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

Müller, Timo; Gessi, Marco; Waha, Anke; Isselstein, Lukas Jan; Luxen, D; Freihoff, D; Freihoff, J; Becker, Albert; Simon, Matthias; Hammes, Jennifer; Denkhaus, Dorota; Mühlen, Anja zur; Pietsch, Torsten; Waha, Andreas

doi:10.1016/j.ajpath.2012.04.017

Cited by 96 publications

(93 citation statements)

References 28 publications

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“…reported that a loss of 5hmC is attributable to the nuclear exclusion of TET1 from the nuclei of glioma cells [35]. Peng Xiao et al determined that KKRK, a nuclear localization signal of mouse TET3, is conserved and located in the C-terminus and mediated by importin (a type of nuclear pore complex) which can catalyze the 5mC into 5hmC in the nucleus [10,36,37].…”

Section: Discussionmentioning

confidence: 98%

Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype

Tsai

Chen

et al. 2015

Breast Cancer Res Treat

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DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.

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Section: Discussionmentioning

confidence: 98%

Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype

Tsai

Chen

et al. 2015

Breast Cancer Res Treat

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“…In addition, some brain tumors have been shown to have prognostically lower 5hmC levels than normal brain tissue. Despite this, there has been no correlation with IDH mutations and 5hmC levels in these cancers to date [91,[143][144][145]. It therefore raises the possibility that IDH mutations may drive oncogenesis through alternative pathways to 5hmC.…”

Section: Hmc Patterns In Cancermentioning

confidence: 91%

5-Hydroxymethylcytosine Profiling as an Indicator of Cellular State

et al. 2013

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DNA methylation is widely studied in the context of cancer. However, the rediscovery of 5-hydroxymethylation of DNA adds a new layer of complexity to understanding the epigenetic basis of development and disease, including carcinogenesis. There have been significant advances in techniques for the detection of 5-hydroxymethylcytosine and, with this, greater insight into the distribution, regulation and function of this mark, which are reviewed here. Better understanding of the associated pathways involved in regulation of, and by, 5-hydroxymethylcytosine may give promise to new therapeutic targets. We discuss evidence to support the view of 5-hydroxymethylcytosine as a unique and dynamic mark of cellular state. These 5-hydroxymethylcytosine profiles may offer optimism for the development of diagnostic, prognostic and predictive biomarkers.

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“…In glioma, a tumor phenotype known as the CpG island methylator phenotype is highly associated with IDH1 mutations ( 45 ). Although TET loss-of-function mutations have not been observed in gliomas, both silencing of TET2 by promoter hypermethylation ( 46 ) and nuclear exclusion of TET1 ( 47 ) the TET enzymes may play a role in disease pathogenesis. In cholangiocarcinomas and chondrosarcomas, IDH mutations are associated with DNA hypermethylation of CpG islands in a manner also seen in glioblastomas and AML ( 20,21 ).…”

Section: Epigenetic Regulationmentioning

confidence: 99%

Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities

2013

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Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutant enzymes acquire a neomorphic activity that converts α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D2HG), a rare metabolite. In cells and tissues expressing mutant IDH, D2HG concentrations are highly elevated. D2HG may act as an "oncometabolite" by inhibiting a class of α-KG-dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling. Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation.Signifi cance: Mutations in IDH1 and IDH2 promote the development of a number of malignancies. These active site mutations cause a gain-of-function leading to the accumulation of the rare metabolite D2HG. Mouse models of these mutations should provide insights into the mechanisms driving tumorigenesis and facilitate evaluation of new treatments. Cancer Discov; 3(7); 730-41.

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

Cited by 96 publications

References 28 publications

Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype

Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype

5-Hydroxymethylcytosine Profiling as an Indicator of Cellular State

Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities

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