IDH1

Primary Author(s)*

Paul De Fazio, MSc, Monash Health

Synonyms

Isocitrate Dehydrogenase NADP(+) 1 Cytosolic, Isocitrate Dehydrogenase 1 (NADP+) Soluble, Oxalosuccinate Decarboxylase, NADP(+)-Specific ICDH, PICD, IDH, IDP, NADP-Dependent Isocitrate Dehydrogenase Peroxisomal, NADP-Dependent Isocitrate Dehydrogenase Cytosolic, Isocitrate Dehydrogenase [NADP] Cytoplasmic, Cytosolic NADP-Isocitrate Dehydrogenase, Isocitrate Dehydrogenase 1 (NADP+), Epididymis Secretory Protein Li 26, Epididymis Luminal Protein 216, HEL-S-26, HEL-216, IDCD, IDPC

Genomic Location

Cytoband: 2q34

Genomic Coordinates:

chr2:209,100,951-209,130,798 [hg19]

chr2:208,236,227-208,266,074 [hg38]

Cancer Category/Type

Glioma, astrocytoma, oligodendroglioma, acute myeloid leukaemia, myelodysplastic syndrome, lymphoma, prostate cancer, thyroid cancer

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 IDH2 protein is found in the mitochondria, IDH1 is localised to the cytoplasm and in peroxisomes.

NADP+-dependent isocitrate dehydrogenases function as homodimers to catalyse the reversible NAPD+-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.

IDH1 is most highly expressed in the mammalian liver, with moderate expression in other tissues[1]. A C-terminal peroxisome targeting signal 1 sequence allows for its peroxisomal localisation[2]. The IDH1 protein is comprised of a large domain (residues 1-103 and 286-414, NM_005896.2/NP_005887.2), a small domain (residues 104-136 and 186-285, NM_005896.2/NP_005887.2) and a clasp domain (residues 137-185, NM_005896.2/NP_005887.2)[3]. The clasp domain holds together two IDH1 subunits and the enzyme active site is formed in a cleft created by the large and small domains of each subunit. Each active site can bind NADP+ and a metal ion in addition to the isocitrate substrate.

With no bound substrate, the Asp279 residue (NM_005896.2/NP_005887.2) occupies the active site where isocitrate would ordinarily form a hydrogen bond with the Ser94 residue (NM_005896.2/NP_005887.2). This steric hindrance prohibits substrate binding until Asp279 (NM_005896.2/NP_005887.2) moves away, contacting Arg132 (NM_005896.2/NP_005887.2) in the process[3]. Once the isocitrate substrate is bound, it forms three hydrogen bonds with Arg132 (NM_005896.2/NP_005887.2)[4]. Arg132 (NM_005896.2/NP_005887.2) therefore plays a critical role in the conformational changes of the IDH enzyme that allow the enzyme to function normally.

The conversion of isocitrate to αKG for use in the TCA cycle is primarily carried out by IDH3 in mitochondria. Although the expression profile of genes involved in metabolism is altered in IDH1-mutated cells[5], IDH1 likely evolved primarily for the purpose of NADPH production and is the main producer of NADPH in the brain[6]. NADPH generated by IDH1 contributes to the cellular defence against reactive oxygen species (ROS), and IDH1 activity increases in response to oxidative insults[7,8]. IDH1 can also modulate the availability of αKG, which itself can function as a potent antioxidant[8].

IDH1 deficiency leads to increased lipid peroxidation, oxidative DNA damage, intracellular peroxide generation, and decreased survival after oxidant exposure, while overexpression confers protection from these effects[9]. Cellular IDH1 levels are associated with decreased apoptosis after exposure to ultraviolet B radiation and gamma radiation[10–12]. Despite playing such a crucial role in oxidative stress response, IDH1 is itself inactivated by oxidation[13]. Other antioxidant enzymes may protect against this inactivation, and cells may respond with increased IDH1 synthesis[14].

