title: Histone 3 lysine 9 trimethylation is differentially associated with isocitrate dehydrogenase mutations in oligodendrogliomas and high-grade astrocytomas.
abstract: Trimethylation of histone 3 lysine 9 (H3K9me3) is a marker of repressed transcription. Cells transfected with mutant isocitrate dehydrogenase (IDH) show increased methylation of histone lysine residues, including H3K9me3, because of inhibition of histone demethylases by 2-hydroxyglutarate. Here, we evaluated H3K9me3 and its association with IDH mutations in 284 gliomas. Trimethylation of H3K9 was significantly associated with IDH mutations in oligodendrogliomas. Moreover, 72% of World Health Organization grade II and 65% of grade III oligodendrogliomas showed combined H3K9me3 positivity and 1p19q codeletion. In astrocytic tumors, H3K9me3 positivity was found in all grades of tumors; it showed a significant relationship with IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas. Finally, H3K9me3-positive grade II oligodendrogliomas, but not other tumor subtypes, showed improved overall survival compared with H3K9me3-negative cases. These results suggest that repressive trimethylation of H3K9 in gliomas may occur in a context-dependent manner and is associated with IDH mutations in oligodendrogliomas but may be differently regulated in high-grade astrocytic tumors. Furthermore, H3K9me3 may define a subset of grade II oligodendrogliomas with better overall survival. Our results suggest variable roles for IDH mutations in the pathogenesis of oligodendrogliomas versus astrocytic tumors.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.forename: Michelle Madden
authors.initials: MM
authors.lastname: Felicella
authors.forename: Thomas
authors.initials: T
authors.lastname: Coyne
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.forename: Daniel
authors.initials: D
authors.lastname: Gorovets
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.forename: Julia
authors.initials: J
authors.lastname: Kofler
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sullivan
authors.forename: Mariarita
authors.initials: M
authors.lastname: Santi
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Judkins
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D002648:Child; D019175:DNA Methylation / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D006649:Histocompatibility Antigens; D006657:Histones; D007521:Isocitrate Dehydrogenase; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase