Genetic Characterization of Ten-Eleven-Translocation Methylcytosine Dioxygenase Alterations in Human Glioma

Abstract

The molecular mechanisms leading to brain tumors still remain unclear. Nevertheless, there is increasing evidence that epigenetic effects play crucial roles in tumor development and progression. Thereby, 5-hydroxymethylcytosine (5hmC) represents a further base modification of cytosine besides 5-methylcytosine (5mC). In addition to the role of 5hmC as an intermediate in demethylation, 5hmC is of reasonable importance for cellular control. Previous studies showed that loss of 5hmC is a hallmark of human malignancies, e.g. in glioma, melanoma, and myeloid tumors. In myeloid malignancies studies showed that loss of 5hmC was due to mutations within ten-eleven-translocation (TET) genes, enzymes being responsible for conversion of 5mC to 5hmC. Nevertheless, till date there are no genetic characterization data of TET enzymes available for glioma.In this study, we genetically characterized TET2 and TET3 alterations in 50 human gliomas (WHO-Grade II-IV) and in 19 healthy brain samples. We identified 7 genetic alterations within TET2 (p.V218M, p.G355N, p.P363L, p.L1721W, p.P1723S, p.I1762V, p.H1778R). Additionally, we performed quantification of 5hmC amount and added functional prediction analysis of identified TET alterations to evaluate the biological impact of these alterations on the hydroxymethylome. An analysis of TET3 showed no non-synonymous alterations.In summary, we did not find correlations of TET alterations with 5hmC amount. Thus, our data emphasize that, in contrast to leukemia, loss of 5hmC in glioma is not caused by TET gene alterations. Moreover, other disturbances, such as disrupted gene expressions or functional inhibitions of TET proteins may be responsible for the aberrant epigenome of human glioma.

Repression of the expression of TET2 by ZEB1 contributes to invasion and growth in glioma cells

“…Human brain tissue exhibits high levels of 5hmC, and there is loss of 5hmC in brain tumors leading to a disturbance of hydroxymethylome (24). However, in a previous study by Kraus et al (25) no correlation was found between alterations in TETs and the levels of 5hmC in gliomas. This suggests other disturbances, including disrupted gene expression or functional inhibition of TET proteins, may be responsible for the aberrant epigenome of gliomas.…”

TET2 in Normal and Malignant Hematopoiesis

“…CpG-island hypermethylator phenotypes (CIMPs) have also been identified in low-grade gliomas, as well as some glioblastoma patients. Although TET2 promoter methylation has been identified in glioma , the predominant mechanism appears to be driven by mutations in IDH1, with few loss-of-function mutations present in TET2 (Kraus et al 2015). This is in stark contrast to MPN and AML studies in which TET2, IDH1, and IDH2 mutations are all present.…”

A benign course of MDS with del 7q and ASXL1 mutation

“…Mutations in TET2 gene are detected in 19% MDS patients and are associated with poor overall survival in intermediate risk AML. 7 We identified missense variant c. 5162 T>G, p. L1721W (rs34402524) in TET2 gene with polyphen score (0.0643) and possibly damaging status. This missense variant however it is not considered as true missense mutation because it lies on non conserved domain of TET2.…”

“…This missense variant however it is not considered as true missense mutation because it lies on non conserved domain of TET2. 7 Mutations in ASXL1 gene are detected in 11-22% of MDS and are generally associated with aggressive diseases and poor outcome. [1][2][3] We found p.Q1039Ter mutation in exon 13 of ASXL1 in our patient.…”