NADPH provided by IDH1 is also used in hepatocytes for peroxisomal fat and cholesterol synthesis; in this context, IDH1 expression is regulated by sterol regulatory element-binding proteins 1a and 2[15].

IDH1 appears to have a role in glucose sensing through a novel anaplerotic pyruvate cycle where glucose-derived pyruvate enters the TCA cycle through pyruvate carboxylase, is converted to isocitrate, and exits the mitochondria via the citrate-isocitrate carrier[16]. IDH1 converts isocitrate to αKG, producing NADPH, and αKG and/or NADPH promote insulin secretion possibly through modulation of αKG hydroxylases or voltage-gated potassium channels, respectively. Functional studies in mice and mammalian pancreatic islets appear to support this hypothesis[17,18].

Role in Cancer

IDH1 mutations are most common in certain glioma subtypes, having been identified in approximately 80% of WHO grade II and III astrocytomas and oligodendrogliomas, and secondary glioblastomas[20]. In the context of glioma, IDH1 mutations are associated with an improved outcome and a younger age at diagnosis[21,22]. They are, however, rare in patients younger than 18 years.

Up to 40% of chondrosarcomas have been observed with IDH1 mutations, where they predict a shorter survival than in patients without IDH1 mutations. There are no clear associations with IDH1 mutation status and histological grade or age at diagnosis in the context of chondrosarcomas[23,24]. IDH1 mutations are not observed in other mesenchymal tumours. One study found somatic IDH1 mutations in a majority (~80%) of enchondromas and spindle cell hemangiomas from patients with Ollier disease and Maffucci syndrome[25].

Although IDH1 mutations are rare in gastrointestinal malignancies, they are found in around 20% of intrahepatic cholangiocarcinomas (ICC). In this context, IDH1 mutations are associated with a longer time to tumour recurrence and a lower probability of recurrence[26–28]. The prognostic outlook for overall survival in these patients is unclear as data in the literature is mixed[26,29,30].

Approximately 8% of acute myeloid leukaemias (AML) harbour IDH1 mutations, although the frequency is higher in patients with normal karyotype[31]. Studies have been conflicted regarding the prognostic outlook of IDH1 mutations in AML, but a meta-analysis of published data in 2017 found that overall survival and event-free survival were negatively impacted by IDH1 mutations, particularly in patients with normal karyotype[32]. The cumulative incidence of relapse in patients with intermediate-risk karyotype was improved, however. Interestingly, the synonymous single nucleotide polymorphism rs11554137 in IDH1 was also associated with poorer overall survival. IDH1-mutated AML is not found significantly more frequently in younger patients[31]. IDH1 mutations are seen more often in the M1 French-American-British AML subtype when compared to IDH1 wild-type AML[33].

IDH1 mutations are seen less commonly in other haematological malignancies such as myelodysplastic syndrome[34] and also in cancers of the prostate and thyroid[19], and are less well-studied in these contexts. Mutations of IDH1 have been shown to often be stem or early subclonal events in carcinogenesis in all cancers studied thus far, including AML[25,35–38].

The precise mechanisms linking IDH1 mutations to various cancers are as yet unknown and are likely to be tissue-specific, but IDH1-mutant cells do exhibit defects in multiple cellular processes. The most commonly seen IDH1 variants across all tumour types are heterozygous missense mutations at Arg132 (R132, NM_005896.2/NP_005887.2)[19]. Consistent with the role of R132 in active site conformation transition, alteration of R132 changes the equilibrium between open and closed conformations[39]. The IDH1 R132 mutation results in decreased enzyme affinity for isocitrate[4] and reduced NADPH production[20]. Most notably, the mutation also leads to IDH1 gaining the ability to reduce αKG to D-2-hydroxyglutarate (2HG)[39]. This neomorphic activity causes accumulation of 2HG and reduction of αKG levels.

