DNA demethylation is associated with malignant progression of lower-grade gliomas

Abstract

To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

Comprehensive Analysis of Expression Regulation for RNA m6A Regulators With Clinical Significance in Human Cancers

“…For example, hsa-miR-150/ IGF2BP1 regulatory pair was reported to be a novel potential therapeutic target for osteosarcoma treatment ( 65 ), and IGF2BP1 was identified as a novel target gene of hsa-miR-98-5p in hepatocellular carcinoma ( 66 ). Similarly, the DNA demethylation in the promoter region of IGF2BP3 could influence the progression of G-CIMP gliomas ( 67 ), and cg07166550/ ALKBH5 could be used as prognostic biomarkers in prostate cancer ( 68 ). Finally, we identified some regulatory pairs with prognostic significance in several cancers.…”

Sphere-Forming Culture for Expanding Genetically Distinct Patient-Derived Glioma Stem Cells by Cellular Growth Rate Screening

“…Owing to their relatively favorable prognosis compared to IDH1-wt glioblastomas, IDH1-mut glioblastomas and LGGs have not been extensively investigated [33]. However, all DIGs are characterized by extensive infiltrative growth, neovascularization and resistance to various combined therapies and, despite variable intervals, the remaining tumors after neurosurgical resection result in tumor evolution to a more refractory and aggressive form [3][4][5]. GSCs are critical therapeutic targets, because these cells are responsible for DIG progression and evolution [17].…”

Reduced Neoantigen Expression Revealed by Longitudinal Multiomics as a Possible Immune Evasion Mechanism in Glioma

“…The remaining 25 cases were analyzed in this study (Supplementary Table S1). The study cohort partly overlapped with cases from our previous studies (22,(27)(28)(29). Histopathologic diagnoses were made based on isocitrate dehydrogenase 1 or 2 gene (IDH1/2) mutation and chromosome 1p/19q status as well as histology, according to the 2016 WHO guidelines (1).…”