Artikel
Association of TET1 nuclear exclusion with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas
Suche in Medline nach
Autoren
Veröffentlicht: | 11. September 2012 |
---|
Gliederung
Text
The identification of isocitrate dehydrogenase 1(IDH1) gene mutations in gliomas inspired various studies exploring the molecular consequences and the clinical implications of such alterations. The Cancer Genome Atlas Research Network uncovered a CpG island methylator phenotype (G-CIMP) in glioblastomas that was associated with IDH1-mutations. Mutant IDH1 protein produces the onco-metabolite 2-hydroxyglutarate that inhibits a-ketoglutarate dependent oxygenases, e.g., TET enzymes involved in the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine. We investigated 60 gliomas for the presence of 5-hydroxymethylcytosine, 5-methylcytosine content, TET1 expression and IDH1 mutation to gain insight into their relationship on the histological level. 61% of gliomas revealed no immunoreactivity for 5-hydroxymethylcytosine and no correlation was observed between IDH1 mutations and loss of 5-hydroxymethylcytosine. Interestingly, expression of TET1 showed remarkable differences with regard to overall protein levels as well as subcellular localization. We found a highly significant (p=0.0007) correlation between IDH1 mutations and nuclear accumulation of TET1 but not with loss of 5hmC. 70% of 5-hydroxymethylcytosine negative gliomas showed either exclusive or dominant cytoplamic expression or no detectable TET1 protein (p=0.0122). Methylation of MGMT and DUSP4/MKP2 was more abundant in gliomas showing nuclear expression of TET1 and harboring mutant IDH1 alleles, but no correlation between global 5-hmC levels and methylation of these genes was observed.
Our data suggest that loss of 5-hydroxymethylcytosine is a frequent event in gliomas independent of IDH1 mutation and may be influenced by nuclear exclusion of TET1 from nuclei of glioma cells.