical significance of T2Ms in glioma. The current study was undertaken to investigate the regulatory mechanism responsible for altered expression of T2Ms, their cellular functions, and clinical significance in glioma using large scale multi-omics datasets
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