• What is IDH1?
  • IDH1 in Glioma
  • IDH1 c.395G>A (R132H)
  • Clinical Trials

IDH1

Isocitrate dehydrogenase 1 (NADP+), soluble (IDH1) is a gene that encodes an epigenetic modifier, a NADP(+)-dependent enzyme that catalyzes oxidative decarboxylation of isocitrate (Gene 2013). Wild type IDH1 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).

IDH1 is frequently mutated in glioma and acute myeloid leukemia, myelodysplastic syndromes, and other cancer types (Rohle et al. 2013; Walter et al. 2013). Mutations generally involve point mutations at the R132 residue of the protein, although a synonymous variant (G105G) has been found to be prognostically relevant in AML. 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 A. Strickland, M.D., MSCI, Annette S. Kim, M.D., Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones, S. Strickland, A. Kim. 2015. IDH1. My Cancer Genome https://www.padiracinnovation.org/content/disease/glioma/idh1/?tab=0 (Updated December 4).

Last Updated: December 4, 2015

IDH1 in Glioma

IDH1 is mutated in the majority of lower grade diffuse gliomas (grades II–III) and also in most secondary glioblastomas. It is rare (5–8%) in newly diagnosed glioblastoma. IDH1 mutations occur in 32% of glioma cases (COSMIC). Mutations of the R132 residue in IDH1 result in a protein with different function; the new function is believed to contribute to carcinogenesis and tumor growth. The majority (80–90%) of IDH1 mutations in glioma are R132H.​

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. IDH1 in Glioma. My Cancer Genome https://www.padiracinnovation.org/content/disease/glioma/idh1/ (Updated June 18).

Last Updated: June 18, 2015

IDH1 c.395G>A (R132H) Mutation in Glioma

Properties
Location of mutation Exon 4 (Ensembl)
Frequency of IDH1 mutations in glioma 33.0% (COSMIC)
Frequency of IDH1 R132H mutation in IDH1-mutated glioma 87.6% (COSMIC)
Implications for Targeted Therapeutics
Response to IDH1 inhibitors Unknown at this timea
Response to VEGF antibodies/inhibitors Unknown at this time

The R132H mutation results in an amino acid substitution at position 132 in IDH1, from an arginine (R) to a histidine (H).

a In a phase I study of patients with IDH1-mutated AML or MDS, treatment with the IDH1 inhibitor AG-120 resulted in a 50% response rate; four of seven responses were complete responses (Pollyea et al. 2014). A parallel phase I study of AG-120 in patients with IDH1-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. IDH1 c.395G>A (R132H) Mutation in Glioma. My Cancer Genome https://www.padiracinnovation.org/content/disease/glioma/idh1/263/ (Updated October 8).

Last Updated: October 8, 2015

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