Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas

Tim Müller; Marco Gessi; Anke Waha; Lukas Jan Isselstein; Daniel Luxen; Dorothee Freihoff; Johannes Freihoff; Albert Becker; Matthias Simon; Jennifer Hammes; Dorota Denkhaus; Anja zur Mühlen; Torsten Pietsch; Andreas Waha

doi:10.1016/j.ajpath.2012.04.017

Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas

Am J Pathol. 2012 Aug;181(2):675-83. doi: 10.1016/j.ajpath.2012.04.017. Epub 2012 Jun 9.

Authors

Tim Müller¹, Marco Gessi, Anke Waha, Lukas Jan Isselstein, Daniel Luxen, Dorothee Freihoff, Johannes Freihoff, Albert Becker, Matthias Simon, Jennifer Hammes, Dorota Denkhaus, Anja zur Mühlen, Torsten Pietsch, Andreas Waha

Affiliation

¹ Department of Neuropathology, University of Bonn, Bonn, Germany.

PMID: 22688054
DOI: 10.1016/j.ajpath.2012.04.017

Abstract

The recent identification of isocitrate dehydrogenase 1 (IDH1) gene mutations in gliomas stimulated various studies to explore the molecular consequences and the clinical implications of such alterations. The Cancer Genome Atlas Research Network showed evidence for a CpG island methylator phenotype in glioblastomas that was associated with IDH1 mutations. These alterations were associated with the production of the oncometabolite, 2-hydroxyglutarate, that inhibits oxygenases [ie, ten-eleven translocation (TET) enzymes involved in the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC)]. We investigated 60 gliomas for 5hmC presence, 5-methylcytosine content, TET1 expression, and IDH1 mutation to gain insight into their relationships on a histological level. Of gliomas, 61% revealed no immunoreactivity for 5hmC, and no correlation was observed between IDH1 mutations and loss of 5hmC. Interestingly, expression of TET1 showed remarkable differences regarding overall protein levels and 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. Of 5hmC-negative gliomas, 70% showed either exclusive or dominant cytoplasmic expression, or no detectable TET1 protein (P = 0.0122). Our data suggest that the loss of 5hmC is a frequent event in gliomas, independent of IDH1 mutation, and may be influenced by the nuclear exclusion of TET1 from the nuclei of glioma cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5-Methylcytosine / metabolism
Brain Neoplasms / enzymology
Brain Neoplasms / genetics
Brain Neoplasms / pathology*
Cell Line, Tumor
Cell Nucleus / metabolism*
Cytosine / analogs & derivatives*
Cytosine / metabolism
DNA Methylation / genetics
DNA Modification Methylases / genetics
DNA Repair Enzymes / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Dioxygenases
Dual-Specificity Phosphatases / genetics
Female
Gene Expression Regulation, Enzymologic
Glioblastoma / enzymology
Glioblastoma / genetics
Glioblastoma / pathology
Glioma / enzymology*
Glioma / genetics
Glioma / pathology*
Humans
Immunohistochemistry
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism*
Male
Mitogen-Activated Protein Kinase Phosphatases / genetics
Mixed Function Oxygenases
Mutation / genetics
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
Real-Time Polymerase Chain Reaction
Sequence Analysis, DNA
Subcellular Fractions / metabolism
Tumor Suppressor Proteins / genetics

Substances

DNA-Binding Proteins
Proto-Oncogene Proteins
RNA, Messenger
Tumor Suppressor Proteins
5-hydroxymethylcytosine
5-Methylcytosine
Cytosine
Mixed Function Oxygenases
TET1 protein, human
IDH2 protein, human
Isocitrate Dehydrogenase
IDH1 protein, human
Dioxygenases
TET2 protein, human
DNA Modification Methylases
MGMT protein, human
Mitogen-Activated Protein Kinase Phosphatases
DUSP4 protein, human
Dual-Specificity Phosphatases
DNA Repair Enzymes