Due to this altered enzyme function, IDH1 R132 mutants exhibit complex metabolic perturbations. Like other Warburg-like cancer cells, IDH1 wild-type glioma overexpresses enzymes involved in anaerobic glycolysis[5], as glycolysis and lactate production has the ability to generate both the energy and carbon required for sustained proliferation[41]. IDH1 R132 mutant glioma in contrast downregulates glycolytic enzymes, instead preferring to catabolise glutamate and glucose in the TCA cycle to produce αKG[5]. Genes downstream of isocitrate in the TCA cycle are downregulated in IDH1 R132 mutant glioma while expression of genes functioning upstream of isocitrate is increased[5]. IDH1 R132 mutant cells are therefore more reliant on oxidative phosphorylation compared to IDH1 wild-type cells. The metabolic rewiring in IDH1 R132 mutants is further evidenced by observations of increased mitochondrial gene expression and mitochondrial number in mutant ICC cells[36].

Much of the work exploring the role of IDH1 in cancer has revolved around the suggestion that 2HG functions as an ‘onco-metabolite’. 2HG accumulation and the concomitant depletion of αKG has been implicated in the stabilisation of hypoxia-inducible factor 1α (HIF-1α), a transcription factor which modulates apoptosis, cell survival, and angiogenesis and is involved in tumourigenesis[4]. This is through inhibition of the αKG-dependent HIF hydroxylases, negative regulators of HIF-1α, either through competitive binding of 2HG over αKG or by the depletion of αKG[42]. In AML cells 2HG has been shown to inhibit the activity of mitochondrial cytochrome c oxidase, which besides impacting oxidative metabolism also puts IDH1 R132 mutant cells on the brink of BAX/BAK-mediated apoptosis[43], and evidence suggests the case is similar in glioma[44]. The NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (NAPRT1) is also inhibited by 2HG in glioma cells[45].

2HG production impacts DNA repair by inhibiting the αKG-dependent DNA repair enzyme alkB homolog[46] and DNA damage response proteins lysine-specific methylase 4A and B (KDM4A/B)[47]. The altered histone methylation due to KDM4A/B inhibition results in downregulation of the DNA repair protein ATM[48]. This is consistent with the observation that IDH1 R132 mutant cells have increased DNA damage[47,48], although the DNA repair defects only seem to extend to the homologous recombination pathway and not the non-homologous end-joining pathway[47].

Increasingly, αKG and 2HG have been implicated in epigenetic regulation of gene expression, and widespread hypermethylation has been reported in IDH1 R132 mutant glioma and leukemia[49,50]. This phenotype has been referred to as the CpG island methylator phenotype (CIMP)[51]. 2HG has been established as an inhibitor of αKG-dependent deoxygenases involved in histone demethylation, including lysine-specific methylases as mentioned above as well as the myeloid tumour suppressor TET2[52]. Downstream effects include the downregulation of ATM, as already described, and likely also the expression of branched-chain amino acid transaminase 1 (BCAT1), which metabolises branched chain amino acids as a nitrogen source for neurotransmitter glutamate synthesis[53].

NADPH is required to recharge, activate, or generate reduced glutathione (GSH), thioredoxin, catalase tetramers, and cytochrome p450, which are all involved in cellular protection against oxidative stress. NADPH production in IDH1 R132-mutants is hampered and, moreover, the conversion of αKG to 2HG by these mutants is NADPH-dependent which reduces NADPH levels even further[6]. NADPH has shown to be depleted in colorectal cancer and glioma cells[54,55], although glucose-6-phosphate dehydrogenase (G6PDH) is the major source of NADPH in myeloid cells[56]. 2HG accumulation can also induce oxidative stress independently of IDH1 mutations[57].

Concurrent Mutations

IDH1 mutations do not increase in frequency as gliomas progress, which, coupled with the evidence that IDH1 mutations occur before other genetic changes, suggests that IDH1 mutations are involved early in the transition of a normal cell to a tumour cell[19,58].

