title: Isocitrate dehydrogenase mutations in gliomas.
abstract: Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg(132) of IDH1 and Arg(172) of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2 mutations on molecular classification and glioma therapy.
authors.affiliation: The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute at Duke, and Department of Pathology, Duke University Medical Center, Durham, North Carolina (M.S.W., B.H.D., H.Y.).
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Waitkus
authors.affiliation: The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute at Duke, and Department of Pathology, Duke University Medical Center, Durham, North Carolina (M.S.W., B.H.D., H.Y.).
authors.forename: Bill H
authors.initials: BH
authors.lastname: Diplas
authors.affiliation: The Preston Robert Tisch Brain Tumor Center at Duke, Pediatric Brain Tumor Foundation Institute at Duke, and Department of Pathology, Duke University Medical Center, Durham, North Carolina (M.S.W., B.H.D., H.Y.).
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D007656:Ketoglutaric Acids / Q000378:metabolism; D009154:Mutation
chemical_list: D005977:Glutarates; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: D-2-hydroxyglutarate; brain tumor metabolism; epigenetics; glioma genetics; isocitrate dehydrogenase mutations