• What is IDH2?
  • IDH2 in Glioma
  • IDH2 c.514A>T (R172W)
  • Clinical Trials

IDH2

Isocitrate dehydrogenase 2 (NADP+), mitochondrial (IDH2) is a gene that encodes an epigenetic modifier, a NADP(+)-dependent enzyme that is found in mitochondria (Gene 2013). Wild type IDH2 converts isocitrate to α-ketoglutarate, a step in the Krebs cycle, an important metabolic pathway that affects many other cellular biochemical processes (Shih et al. 2012).

IDH2 is frequently mutated in glioma, acute myeloid leukemia, and myelodysplastic syndromes (Haferlach et al. 2014; Walter et al. 2013; Yang et al. 2012). Mutations generally involve point mutations at the R140 and R172 residues of the protein. Mutations in IDH1 and IDH2 result in deleterious “gain of function”: instead of converting isocitrate to α-ketoglutarate, mutated IDH1 or IDH2 converts isocitrate to 2-hydroxyglutarate (Shih et al. 2012; Yang et al. 2012). 2-hydroxyglutarate inhibits other proteins involved in epigenetic regulation (Shih et al. 2012).

Related Pathways

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D., Stephen W. Clark, M.D., Ph.D., Annette S. Kim, M.D., Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones, S. Clark, A. Kim. 2015. IDH2. My Cancer Genome https://www.padiracinnovation.org/content/disease/glioma/idh2/?tab=0 (Updated December 4).

Last Updated: December 4, 2015

IDH2 in Glioma

IDH2 is mutated in 1.7% of glioma cases (COSMIC). IDH2 mutations account for 5–10% of all IDH mutations in glioma and occur at codon 172 with similar functional consequences (Dang, Jin, and Su 2010). Mutations of the R140 or R172 residues both result in a protein with different function; the new function is believed to contribute to carcinogenesis and tumor growth (Dang, Jin, and Su 2010).​

Contributors: Ty W. Abel, M.D., Ph.D., Kenneth D. Aldape, M.D., Stephen W. Clark, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D., Bret Mobley, M.D., M.S.

Suggested Citation: Abel, T., K. Aldape, S. Clark, C. Vnencak-Jones, B. Mobley. 2014. IDH2 in Glioma. My Cancer Genome https://www.padiracinnovation.org/content/disease/glioma/idh2/ (Updated September 9).

Last Updated: September 9, 2014

IDH2 c.514A>T (R172W) Mutation in Glioma

Properties
Location of mutation Exon 4 (Ensembl)
Frequency of IDH2 mutations in glioma 1.7% (COSMIC)
Frequency of IDH2 R172W mutation in IDH2-mutated glioma 8.2% (COSMIC)
Implications for Targeted Therapeutics
Response to IDH2 inhibitors Unknown at this timea
Response to VEGF antibodies/inhibitors Unknown at this time

The R172W mutation results in an amino acid substitution at position 172 in IDH2, from an arginine (R) to a tryptophan (W).

a In a phase I study of 48 patients with IDH2-mutated hematologic malignancies, of the 32 evaluable patients, treatment with the IDH2 inhibitor AG-221 resulted in 12 patients with complete responses, 8 patients with partial responses, 5 patients with stable disease, and 7 patients with progressive disease. Of the remaining 16 patients, 8 died before analysis at 28 days and 8 were not evaluable at time of analysis because they hadn’t been on the drug 28 days (NCT01915498; Stein et al. 2014). A parallel phase I study of AG-221 in patients with IDH2-mutated solid tumors is ongoing.

Contributors: Ty W. Abel, M.D., Ph.D., Kenneth D. Aldape, M.D., Stephen W. Clark, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D., Bret Mobley, M.D., M.S.

Suggested Citation: Abel, T., K. Aldape, S. Clark, C. Vnencak-Jones, B. Mobley. 2015. IDH2 c.514A>T (R172W) Mutation in Glioma. My Cancer Genome https://www.padiracinnovation.org/content/disease/glioma/idh2/318/ (Updated October 8).

Last Updated: October 8, 2015

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