Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma

Abstract

Ten to twenty percent of newly diagnosed glioblastoma (GBM) patients initially present with multiple lesions, termed multifocal or multicentric GBM (M-GBM). The prognosis of these patients is poorer than is that of solitary GBM (S-GBM) patients. However, it is unknown whether multifocality has a genetic, epigenetic, or molecular basis. Here, we identified the genetic and epigenetic characteristics of M-GBM by performing a comprehensive analysis of multidimensional data, including imaging, genetic, epigenetic, and gene expression profiles, from 30 M-GBM cases in The Cancer Genome Atlas (TCGA) database and comparing the results with those of 173 S-GBM cases. We found that M-GBMs had no IDH1, ATRX, or PDGFRA mutations and were significantly associated with the mesenchymal subtype. We also identified the CYB5R2 gene to be hypo-methylated and overexpressed in M-GBMs. The expression level of CYB5R2 was significantly associated with patient survival in two major independent GBM cohorts, totaling 758 cases. The IDH1 mutation was markedly associated with CYB5R2 promoter methylation, but the survival influence of CYB5R2 was independent of IDH1 mutation status. CYB5R2 expression was significantly associated with collagen maturation and the catabolic process and immunoregulation pathways. These results reveal that M-GBMs have some underlying genetic and epigenetic characteristics that are associated with poor prognosis and that CYB5R2 is a new epigenetic marker for GBM prognosis.

IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced

“…IDH1 R132H mutation confers a gain-of-function activity that reduces α- KG to produce D-2-hydroxyglutarate (D2HG) and consumes NADPH [12] at the same time. Several studies have demonstrated that IDH1 R132H mutation causes widespread metabolic changes including affecting DNA methylation and DNA repair.…”

“…[9–11] The depletion of α- KG caused by IDH mutations in human tumor causes deregulation of multiple α-KG-dependent dioxygenases, which are involved in the hydroxylation of various protein, histones, transcription factors and alkylated DNA and RNA. [12–16] Due to such a broad spectrum of substrates of α-KG-dependent dioxyneases, IDH1 mutation is expected to potentially affect multiple cellular pathways.…”

Multicentric Glioma Develops via a Mutant IDH1-Independent Pathway: Immunohistochemical Study of Multicentric Glioma

“…A study of 258 glioblastomas by Liu et al [33] reported that multicentric glioblastoma was dominated by the mesenchymal subtype, without mutation in IDH1 and ATRX, contrary to the common proneural or G-CIMP subtype. They also have poorer survival than the solitary ones.…”

“…Glioblastoma has different characteristics and a different pathogenesis from the solitary ones [33] . In lowergrade multicentric gliomas, the predominant characteristics and pathogenesis are those of primary glioblastoma.…”

Spatiotemporal genomic architecture informs precision oncology in glioblastoma

“…Additionally, we analyzed transcriptomes of 83 tumor specimens from 41 patients (bulk) and 305 single cells from seven samples of three patients. Tumors were classified into three distinct groups according to spatial and temporal tissue acquisition: from the same location and time (locally adjacent), from different locations at the same time (multifocal/multicentric, referred as multiple) 17 , and from local and distant recurrences at different times (longitudinal local or distant, respectively) (Fig. 1a).…”