Differential gene methylation in paired glioblastomas suggests a role of immune response pathways in tumor progression

Abstract

DNA and histone methylation are post-transcriptional modifications that have been recently described in gliomas. Indeed, glioma CpG island hypermethylated phenotype has been identified as prognostic biomarker and as a surrogate marker of IDH1/2 mutations. However, the role of DNA methylation in glioblastoma progression is unknown. We sought to analyze DNA methylation levels in paired (initial and recurrent) primary glioblastoma samples to identify candidate pathways that may prone to glioblastoma progression. We have analyzed 12 samples (5 paired samples, two of them with three surgeries) using methylation arrays. We have analyzed differential methylation at probe and at gene region level. Finally, pathway analysis has been performed using differentially methylated regions. All analysis has been performed with R and Bioconductor packages. Mean methylation level at initial sample compared to recurrence was strongly positively correlated (R(2) = 0.98). There was no differentially methylation at probe level. However, at gene level 3080 regions were differentially methylated. Interestingly, pathways analysis showed that the most differentially methylated genes are involved in cellular response to macrophage colony-stimulating factor stimulus (GO:0036006). Methylation levels were strongly conserved when comparing initial to recurrence in primary glioblastomas. Interestingly, differentially methylated pathway analysis suggests that a modulation of methylation in immune response genes may play a role in glioblastoma progression. Further studies are needed to validate the role of methylation of glioblastoma immune response genes in tumor progression.

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

“…A comparison of methylation levels in initial and recurrent tumors found an enrichment of macrophage activation genes in recurrent tumors, suggesting modulation of immune genes occurs in glioma progression. 71 In the genome-based subtypes described by Phillips et al in 2006, 13 it was proposed that the proneural and classical gliomas could progress to mesenchymal tumors. However, in the genome subtypes proposed by Verhaak et al in 2010 (ref.…”

Musashi-1 Regulates MIF1-Mediated M2 Macrophage Polarization in Promoting Glioblastoma Progression

“…For instance, some immunosuppressive factors like IL-10 and TGF beta can induce regulatory T cells to suppress cytotoxic T cell activation and blunt immune responses to attack cancer cells [15]. Accumulated evidence indicates that tumor microenvironment, especially its immune constituent, plays an important role in promoting GBM progression [18][19][20][21]. Recently, tumor-associated macrophages (TAMs), one of the types of infiltrating immune cells, were found to be abundant in GBM tissues and were proposed to play a key role in tumor growth [22].…”

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

“…Glioblastoma shows extensive temporal and spatial heterogeneity, which appears to contribute to therapeutic resistance and inevitable relapse [7][8][9][10][11][12][13] . Prior research on tumor heterogeneity in glioblastoma has focused mainly on the genomic and transcriptomic dimensions [7][8][9][10][11][12][13][14][15][16][17][18][19][20] , while the dynamic role of the epigenome in glioblastoma disease progression is much less understood 21 .…”