Nuclear Exclusion of TET1 Is Associated with Loss of 5-Hydroxymethylcytosine in IDH1 Wild-Type Gliomas

被引:95
|
作者
Mueller, Tim
Gessi, Marco
Waha, Anke
Isselstein, Lukas Jan
Luxen, Daniel
Freihoff, Dorothee
Freihoff, Johannes
Becker, Albert
Simon, Matthias [2 ]
Hammes, Jennifer
Denkhaus, Dorota
zur Muehlen, Anja
Pietsch, Torsten
Waha, Andreas [1 ]
机构
[1] Univ Bonn, Med Ctr, Dept Neuropathol, Sigmund Freud Str 25, D-53105 Bonn, Germany
[2] Univ Bonn, Dept Neurosurg, D-53105 Bonn, Germany
来源
AMERICAN JOURNAL OF PATHOLOGY | 2012年 / 181卷 / 02期
关键词
PROMOTER METHYLATION; DNA; MUTATIONS; GENOME; 5-METHYLCYTOSINE; CLASSIFICATION; TUMORS;
D O I
10.1016/j.ajpath.2012.04.017
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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 glibblastomas 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 5hinC presence, 5-methylcytosine content, TETI expression, and IDH1 mutation to gain insight into their relationships on a histological level Of gliomas, 61% revealed no irnmunoreactivity for 51unC, and no correlation was observed between IDH1 mutations and loss of 51unC. Interestingly, expression of TETI 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 TETI, but not with loss of 51unC. Of 5hmC-negative gliomas, 70% showed either exclusive or dominant cytoplasmic expression, or no detectable TETI 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. (Am J Pathol 2012, 181: 675-683; http://dx.doLorg/10.1016/j.ajpath.2012.04.017)
引用
收藏
页码:675 / 683
页数:9
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