From Compendium of Cancer Genome Aberrations
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Primary Author(s)*

Paul De Fazio, MSc, Monash Health


Isocitrate Dehydrogenase (NADP(+)) 2 Mitochondrial, Isocitrate Dehydrogenase 2 (NADP+) Mitochondrial, Oxalosuccinate Decarboxylase, NADP(+)-Specific ICDH, ICD-M, IDH, IDP, Isocitrate Dehydrogenase [NADP] Mitochondrial, MNADP-IDH, D2HGA2, IDHM, IDPM

Genomic Location

Cytoband: 15q26.1

Genomic Coordinates:

chr15:90,626,277-90,645,736 [hg19]

chr15:90,083,045-90,102,554 [hg38]

Cancer Category/Type

  • Glioblastoma

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  • Astrocytoma

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  • Oligodendroglioma

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  • Chondrosarcoma

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  • Intrahepatic cholangiocarcinoma

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  • Acute myeloid leukaemia

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  • Myelodysplastic syndrome

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  • Angioimmunoblastic T-cell lymphoma

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Gene Overview

Structure and function

IDH1 and IDH2 encode the two NADP+-dependent isocitrate dehydrogenases in humans. IDH1 and IDH2 share approximately 70% sequence homology. There are five IDH genes in total in the human genome encoding three distinct IDH enzymes: IDH1, IDH2, and IDH3, an NAD+-dependent isocitrate dehydrogenase unrelated to IDH1 or IDH2. While IDH1 is localised to the cytoplasm and in peroxisomes, IDH2 and IDH3 are mitochondrial.

NADP+-dependent isocitrate dehydrogenases function as homodimers to catalyse the reversible NADP-dependent oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (αKG), a key molecule in the tricarboxylic acid (TCA) cycle. In the process, NADP+ is reduced into NADPH which is required for cellular detoxification processes.

IDH2 is highly expressed in mammalian heart and muscle tissue and in activated lymphocytes, with moderate expression elsewhere [1,2]. The IDH2 protein contains an N-terminal mitochondrial signal peptide, which allows for its mitochondrial localization [3]. Less is known about the structure of human IDH2 than of IDH1, although studies on porcine IDH2 indicate that they are largely similar [4]. Both IDH1 and IDH2 function by combining two IDH subunits to create binding sites for the substrate along with NADP+ and a metal ion [4]. Crucially, the Arg172 (NM_002168.2/NP_002159.2) residue of IDH2 demonstrates similar functional importance as the equivalent Arg132 (NM_005896.2/NP_005887.2) residue of IDH1 [3,4]. In IDH2, the Arg140 (NM_002168.2/NP_002159.2) residue situated adjacent to Arg172 in the active site additionally forms hydrogen bonds with the isocitrate substrate, and so likely also has an important functional role [5].

IDH2 plays a role in the regulation of oxidative respiration in multiple tissues. There is evidence that in the heart and in glioma cells, IDH2 regulates the TCA cycle by reverse flux, catalysing the conversion of αKG and NADPH to isocitrate and NADP+ [5,6]. This has led to the proposal of an isocitrate/αKG cycle wherein IDH2 functions in the reverse direction and IDH3 in the forward (i.e. isocitrate to αKG), thereby maintaining tight control of flux through the TCA cycle [7,8].

NADP+-dependent isocitrate dehydrogenases are upregulated after oxidative insult and can modulate the availability of αKG, itself a potent antioxidant [9]. Overexpression of IDH2 confers protection against oxidative DNA damage and increases survival after oxidant exposure, implicating it in the same oxidative defence pathways as IDH1[10]. IDH2 also protects against ionising radiation [11,12], exposure to high glucose [13], treatment with tumor necrosis factor-alpha (TNF-α) [14], and apoptosis induced by heat-shock [13].

Germline mutations in IDH2 are rare, but result in D-2-hydroxyglutaric aciduria, which can cause developmental delay, epilepsy, and cardiomyopathy, among other presentations [15].

Role in Cancer

IDH2 mutations are seen much less frequently in glioma than IDH1 mutations, with a frequency of 0-3% in grade 2 and 3 glioma and secondary glioblastoma [8,16]. IDH1 and IDH2 mutations in these malignancies are often mutually exclusive, suggesting overlapping pathogenic effects [16,17]. IDH2 mutations are also seen at low frequency in other solid tumors including chondrosarcoma and intrahepatic cholangiocarcinoma (ICC) [18,19]. Like IDH1 mutations, alterations in IDH2 are associated with a younger age at diagnosis in adults and improved survival relative to wild-type IDH2 in glioma, presumably due to increased sensitivity to therapy [16,20]. However, IDH2 mutations predict decreased overall survival in chondrosarcoma [21].

The frequency of IDH2 mutations in AML is higher, with studies indicating mutation rates of up to 15% [8,22]. The younger diagnostic age seen in IDH2-mutated glioma appears to hold true for AML in adult patients, but the prognostic impact of IDH2 mutations is unclear and may depend on the specific mutation, with Arg140 (NM_002168.2/NP_002159.2) mutations having more favorable prognostic outlook than Arg172 (NM_002168.2/NP_002159.2) mutations [23–26].

IDH2 R172 mutations also appear in approximately 20% of angioimmunoblastic T-cell lymphomas (AITL) (but not in other lymphomas), although they do not provide prognostic information [27]. In AITL, IDH2 R172 mutations define a subgroup with a distinct gene expression signature, and when paired with TET2 mutations correlate with a gene expression profile indicative of a T follicular helper cell (TFH) phenotype rather than that of other T helper cells, possibly through downregulation of non-TFH differentiation genes [28].

