Difference between revisions of "IDH2"
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==Primary Author(s)*== | ==Primary Author(s)*== | ||
− | + | Paul De Fazio, MSc, Monash Health | |
__TOC__ | __TOC__ | ||
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==Synonyms== | ==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 | ||
+ | Put your text here | ||
+ | |||
+ | |||
+ | * Astrocytoma | ||
Put your text here | Put your text here | ||
− | |||
− | + | * Oligodendroglioma | |
+ | Put your text here | ||
+ | |||
+ | |||
+ | * Chondrosarcoma | ||
+ | Put your text here | ||
− | |||
− | + | * Intrahepatic cholangiocarcinoma | |
+ | Put your text here | ||
+ | |||
− | Put your text here | + | * Acute myeloid leukaemia |
+ | Put your text here | ||
− | |||
− | + | * Myelodysplastic syndrome | |
+ | Put your text here | ||
− | |||
+ | * Angioimmunoblastic T-cell lymphoma | ||
Put your text here | Put your text here | ||
==Gene Overview== | ==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== | ==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) | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
Line 39: | Line 118: | ||
! Copy Number Loss !! Copy Number Gain !! LOH !! Loss-of-Function Mutation !! Gain-of-Function Mutation !! Translocation/Fusion | ! Copy Number Loss !! Copy Number Gain !! LOH !! Loss-of-Function Mutation !! Gain-of-Function Mutation !! Translocation/Fusion | ||
|- | |- | ||
− | | | + | | || || || || X || |
|} | |} | ||
Line 50: | Line 129: | ||
==External Links== | ==External Links== | ||
− | + | '''[http://atlasgeneticsoncology.org/Genes/GC_IDH2.html ''IDH2'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information | |
+ | |||
+ | '''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=IDH2 ''IDH2'' by COSMIC]''' - sequence information, expression, catalogue of mutations | ||
+ | |||
+ | '''[https://civicdb.org/events/genes/27/summary/variants/570/summary ''IDH2'' by CIViC]''' - general knowledge and evidence-based variant specific information | ||
+ | |||
+ | '''[https://pecan.stjude.cloud/proteinpaint/idh2 ''IDH2'' by St. Jude ProteinPaint]''' mutational landscape and matched expression data. | ||
+ | |||
+ | '''[https://pmkb.weill.cornell.edu/search?utf8=✓&search=idh2 ''IDH2'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs | ||
+ | |||
+ | '''[http://www.cancerindex.org/geneweb/IDH2.htm ''IDH2'' by Cancer Index]''' - gene, pathway, publication information matched to cancer type | ||
+ | |||
+ | '''[http://oncokb.org/#/gene/IDH2 ''IDH2'' by OncoKB]''' - mutational landscape, mutation effect, variant classification | ||
+ | |||
+ | '''[https://www.mycancergenome.org/content/gene/idh2/ ''IDH2'' by My Cancer Genome]''' - brief gene overview | ||
+ | |||
+ | '''[https://www.uniprot.org/uniprot/P48735 ''IDH2'' by UniProt]''' - protein and molecular structure and function | ||
+ | |||
+ | '''[https://pfam.xfam.org/family/PF00180 ''IDH2'' by Pfam]''' - gene and protein structure and function information | ||
+ | |||
+ | '''[https://www.genecards.org/cgi-bin/carddisp.pl?gene=IDH2&keywords=idh2 ''IDH2'' by GeneCards]''' - general gene information and summaries | ||
− | + | ==References== | |
− | + | 1. Jennings GT, et al., (1994). Cytosolic NADP (+)-dependent isocitrate dehydrogenase. Isolation of rat cDNA and study of tissue-specific and developmental expression of mRNA. J Biol Chem 269:23128–23134, PMID 8083215. | |
− | + | 2. Luo H, et al., (1996). Expression of human mitochondrial NADP‐dependent isocitrate dehydrogenase during lymphocyte activation. J Cell Biochem 60:495–507, PMID 8707889. | |
− | + | 3. Nekrutenko A, et al., (1998). Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family. Mol Biol Evol 15:1674–1684, PMID 9866202. | |
− | + | 4. Ceccarelli C, et al., (2002). 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, PMID 12207025. | |
− | + | 5. Ward PS, et al., (2010). 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, PMID 20171147. | |
− | + | 6. Comte B, et al., (2002). Reverse flux through cardiac NADP + -isocitrate dehydrogenase under normoxia and ischemia. Am J Physiol-Heart Circ Physiol 283:H1505–H1514, PMID 12234803. | |
− | + | 7. Sazanov LA and Jackson JB, (1994). Proton-translocating transhydrogenase and NAD- and NADP-linked isocitrate dehydrogenases operate in a substrate cycle which contributes to fine regulation of the tricarboxylic acid cycle activity in mitochondria. FEBS Lett 344:109–116, PMID 8187868. | |
− | + | 8. Reitman ZJ and Yan H (2010). Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. JNCI J Natl Cancer Inst 102:932–941, PMID 20513808. | |
− | + | 9. Mailloux RJ, et al., (2007). The tricarboxylic acid cycle, an ancient metabolic network with a novel twist. PLoS ONE 2:e690, PMID 17668068. | |
− | + | 10. Lee SM, et al., (2002). Cytosolic NADP+-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med 32:1185–1196, PMID 12031902. | |
− | + | 11. Lee S‐H, et al., (2004). Role of NADP+‐dependent isocitrate dehydrogenase (NADP+‐ICDH) on cellular defence against oxidative injury by γ‐rays. Int J Radiat Biol 80:635–642, PMID 15586883. | |
