Difference between revisions of "IDH2"

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==Primary Author(s)*==
 
==Primary Author(s)*==
  
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Paul De Fazio, MSc, Monash Health
  
 
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Revision as of 09:44, 3 August 2018

Primary Author(s)*

Paul De Fazio, MSc, Monash Health

Synonyms

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, astrocytoma, oligodendroglioma, chondrosarcoma, intrahepatic cholangiocarcinoma, acute myeloid leukaemia, myelodysplastic syndrome, angioimmunoblastic T-cell lymphoma

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 localisation[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 plays 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 tumour 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 tumours including chondrosarcoma and intrahepatic cholangiocarcinoma (ICC)[18,19]. Like IDH1 mutations, mutations 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 favourable 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 appear to 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 mutations 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, mutations in IDH2 Arg172 decrease enzyme affinity for isocitrate and hence reduce NADPH production16,29. 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 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 sensitised 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

Put your text here and/or fill in the table with an X where applicable

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

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)

EXAMPLE: X

Internal Pages

Put your text here

EXAMPLE Germline Cancer Predisposition Genes

External Links

Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.

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

References

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2. Luo, H., Shan, X. & Wu, J. Expression of human mitochondrial NADP‐dependent isocitrate dehydrogenase during lymphocyte activation. J. Cell. Biochem. 60, 495–507 (1996). PMID: 8707889

3. Nekrutenko, A., Hillis, D. M., Patton, J. C., Bradley, R. D. & Baker, R. J. Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family. Mol. Biol. Evol. 15, 1674–1684 (1998). PMID: 9866202

4. Ceccarelli, C., Grodsky, N. B., Ariyaratne, N., Colman, R. F. & Bahnson, B. J. Crystal Structure of Porcine Mitochondrial NADP+-dependent Isocitrate Dehydrogenase Complexed with Mn2+ and Isocitrate. INSIGHTS INTO THE ENZYME MECHANISM. J. Biol. Chem. 277, 43454–43462 (2002). PMID: 12207025

5. Ward, P. S. et al. The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate. Cancer Cell 17, 225–234 (2010). PMID: 20171147

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9. Mailloux, R. J. et al. The Tricarboxylic Acid Cycle, an Ancient Metabolic Network with a Novel Twist. PLoS ONE 2, e690 (2007). PMID: 17668068

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11. Lee, S. ‐H. et al. Role of NADP+‐dependent isocitrate dehydrogenase (NADP+‐ICDH) on cellular defence against oxidative injury by γ‐rays. Int. J. Radiat. Biol. 80, 635–642 (2004). PMID: 15586883

12. Lee, J. H., Kim, S. Y., Kil, I. S. & Park, J.-W. Regulation of Ionizing Radiation-induced Apoptosis by Mitochondrial NADP + -dependent Isocitrate Dehydrogenase. J. Biol. Chem. 282, 13385–13394 (2007). PMID: 17350954

13. Shin, S. W., Kil, I. S. & Park, J.-W. Silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase by small interfering RNA enhances heat shock-induced apoptosis. Biochem. Biophys. Res. Commun. 366, 1012–1018 (2008). PMID: 18096511

14. Kil, I. S., Kim, S. Y., Lee, S. J. & Park, J.-W. Small interfering RNA-mediated silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase enhances the sensitivity of HeLa cells toward tumor necrosis factor-α and anticancer drugs. Free Radic. Biol. Med. 43, 1197–1207 (2007). PMID: 17854715

15. Kranendijk, M. et al. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330, 336 (2010). PMID: 20847235

16. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). PMID: 23532369

17. Hartmann, C. et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. (Berl.) 118, 469–474 (2009). PMID: 19554337

18. Amary, M. F. et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334–343 (2011). PMID: 21598255

19. Borger, D. R. et al. Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in Cholangiocarcinoma Identified Through Broad-Based Tumor Genotyping. The Oncologist 17, 72–79 (2012). PMID: 22180306

20. Houillier, C. et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75, 1560–1566 (2010). PMID: 20975057

21. Lugowska, I. et al. IDH1/2 Mutations Predict Shorter Survival in Chondrosarcoma. J. Cancer 9, 998–1005 (2018). PMID: 29581779

22. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation. Cancer Cell 18, 553–567 (2010). PMID: 21130701

23. Green, C. L. et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood 118, 409–412 (2011). PMID: 21596855

24. Chou, W.-C. et al. The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 25, 246–253 (2011). PMID: 21079611

25. Aref, S. et al. Prevalence and Clinical Effect of IDH1 and IDH2 Mutations Among Cytogenetically Normal Acute Myeloid Leukemia Patients. Clin. Lymphoma Myeloma Leuk. 15, 550–555 (2015). PMID: 26189213

26. Yamaguchi, S. et al. IDH1 and IDH2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1 mutation. Eur. J. Haematol. 92, 471–477 (2013). PMID: 24443894

27. Cairns, R. A. et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119, 1901–1903 (2012). PMID: 22215888

28. Wang, C. et al. IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood 126, 1741–1752 (2015). PMID: 26268241

29. Soundar, S., Danek, B. L. & Colman, R. F. Identification by Mutagenesis of Arginines in the Substrate Binding Site of the Porcine NADP-dependent Isocitrate Dehydrogenase. J. Biol. Chem. 275, 5606–5612 (2000). PMID: 10681542

30. Gross, S. et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med. 207, 339–344 (2010). PMID: 20142433

31. Grassian, A. R. et al. IDH1 Mutations Alter Citric Acid Cycle Metabolism and Increase Dependence on Oxidative Mitochondrial Metabolism. Cancer Res. 74, 3317–3331 (2014). PMID: 24755473

32. Chan, S. M. et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21, 178–184 (2015). PMID: 25599133

33. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). PMID: 22343901

34. Xu, W. et al. Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases. Cancer Cell 19, 17–30 (2011). PMID: 26686626

35. Sulkowski, P. L. et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl. Med. 9, eaal2463 (2017). PMID: 28148839

36. Molenaar, R. J. et al. IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors. Clin. Cancer Res. 24, 1705–1715 (2018). PMID: 29339439

37. Saha, S. K. et al. Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma. Cancer Discov. 6, 727–739 (2016). PMID: 27231123

38. Li, S. et al. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro-Oncol. 15, 57–68 (2013). PMID: 23115158

39. Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722–731 (2017). PMID: 28588020

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Notes

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