IDH2 mutations in cancer are almost invariably heterozygous affecting the Arg172 residue, except in AML where mutations in Arg140 have also been observed [5,8,16]. Like in IDH1 Arg132 (NM_005896.2/NP_005887.2) mutations, alterations in IDH2 Arg172 decrease enzyme affinity for isocitrate and hence reduce NADPH production [16,29]. IDH2 R172 and IDH2 R140 mutations result in the same neomorphic enzyme activity as the IDH1 R132 mutant, whereby αKG is reduced to D-2-hydroxyglutarate (2HG) [5,30].

Studies on IDH1 R132 mutants have shown impaired TCA cycle flux under hypoxic conditions, but this doesn’t appear to hold true for IDH2 mutants [31]. IDH2 mutants are, however, affected by the same sensitivity to BAX/BAK-mediated apoptosis [32]. IDH2 mutants also have the same widespread hypermethylation found in IDH1 mutants [22,33]. This is likely caused by 2HG inhibition of αKG-dependent proteins such as the alkB homolog (ALKBH) DNA repair enzyme, the lysine-specific demethylase 4A/B (KDM4A/B) DNA damage response proteins, and the methylcytosine dioxygenase TET2 [34,35]. IDH2-mutant cells show also reduced expression of the DNA damage response gene ATM and, predictably, increased levels of DNA damage [35,36].

Concurrent Mutations

Due to the infrequency of IDH2 mutations relative to IDH1 mutations in glioma, less data exists for concurrent or cooperating mutations. As mentioned, IDH1 and IDH2 mutations often occur in a mutually exclusive manner. IDH2-mutants in glioma appear to show the same pattern of concurrent mutations as do IDH1-mutants, demonstrating increased association with TP53 mutations and lowered association with mutations in other genes common to glioma such as epidermal growth factor receptor (EGFR) amplification, cyclin-dependent kinase inhibitor 2A or 2B (CDKN2A/2B) deletion, and phosphatase or tensin homolog (PTEN) mutations [16].

In AML, where IDH2 mutations are more prevalent, most IDH2-mutant patients have at least one other concurrent mutation in a pathogenic gene [24]. IDH2-mutant AML has a lower incidence of WT1 mutations, a positive association with NPM1 mutations, and a negative association with CEBPA mutations, although these genetic lesions are much more commonly found concomitantly with IDH2 Arg140 (NM_002168.2/NP_002159.2) mutants than with Arg172 (NM_002168.2/NP_002159.2) mutants [23,24]. There is greater incidence of IDH2 mutations in patients with cytogenetically normal or intermediate-risk AML as well as isolated trisomy 8, but lower association in patients with core-binding factor AML or AML with t(15;17)[23,24]. TET2 mutations occur at high frequency in AML but are mutually exclusive with IDH2 mutations, consistent with the notion that TET2 inhibition is a pathogenic factor in IDH2 mutant AML [22]. In AITL, however, IDH2 and TET2 mutations are commonly found together [28].

Therapeutic Implications

In ICC cells, IDH2 mutations confer sensitivity to the multikinase inhibitor dasatinib due to their dependence on the kinase SRC for mTOR-mediated proliferation [37]. Overexpression of mutant IDH2 in glioblastoma cells increases their sensitivity to radiation [38].

An IDH2-mutant inhibitor, enasidenib, suppresses 2HG production, reverses epigenetic dysregulation, and induces cellular differentiation in IDH2-mutated AML. It has shown response rates of approximately 40% in relapsed and refractory AML patients and a remission rate of 19% [39]. IDH2-mutant AML is also more susceptible to venetoclax therapy owing to increased sensitivity to BAX/BAK-mediated apoptosis [40]. In vitro studies show IDH2-mutant AML is sensitized to radiation, daunorubicin, and the PARP inhibitors olaparib and talazoparib; these phenotypes are reversed by treatment with IDH2-mutant inhibitor [36], suggesting that there may be some benefit in exploiting rather than diminishing the effect of IDH2 mutations in certain malignancies.

Common Alteration Types

Gain-of-function mutations in IDH2 include:

c.419G>A, p.R140Q (NM_002168.2/NP_002159.2)

c.515G>A, p.R172K (NM_002168.2/NP_002159.2)

c.516G>T, p.R172S (NM_002168.2/NP_002159.2)

c.515G>T, p.R172M (NM_002168.2/NP_002159.2)

c.514A>T, p.R172W (NM_002168.2/NP_002159.2)

c.514A>G, p.R172G (NM_002168.2/NP_002159.2)

Copy Number Loss Copy Number Gain LOH Loss-of-Function Mutation Gain-of-Function Mutation Translocation/Fusion

Internal Pages

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EXAMPLE Germline Cancer Predisposition Genes

External Links

IDH2 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

IDH2 by COSMIC - sequence information, expression, catalogue of mutations

IDH2 by CIViC - general knowledge and evidence-based variant specific information

IDH2 by St. Jude ProteinPaint mutational landscape and matched expression data.

IDH2 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

IDH2 by Cancer Index - gene, pathway, publication information matched to cancer type

IDH2 by OncoKB - mutational landscape, mutation effect, variant classification

IDH2 by My Cancer Genome - brief gene overview

IDH2 by UniProt - protein and molecular structure and function

IDH2 by Pfam - gene and protein structure and function information

IDH2 by GeneCards - general gene information and summaries


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