In:
Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 10 ( 2019-10-01), p. 2042-2050
Kurzfassung:
Mutations in isocitrate dehydrogenases 1 and 2 (IDH) occur in the majority of World Health Organization grade II and III gliomas. IDH1/2 active site mutations confer a neomorphic enzyme activity producing the oncometabolite D-2-hydroxyglutarate (D-2HG), which generates the glioma CpG island methylation phenotype (G-CIMP). While IDH1/2 mutations and G-CIMP are commonly retained during tumor recurrence, recent work has uncovered losses of the IDH1 mutation in a subset of secondary glioblastomas. Cooccurrence of the loss of the mutant allele with extensive methylation changes suggests a possible link between the two phenomena. Here, we utilize patient-derived IDH1R132H/WT glioma cell lines and CRISPR-Cas9–mediated gene knockout to model the genetic loss of IDH1R132H, and characterize the effects of this deletion on DNA methylation. After D-2HG production has been abolished by deletions within the IDH1 alleles, these models show persistent DNA hypermethylation at seven CpG sites previously used to define G-CIMP–positivity in patient tumor samples. Despite these defining G-CIMP sites showing persistent hypermethylation, we observed a genome-wide pattern of DNA demethylation, enriched for CpG sites located within open sea regions of the genome, as well as in CpG-island shores of transcription start sites, after loss of D-2HG production. These results suggest that inhibition of D-2HG from genetic deletion of IDH alleles is not sufficient to reverse hypermethylation of all G-CIMP–defining CpG sites, but does result in more demethylation globally and may contribute to the formation of a G-CIMP-low–like phenotype. Implications: These findings show that loss of the IDH1 mutation in malignant glioma cells leads to a pattern of DNA methylation alterations, and shows plausibility of IDH1 mutation loss being causally related to the gain of a G-CIMP-low–like phenotype.
Materialart:
Online-Ressource
ISSN:
1541-7786
,
1557-3125
DOI:
10.1158/1541-7786.MCR-19-0309
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2019
ZDB Id:
2097884-4
SSG:
12
