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5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma.

ABSTRACT: Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these regions, IDH1 mutant tumors possess greater 5hmC compared to wild type. 5hmC contributes to overall methylation status of G-CIMP genes. 5hmC targeting gene body regions correlates significantly with increased gene expression. In particular, a strong correlation between increased 5hmC and increased gene expression is identified for genes highly expressed in the IDH1 mutant cohort. Overall, locus-specific gain of 5hmC targeting regulatory regions and associated with overexpressed genes suggests a significant role for 5hmC in IDH1 mutant HGG.

SUBMITTER: Glowacka WK

PROVIDER: S-EPMC5978937 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma.

Glowacka Wioletta K WK Jain Harshika H Okura Makiko M Maimaitiming Abulizi A Mamatjan Yasin Y Nejad Romina R Farooq Hamza H Taylor Michael D MD Aldape Kenneth K Kongkham Paul P

Acta neuropathologica 20180210 4

Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance ...[more]

PMID: 29428975

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Project description:Simple Summary Patients diagnosed with isocitrate dehydrogenase (IDH)-mutated brain tumors frequently suffer from seizures, and the seizures were shown to promote tumor growth. Anti-seizure medications (antiepileptic drugs) might be able to break this vicious circle. However, it is not yet known which antiepileptic drugs might have additional anti-tumor effects. In this study, 20 commonly used antiepileptic drugs were tested on patient-derived tumor models. Only oxcarbazepine promoted additional tumor cell killing, making it an interesting drug to use in this special population of brain tumor patients. Abstract Patients diagnosed with isocitrate dehydrogenase mutant (IDHmut) gliomas suffer frequently from seizures. Although the clinical course is less aggressive than that of its IDH wildtype counterpart, recent discoveries have shown that epileptic activity can promote tumor proliferation. However, it is not known if antiepileptic drugs confer additional value by inhibiting tumor growth. In this study, the antineoplastic properties of 20 FDA-approved antiepileptic drugs (AEDs) were tested in six patient-derived IDHmut glioma stem-like cells (GSCs). Cell proliferation was assessed using the CellTiterGlo-3D assay. Two of the screened drugs (oxcarbazepine and perampanel) demonstrated an antiproliferative effect. A subsequent eight-point dose–response curve proved the dose-dependent growth inhibition for both drugs, but only oxcarbazepine reached an IC50 value below 100 µM in 5/6 GSCs (mean 44.7 µM; range 17.4–98.0 µM), approximating the possible cmax for oxcarbazepine in patient serums. Furthermore, the treated GSC spheroids were 82% smaller (mean volume 1.6 nL vs. 8.7 nL; p = 0.01 (live/deadTM fluorescence staining)), and the apoptotic events increased by more than 50% (caspase-3/7 activity; p = 0.006). Taken together, this drug screen of a large series of antiepileptic drugs identified oxcarbazepine as a potent proapoptotic drug in IDHmut GSCs, which combines antiepileptic and antineoplastic properties to treat this seizure-prone patient population.

Project description:BackgroundAlthough much is known about molecular and chromosomal characteristics that distinguish glioma histological subtypes, DNA methylation patterns of gliomas and their association with other tumor features such as mutation of isocitrate dehydrogenase (IDH) genes have only recently begun to be investigated.MethodsDNA methylation of glioblastomas, astrocytomas, oligodendrogliomas, oligoastrocytomas, ependymomas, and pilocytic astrocytomas (n = 131) from the Brain Tumor Research Center at the University of California San Francisco, as well as nontumor brain tissues (n = 7), was assessed with the Illumina GoldenGate methylation array. Methylation data were subjected to recursively partitioned mixture modeling (RPMM) to derive methylation classes. Differential DNA methylation between tumor and nontumor was also assessed. The association between methylation class and IDH mutation (IDH1 and IDH2) was tested using univariate and multivariable analysis for tumors (n = 95) with available substrate for sequencing. Survival of glioma patients carrying mutant IDH (n = 57) was compared with patients carrying wild-type IDH (n = 38) using a multivariable Cox proportional hazards model and Kaplan-Meier analysis. All statistical tests were two-sided.ResultsWe observed a statistically significant association between RPMM methylation class and glioma histological subtype (P < 2.2 × 10(-16)). Compared with nontumor brain tissues, across glioma tumor histological subtypes, the differential methylation ratios of CpG loci were statistically significantly different (permutation P < .0001). Methylation class was strongly associated with IDH mutation in gliomas (P = 3.0 × 10(-16)). Compared with glioma patients whose tumors harbored wild-type IDH, patients whose tumors harbored mutant IDH showed statistically significantly improved survival (hazard ratio of death = 0.27, 95% confidence interval = 0.10 to 0.72).ConclusionThe homogeneity of methylation classes for gliomas with IDH mutation, despite their histological diversity, suggests that IDH mutation is associated with a distinct DNA methylation phenotype and an altered metabolic profile in glioma.

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5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma.

Publications

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma.

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