My Cancer Genome: Genetically Informed Cancer Medicine

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  • CALR
    • CALR c.1154_1155insTTGTC (K385fs*47)
    • CALR c.1099_1150del (L367fs*46)
  • CBFB-MYH11
    • CBFB-MYH11 Inversion
    • CBFB-MYH11 Translocation
  • CEBPA
    • CEBPA Biallelic Mutation
  • DEK-NUP214
    • DEK-NUP214 Fusion
  • DNMT3A
    • DNMT3A c.2644C>T (R882C)
    • DNMT3A c.2644C>G (R882G)
    • DNMT3A c.2644C>A (R882S)
    • DNMT3A c.2645G>A (R882H)
    • DNMT3A c.2645G>T (R882L)
    • DNMT3A c.2645G>C (R882P)
  • FLT3
    • FLT3 ITD
    • FLT3 c.2503G>C (D835H)
    • FLT3 c.2503G>A (D835N)
    • FLT3 c.2503G>T (D835Y)
    • FLT3 c.2504A>C (D835A)
    • FLT3 c.2504A>T (D835V)
    • FLT3 c.2505T>A (D835E)
    • FLT3 c.2505T>G (D835E)
    • FLT3 c.2506A>T (I836F)
    • FLT3 c.2506A>C (I836L)
    • FLT3 c.2506A>G (I836V)
    • FLT3 c.2506_2507delATinsGA (I836D)
    • FLT3 c.2506_2507delATinsCA (I836H)
    • FLT3 c.2508C>G (I836M)
  • IDH1
    • IDH1 c.394C>T (R132C)
    • IDH1 c.394C>G (R132G)
    • IDH1 c.394C>A (R132S)
    • IDH1 c.395G>A (R132H)
    • IDH1 c.395G>T (R132L)
    • IDH1 c.395G>C (R132P)
  • IDH2
    • IDH2 c.418C>G (R140G)
    • IDH2 c.418C>T (R140W)
    • IDH2 c.419G>T (R140L)
    • IDH2 c.419G>A (R140Q)
    • IDH2 c.515G>A (R172K)
    • IDH2 c.515G>T (R172M)
    • IDH2 c.516G>C (R172S)
  • KIT
    • KIT Exon 8 Mutation
    • KIT c.2446G>C (D816H)
    • KIT c.2446G>T (D816Y)
    • KIT c.2446_2447delGAinsAT (D816I)
    • KIT c.2447A>T (D816V)
  • MLL-MLLT3
    • MLL-MLLT3 Fusion
  • NPM1
    • NPM1 Exon 12 Mutations
  • PML-RARA
    • PML-RARA Fusion
  • RBM15-MKL1
    • RBM15-MKL1 Fusion
  • RPN1-EVI1
    • RPN1-EVI1 Inversion
    • RPN1-EVI1 Translocation
  • RUNX1-RUNX1T1
    • RUNX1-RUNX1T1 Fusion
  • TET2
    • TET2 Mutations
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  • What is IDH2?
  • IDH2 in Acute Myeloid Leukemia
  • IDH2 c.516G>C (R172S)
  • 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

  • Chromatin remodeling/DNA methylation
  • Metabolic signaling

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.mycancergenome.org/content/disease/acute-myeloid-leukemia/idh2/?tab=0 (Updated December 4).

Last Updated: December 4, 2015

IDH2 in Acute Myeloid Leukemia

IDH2 is mutated in 9.1% of acute myeloid leukemia cases (COSMIC). Mutations of the R140 or R172 residues both result in a protein with different function; the new function is believed to contribute to leukemogenesis by inhibiting normal epigenetic regulation (Feng et al. 2012; Green et al. 2011; Jeziskova et al. 2010; Shih et al. 2012; Zhou et al. 2012). IDH2 mutations fall outside the “two-hit” theory of leukemogenesis as it was originally conceived. Some have proposed categorizing IDH2 mutations into a new class of mutations; members of the new class—class III—would be defined as mutations occurring in epigenetic modifiers (Naoe and Kiyoi 2013; Shih et al. 2012). Similar to DNMT3A and IDH1 mutations, IDH2 mutations affect DNA methylation and as such, play a role in cancer development through deregulation of gene expression.​​​

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2013. IDH2 in Acute Myeloid Leukemia. My Cancer Genome https://www.mycancergenome.org/content/disease/acute-myeloid-leukemia/idh2/ (Updated October 1).

Last Updated: October 1, 2013

IDH2 c.516G>C (R172S) Mutation in Acute Myeloid Leukemia

Properties
Location of mutation Exon 4 (Ensembl)
Frequency of IDH2 mutations in AML 9.1% (COSMIC)
Frequency of IDH2 R172S mutation in IDH2-mutated AML < 1% (COSMIC)
Implications for Targeted Therapeutics
Response to FLT3 inhibitors Unknown at this time
Response to MEK inhibitors Unknown at this time
Response to JAK2 inhibitors Unknown at this time

The R172S mutation results in an amino acid substitution at position 172 in IDH2, from an arginine (R) to a serine (S). The prognostic significance of this mutation is unclear (Dohner and Gaidzik 2011; Shih et al. 2012). In patients with normal karyotype and an NPM1 mutation, IDH2 mutations are associated with favorable prognosis in AML (Patel et al. 2012). ​

Contributors: Scott Wheeler, Ph.D. (through June 2014), Adam Seegmiller, M.D., Ph.D., Cindy L. Vnencak-Jones, Ph.D.

Suggested Citation: Wheeler, S., A. Seegmiller, C. Vnencak-Jones. 2013. IDH2 c.516G>C (R172S) Mutation in Acute Myeloid Leukemia. My Cancer Genome https://www.mycancergenome.org/content/disease/acute-myeloid-leukemia/idh2/272/ (Updated September 9).

Last Updated: September 9, 2013

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Disclaimer: The information presented at MyCancerGenome.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.

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