title: 2-Hydoxyglutarate: D/Riving Pathology in gLiomaS.
abstract: Common pathways and mechanisms can be found in both cancers and inborn errors of metabolism. 2-Hydroxyglutarate (2-HG) acidurias and isocitrate dehydrogenase (IDH) 1/2 mutant tumors are examples of this phenomenon. 2-HG can exist in two chiral forms, D(R)-2-HG and L(S)-2-HG, which are elevated in D- and L-acidurias, respectively. D-2-HG was subsequently discovered to be synthesized in IDH 1/2 mutant tumors including ∼70% of intermediate-grade gliomas and secondary glioblastomas (GBM). Recent studies have revealed that L-2-HG is generated in hypoxia in IDH wild-type tumors. Both 2-HG enantiomers have similar structures as α-ketoglutarate (α-KG) and can competitively inhibit α-KG-dependent enzymes. This inhibition modulates numerous cellular processes, including histone and DNA methylation, and can ultimately impact oncogenesis. D-2-HG can be detected in vivo in glioma patients and animal models using advanced imaging modalities. Finally, pharmacologic inhibitors of mutant IDH 1/2 attenuate the production of D-2-HG and show great promise as therapeutic agents.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Wahl
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000502:physiology
chemical_list: C000609670:2-hydoxyglutarate; D005977:Glutarates; D007521:Isocitrate Dehydrogenase
keywords: 2-hydroxyglutarate; epigenetics; isocitrate dehydrogenase mutations; methylation