− | + | 12. Lee JH, et al., (2007). Regulation of ionizing radiation-induced apoptosis by mitochondrial NADP+-dependent isocitrate dehydrogenase. J Biol Chem 282:13385–13394, PMID 17350954. | |
− | + | 13. Shin SW, et al., (2008). Silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase by small interfering RNA enhances heat shock-induced apoptosis. Biochem Biophys Res Commun 366:1012–1018, PMID 18096511. | |
− | + | 14. Kil IS, et al., (2007). 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, PMID 17854715. | |
+ | |||
+ | 15. Kranendijk M, et al., IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:336, PMID 20847235. | ||
+ | |||
+ | 16. Yan H, et al., (2009). IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773, 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, PMID 19554337. | ||
+ | |||
+ | 18. Amary MF, et al., (2011). 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, PMID 21598255. | ||
+ | |||
+ | 19. Borger DR, et al., (2012). Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. The Oncologist 17:72–79, PMID 22180306. | ||
+ | |||
+ | 20. Houillier C, et al., (2010). IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75:1560–1566, PMID 20975057. | ||
+ | |||
+ | 21. Lugowska I, et al., (2018). IDH1/2 mutations predict shorter survival in chondrosarcoma. J Cancer 9:998–1005, PMID 29581779. | ||
+ | |||
+ | 22. Figueroa ME, et al., (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567, PMID 21130701. | ||
+ | |||
+ | 23. Green CL, et al., (2011). The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood 118:409–412, PMID 21596855. | ||
+ | |||
+ | 24. Chou W-C, et al., (2011). The prognostic impact and stability of isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia 25:246–253, PMID 21079611. | ||
+ | |||
+ | 25. Aref S, et al., (2015). Prevalence and clinical effect of IDH1 and IDH2 mutations among cytogenetically normal acute myeloid leukemia patients. Clin Lymphoma Myeloma Leuk 15:550–555, PMID 26189213. | ||
+ | |||
+ | 26. Yamaguchi S, et al., (2013). IDH1 and IDH2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1 mutation. Eur J Haematol 92:471–477, PMID 24443894. | ||
+ | |||
+ | 27. Cairns RA, et al., (2012). IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119:1901–1903, PMID 22215888. | ||
+ | |||
+ | 28. Wang C, et al., (2015). IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood 126:1741–1752, PMID 26268241. | ||
+ | |||
+ | 29. Soundar S, et al., (2000). Identification by mutagenesis of arginines in the substrate binding site of the porcine NADP-dependent isocitrate dehydrogenase. J Biol Chem 275:5606–5612, PMID 10681542. | ||
+ | |||
+ | 30. Gross S, et al., (2010). Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207:339–344, PMID 20142433. | ||
+ | |||
+ | 31. Grassian AR, et al., (2014). IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res 74:3317–3331, PMID 24755473. | ||
+ | |||
+ | 32. Chan SM, et al., (2015). Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 21:178–184, PMID 25599133. | ||
+ | |||
+ | 33. Lu C, et al., (2012). IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474–478, PMID 22343901. | ||
+ | |||
+ | 34. Xu W, et al., (2011). Oncometabolite 2-Hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30, PMID 26686626. | ||
+ | |||
+ | 35. Sulkowski PL, et al., (2017). 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Transl Med 9:eaal2463, PMID 28148839. | ||
+ | |||
+ | 36. Molenaar RJ, et al., (2018). 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, PMID 29339439. | ||
+ | |||
+ | 37. Saha SK, et al., (2016). Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma. Cancer Discov 6:727–739, PMID 27231123. | ||
+ | |||
+ | 38. Li S, et al., (2013). Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro-Oncol 15:57–68, PMID 23115158. | ||
+ | |||
+ | 39. Stein EM, et al., (2017). Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130:722–731, PMID 28588020. | ||
− | + | 40. Konopleva M, et al., (2016). Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 6:1106–1117, PMID 27520294. | |
− | |||
− | + | 41. Tateishi K, et al., (2015). Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28:773–784, PMID 26678339. | |
− | |||
== Notes == | == Notes == | ||
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. | <nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. | ||
+ | |||
+ | [[Category:Cancer Genes I]] |
Latest revision as of 14:44, 10 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
Put your text here
- Astrocytoma
Put your text here
- Oligodendroglioma
Put your text here
- Chondrosarcoma
Put your text here
- Intrahepatic cholangiocarcinoma
Put your text here
- Acute myeloid leukaemia
Put your text here
- Myelodysplastic syndrome
Put your text here
- Angioimmunoblastic T-cell lymphoma
Put your text here
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 |
---|---|---|---|---|---|
X |
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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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