Abstract
Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation.
Highlights
Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS)
The mutant IDH enzyme catalyses the reduction of a-ketoglutarate (a-KG) to D-2-hydroxyglutarate (2-HG), an oncometabolite affecting the activity of a-KG–dependent dioxygenases[6]: these events affect a number of cellular responses, and have been shown to induce CpG island DNA hypermethylation in low-grade gliomas (LGGs)[7], CCs5 and AMLs8 harbouring IDH1 and IDH2 mutations
The effects of gain-of-function mutations in the IDH1/2 enzymes on the methylome have been extensively studied in the context of AML and LGG, and more recently in CC5,7,8
Summary
Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. In a minority of individuals, these tumours are multiple, and affected individuals are at risk of developing other neoplasms, including spindle cell haemangiomas, and highgrade gliomas/secondary glioblastomas, among others[3]. In this setting, the mosaic distribution of tumours is caused by somatic early post-zygotic mutations of IDH1 and IDH2 We aimed to identify the shared and tissue-specific processes by profiling the methylome of central CS with and without IDH mutations, and performing a meta-analysis of the publically available data sets from LGG, AML, CC and our CS data
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