TET2promoter methylation in low-grade diffuse gliomas lackingIDH1/2mutations: Figure 1

Abstract

Background Miscoding mutations of the TET2 gene, which encodes the a-ketoglutarate-dependent enzyme that catalyses the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, thus producing DNA demethylation, have been detected in 10e25% of acute myeloid leukaemias lacking IDH1/2 mutations. Most low-grade diffuse gliomas carry IDH1/2 mutations (>85%), but molecular mechanisms of pathogenesis in those lacking IDH1/2 mutations remain to be elucidated. Methods Miscoding mutations and promoter methylation of the TET2 gene were screened for in 29 low-grade diffuse gliomas lacking IDH1/2 mutations. Results Single-strand conformational polymorphism followed by direct sequencing showed the absence of miscoding mutations in TET2. Methylation-specific PCR revealed methylation of the TET2 promoter in 5 of 35 cases (14%). In contrast, none of 38 low-grade diffuse gliomas with IDH1/2 mutations had TET2 promoter methylation (p¼0.0216). Conclusion Results suggest that TET2 promoter methylation, but not TET2 mutation, may be an alternative mechanism of pathogenesis in a small fraction of low-grade diffuse gliomas lacking IDH1/2 mutations.

5-Hydroxymethylcytosine: An epigenetic mark frequently deregulated in cancer

“…2, 3). Interestingly, TET2 mutations have not been reported, or are very rare, in other malignancies where 5hmC levels are affected, including brain tumors and melanoma [31][32][33].…”

“…In glioma, TET2 mutations have not been described; however TET2 promoter methylation has been detected in 14% of low-grade glioma patients without IDH mutation [32]. Since promoter methylation is associated with transcriptional repression, this suggests a decreased TET2 expression in these patients, possibly leading to decreased levels of 5hmC.…”

IDHmutations: new genetic signatures in cholangiocarcinoma and therapeutic implications

“…This suggests that there may be parallel mechanisms outside of mutant IDH activity that can promote a phenotypically similar CpG island methylator phenotype. In support, inactivation of TET2 function through mutation or promoter methylation in AML samples promotes a pattern of DNA hypermethylation that is similar to IDH1/2-mutant samples, suggesting functional redundancy between these two gene families [11,18]. Together, these observations suggest that agents that inhibit DNA methyltransferases (e.g., 5-azacytidine and 5-aza-2´-deoxycytidine) could provide a beneficial treatment strategy in these tumors.…”

TET2 (tet methylcytosine dioxygenase 2)

“…No TET2 mutation was found but TET2 promoter methylation was detected in 5 of 35 cases (14%). No TET2 alteration was observed in all cases with IDH1/2 mutation (Kim et al, 2011).…”