Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma

Abstract

Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stemlike signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM. In the absence of IDH mutation, several genes associated with metabolism are differentially expressed in these subtypes of primary GBM, implicating metabolic reprogramming occurs in tumor microenvironment. Furthermore, histone lysine methyltransferase EZH2 was upregulated while histone lysine demethylases KDM2 and KDM4 were downregulated in both group I and II primary GBM. Lastly, we identified 9 common genes across large data sets of gene expression profiles among MRI-classified group I/II GBM, a large cohort of GBM subtypes from TCGA, and glioma stem cells by unsupervised clustering comparison. These commonly upregulated genes have known functions in cell cycle, centromere assembly, chromosome segregation, and mitotic progression. Our findings highlight altered expression of genes important in chromosome integrity across all GBM, suggesting a common mechanism of disrupted fidelity of chromosome structure in GBM.

The Ependymal Region Prevents Glioblastoma From Penetrating Into the Ventricle via a Nonmechanical Force

“… Qin et al (2017) reported that precursor neuronal cells of the ependymal region may attract tumor cells to migrate to the ventricle, but he did not mention whether the GBM penetrated into the ventricle. Another study suggested that GBM located in proximity to the ependymal region exhibited mRNA expression profiles associated with stem cell properties and increased DNA repair capacity, and that might be associated with GBM-ependymal contact ( Lin et al, 2017 ; Steed et al, 2020 ). However, Akshitkumar et al reported that after excluding the volume factor of the sample, there was no significant difference in gene expression between GBM with and without contact with the ependymal region.…”

Glioblastoma Distance From the Subventricular Neural Stem Cell Niche Does Not Correlate With Survival

“…Several studies have sought to understand the molecular basis for the increased malignancy of glioblastomas with VSVZ contact (17)(18)(19). Two of them demonstrate a correlation with increased glioblastoma expression of CD133, a glioma stem cell marker, with proximity to the VSVZ (20,21).…”

Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature

“…These molecular approaches to GBMs revolutionized the understanding of the pathophysiology of gliomas, pathologic classification of tumors, and therapeutic approaches, even if all these genetic classifications do not routinely influence treatment choices. 79 It is possible that further GBM subclassifications will lead toward individualized treatments for distinct molecular subtypes. GBM patient samples taken during the first tumor resection and after first-line chemotherapy, done during second tumor resection for recurrent GBMs, can be useful to understand the changes occurring in gene and protein expression, to improve pharmacologic research, and to establish the most effective pharmacotherapy for the single patient.…”