title: Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2.
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.
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Guilhamon
authors.forename: Malihe
authors.initials: M
authors.lastname: Eskandarpour
authors.forename: Dina
authors.initials: D
authors.lastname: Halai
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Wilson
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.forename: Valenti
authors.initials: V
authors.lastname: Gomez
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
authors.forename: Roberto
authors.initials: R
authors.lastname: Tirabosco
authors.forename: M
authors.initials: M
authors.lastname: Fernanda Amary
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.forename: Gernot
authors.initials: G
authors.lastname: Jundt
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ross
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
mesh_terms: D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002813:Chondrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C081976:EBF1 protein, human; D005977:Glutarates; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human