TP53 mutations have been associated with IDH1-mutated astrocytoma and glioblastoma more than with other glioma subtypes[20,59], and astrocytomas are thought to develop via TP53 and ATRX mutations subsequent to IDH1 mutations. Astrocytomas associated with germline TP53 mutations were found to have somatic IDH1 Arg123Cys (NM_005896.2/NP_005887.2) mutations which are otherwise rare in this malignancy, suggesting the preferential occurrence of this specific mutation in cells that already contain a TP53 mutation[60].

Loss of chromosome arms 1p and 19q is observed more frequently in oligodendroglial tumours with IDH1 mutations compared to other IDH1-mutated or IDH1 wild-type gliomas[20]. Oligodendrogliomas often develop mutations in the TERT promoter in addition to 1p/19q deletions after IDH1 mutation[61], and these are thought to be important events in their developmental pathway.

Other genetic changes 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 occur less frequently in IDH1-mutated malignancies compared to those with wild-type IDH1[20].

In AML, IDH1 mutations are associated with NPM1 mutations but show negative association with CEBPA and WT1 mutations[62]. Patients with IDH1 mutations also have a lower frequency of FLT3-ITD mutations and are generally associated with a molecular low-risk group (NPM1-mutated and FLT3-ITD-negative)63 and normal cytogenetics[64].

Therapeutic Implications

Due to their reliance on oxidative phosphorylation IDH1-mutated cancer cells are vulnerable to inhibitors of this metabolic process. The biguanides metformin and phenformin inhibit NADH dehydrogenase (complex I of the electron transport chain (ETC)), and IDH1 mutations confer sensitivity to these agents[65]; metformin is currently undergoing clinical trial for use in patients with IDH1/2-mutant solid tumours[66].

IDH1-mutated cells also have a dependence on the glutaminolysis pathway. Although IDH1-mutated cells need αKG to produce 2HG, they also restrict αKG production[5]. Producing αKG from glutamine allows for an alternative source of αKG in IDH-mutated cells, but makes the cells vulnerable to inhibition of glutaminolysis with agents such as aminooxyacetic acid, BPTES, zaprinast, and chloroquinine in various cell types[67–70].

IDH1 mutation disables the decarboxylation reaction that converts αKG to isocitrate, a reaction important in hypoxic conditions where pyruvate influx from the TCA cycle is compromised and cells must use citrate and acetyl-CoA generated from glutamine and glutamate in order to maintain the ability to synthesise lipids[71]. In primary glioblastoma, where IDH1 is overexpressed, knockdown of IDH1 sensitises glioma-initiating cells with EGFR amplifications to erlotinib through decreased fatty acid and cholesterol synthesis[72].

2HG inhibits cytochrome c oxidase (complex IV of the ETC), preventing cytochrome c release into the mitochondrial matrix. This makes IDH mutated cells vulnerable to apoptosis through BAX/BAK mediated permeabilisation of the outer mitochondrial membrane, although normally this is prevented by BCL-2 binding to the BAX/BAK proapoptotic proteins[43,44]. Disrupting BCL-2 binding with venetoclax, a BH3 mimetic, results in apoptosis of IDH mutated cells but unmutated cells are relatively insensitive[73]. This has been observed in AML patients and glioblastoma models, though in the latter case BCL-xL appeared to be the primary target of the BH3 mimetic rather than BCL-2[44].

2HG downregulates nicotinate phosphoribosyltransferase (NAPRT1), which is an enzyme in the NAD+ salvage pathway. This leads to sensitivity to depletion of NAD+ in IDH1-mutated cells by inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another member of the pathway, with the preclinical compounds FK866 and GMX1778 leading to AMP kinase-initiated autophagy and cell death[45].

IDH1-mutated ICC cells depend on SRC kinase for mTOR mediated proliferation and survival. These cells are sensitive to dasatinib, a multikinase inhibitor with affinity for SRC[74].

In AML, the IDH1 Arg132His (NM_005896.2/NP_005887.2) mutant gene expression signature is indicative of a cellular phenotype that is responsive to treatment with small molecules targeting ROS and NAP+/NADPH signalling and metabolism[75].

