Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2

Paul Guilhamon, Malihe Eskandarpour, Dina Halai, Gareth A. Wilson, Andrew Feber, Andrew E. Teschendorff, Valenti Gomez, Alexander Hergovich, Roberto Tirabosco, M. Fernanda Amary, Daniel Baumhoer, Gernot Jundt, Mark T. Ross, Adrienne M. Flanagan and Stephan Beck ()
Additional contact information
Paul Guilhamon: Medical Genomics, UCL Cancer Institute, University College London
Malihe Eskandarpour: Genetics and Cell Biology of Sarcoma, UCL Cancer Institute, University College London
Dina Halai: Royal National Orthopaedic Hospital NHS Trust
Gareth A. Wilson: Medical Genomics, UCL Cancer Institute, University College London
Andrew Feber: Medical Genomics, UCL Cancer Institute, University College London
Andrew E. Teschendorff: Statistical Cancer Genomics, UCL Cancer Institute, University College London
Valenti Gomez: Tumour Suppressor Signalling Networks, UCL Cancer Institute, University College London
Alexander Hergovich: Tumour Suppressor Signalling Networks, UCL Cancer Institute, University College London
Roberto Tirabosco: Royal National Orthopaedic Hospital NHS Trust
M. Fernanda Amary: Royal National Orthopaedic Hospital NHS Trust
Daniel Baumhoer: Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel
Gernot Jundt: Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel
Mark T. Ross: Illumina Cambridge Ltd., Chesterford Research Park
Adrienne M. Flanagan: Genetics and Cell Biology of Sarcoma, UCL Cancer Institute, University College London
Stephan Beck: Medical Genomics, UCL Cancer Institute, University College London

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3166

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