Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 in tumors

F.G. Schaap, P.J. French, J.V. Bovee

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Heterozygous hotspot mutations in isocitrate dehydrogenases (IDH) IDH1 or IDH2 are frequently observed in specific types of cartilaginous tumors, gliomas, and leukemias. Mutant IDH enzyme loses its normal activity to convert isocitrate into alpha-ketoglutarate (alphaKG) and instead acquires the ability to reduce alphaKG to D-2-hydroxyglutarate. Through direct competition with alphaKG, accumulation of the oncometabolite D-2-hydroxyglutarate in IDH mutated tumors results in inhibition of alphaKG-dependent dioxygenases involved in DNA and histone demethylation. Apart from epigenetic alterations, perturbations in the tricarboxylic acid cycle (depletion of intermediates) and activation of the intricately linked hypoxia signaling pathway are apparent in IDH mutated cells. As molecular details are being unraveled, the emerging concept is that IDH mutations result in tumor formation by epigenetic alterations that affect gene expression and result in inhibition of cellular differentiation. Activation of hypoxic stress signaling reprograms cellular energy metabolism and promotes anabolic processes and angiogenesis, thus, providing an advantage to promote neoplastic growth.
Original languageEnglish
Pages (from-to)32-38
Number of pages7
JournalAdvances in Anatomic Pathology
Volume20
Issue number1
DOIs
Publication statusPublished - 1 Jan 2013

Keywords

  • epigenome
  • hypoxic signaling
  • IDH mutation
  • tumor metabolism
  • HYPOXIA-INDUCIBLE FACTOR-1-ALPHA
  • OLLIER-DISEASE
  • ONCOMETABOLITE 2-HYDROXYGLUTARATE
  • SOMATIC MUTATIONS
  • CARTILAGE TUMORS
  • GENOMIC ANALYSIS
  • CELL
  • EXPRESSION
  • CHONDROSARCOMA
  • 5-HYDROXYMETHYLCYTOSINE

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