Isocitrate dehydrogenase mutations in gliomas

Neuro Oncol. 2016 Jan;18(1):16-26. doi: 10.1093/neuonc/nov136. Epub 2015 Jul 16.

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.

Keywords: D-2-hydroxyglutarate; brain tumor metabolism; epigenetics; glioma genetics; isocitrate dehydrogenase mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Glioblastoma / enzymology
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glioma / enzymology*
  • Glioma / genetics*
  • Glioma / metabolism
  • Glutarates / metabolism
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Ketoglutaric Acids / metabolism
  • Mutation*

Substances

  • Glutarates
  • Ketoglutaric Acids
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human