DNA Methylation-based Diagnostic and Prognostic Biomarkers for Glioblastoma

Abstract

Glioblastomas are the most common primary central nervous system malignancy tumor in adults. Glioblastoma patients have poor prognosis, with an average survival period of approximately 14 mo after diagnosis. To date, there are a limited number of effective treatment methods for glioblastoma, and its molecular mechanisms remain elusive. In this article, we analyzed the key biomarkers and pathways in glioblastoma patients based on gene expression and DNA methylation datasets. The 60 hypomethylated/upregulated genes and 110 hypermethylated/downregulated genes were identified in GSE50923, GSE50161, and GSE116520 microarrays. Functional enrichment analyses indicated that these methylated-differentially expressed genes were primarily involved in collagen fibril organization, chemical synaptic transmission, extracellular matrix-receptor interaction, and GABAergic synapse. The hub genes were screened from a protein–protein interaction network; in selected genes, increased NMB mRNA level was associated with favorable overall survival, while elevated CHI3L1, POSTN, S100A4, LOX, S100A11, IGFBP2, SLC12A5, VSNL1, and RGS4 mRNA levels were associated with poor overall survival in glioblastoma patients. Additionally, CHI3L1, S100A4, LOX, and S100A11 expressions were negatively correlated with their corresponding methylation status. Furthermore, the receiver-operator characteristic curve analysis indicated that CHI3L1, S100A4, LOX, and S100A11 can also serve as highly specific and sensitive diagnostic biomarkers for glioblastoma patients. Collectively, our study revealed the possible methylated-differentially expressed genes and associated pathways in glioblastoma and identified four DNA methylation-based biomarkers of glioblastoma. These results may provide insight on diagnostic and prognostic biomarkers, and therapeutic targets in glioblastoma.

Integrated analysis of the genomic and transcriptional profile of gliomas with isocitrate dehydrogenase-1 and tumor protein 53 mutations

“…5 Calcium signaling pathway, ECM-receptor interaction, and c-AMP signaling pathway were found to be the significant differences between the patients with IDH1 and TP53 mutations and the patients with wild-type, which played important cooperating roles in the glioma tumorigenesis. 30,31 Interestingly, nicotine addiction and morphine addiction were also found to be a significant difference between the patients with IDH1 and TP53 mutations and the patients with wild-type, which was also reported in the previous GBM studies, [32][33][34] but here suggested could be closely related to the IDH1 and TP53 mutations. In the LGG cohort, the patients with IDH1 and TP53 mutations seem to have many immunological changes than the patients with wild-type, for example, the anti-viral function (defense response to virus, negative regulation of viral process, and type I interferon signaling pathway), which might indicate that the immune status in the patients with IDH1 and TP53 mutations is different from the patients with wild-type.…”

Molecular subtyping of glioblastoma based on immune-related genes for prognosis

“…Methylation-based subtypes that predict GBM patient survival have been reported. Notably, the methylation levels of different subgroups could reflect different molecular genetic features 22 , 23 . More and more attention has been paid to the relationship between the immune system and malignancy progression and pathogenesis, which contribute to GBM treatment, thereby promoting the development of anti-tumor treatments.…”

Downregulated the expression of DNMT3B by suppressing PI3K/Akt signaling pathway and enhances the chemosensitivity of glioblastoma to temozolomide.

“…7). The PI3K/Akt signaling pathway regulate DNMT3B protein expression level, thus regulating the chemosensitivity of glioblastoma cells to TMZ It's well known that DNA methylation is a crucial regulator in tumor development [10]. And previous study had demonstrated the PI3K/AKT pathway regulates the expression of DNMT3B in some tumor [21].…”

“…Epigenetic modi cation, a biological process that modi es gene regulation without altering DNA sequence [12,13], is well-established as a key factor in tumor-related gene expression, including chromatin remodeling, histone modi cation, and DNA methylation. [10]. DNA methylation, occurring at the 5th position of Cytosines at CpG site, is catalyzed by DNA methyltransferases (DNMTs) [14,15].…”