In pancreatic cancer cells, IDH1 has been linked to antioxidant defence as an adaptive strategy to cope with stress. Expression of IDH1 is induced by HuR (Hu-Antigen R) after nutrient withdrawal or gemcitabine treatment. It has been suggested that this regulation is critical for pancreatic cancer cell survival under stress[76]. IDH1 mutations are rare in pancreatic cancer, however, probably owing to the importance of wild-type IDH1 function to pancreatic cancer cell survival.

Mutant IDH1 or IDH1 knockdown radiosensitises cancerous and noncancerous cells[54,77], while IDH1 overexpression is chemoprotective[78]. The radiosensitive phenotype of IDH1 mutants is caused by both antioxidant depletion and impaired DNA damage response[54], the latter of which is associated with 2HG accumulation. The inhibition of ALKBH by 2HG also results in sensitisation of IDH1-mutant cells to alkylating agents such as busulfan and CCNU[79], which provides an explanation for the sensitivity of IDH1-mutated glioma to treatment with radiotherapy in the presence or absence of procarbazine, CCNU, and vincristine (the first two of which are alkylating agents)[80]. IDH1 mutations also predict the response of glioblastoma to treatment with the DNA-alkylating agent temozolomide[81].

IDH1-mutated cancers are sensitive to PARP inhibitors, a phenotype that has been observed in AML and glioma[82,83], although the mechanism is unknown. Inhibition of the PARP-associated DNA repair pathway synergises with temozolomide in mutant glioma cells, and with daunorubicin in mutant AML, which suggests a treatment strategy that exploits the impaired DNA-repair pathway in IDH1-mutants rather than using IDH1-mutant inhibitors may be beneficial[82]. In human cell models, a combination of IDH1 mutation and ATM suppression caused sensitivity to irradiation and daunorubicin[82].

The fact that IDH1 mutations arise very early in many cancers makes it an attractive therapeutic target, as the resulting tumour homogeneity decreases the risk of therapy resistance arising. IDH1-mutant inhibitors have been developed and show therapeutic promise in glioma, AML, and chondrosarcoma[84–87], although in AML these inhibitors may induce differentiation syndrome in some patients[88].

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
				c.395G>A, p.R132H (NM_005896.2/NP_005887.2) c.394C>T, p.R132C (NM_005896.2/NP_005887.2) c.394C>G, p.R132G (NM_005896.2/NP_005887.2) c.394C>A, p.R132S (NM_005896.2/NP_005887.2) c.395G>T, p.R132L (NM_005896.2/NP_005887.2)

Internal Pages

Put your text here

EXAMPLE Germline Cancer Predisposition Genes

External Links

IDH1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

IDH1 by COSMIC - sequence information, expression, catalogue of mutations

IDH1 by CIViC - general knowledge and evidence-based variant specific information

IDH1 by St. Jude ProteinPaint mutational landscape and matched expression data.

IDH1 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

IDH1 by Cancer Index - gene, pathway, publication information matched to cancer type

IDH1 by OncoKB - mutational landscape, mutation effect, variant classification

IDH1 by My Cancer Genome - brief gene overview

IDH1 by UniProt - protein and molecular structure and function

IDH1 by Pfam - gene and protein structure and function information

IDH1 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. Yoshihara T, et al., (2001). Localization of cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells: biochemical and immunocytochemical studies. J Histochem Cytochem 49:1123–1131, PMID 11511681.

3. Xu X, et al., (2004). Structures of Human Cytosolic NADP-dependent Isocitrate Dehydrogenase Reveal a Novel Self-regulatory Mechanism of Activity. J Biol Chem 279:33946–33957, PMID 15173171.

4. Zhao S, et al., (2009). Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324:261–265, PMID 19359588.

5. Khurshed M, et al., (2017). In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma. Oncotarget 8(30):49165-49177, PMID 28467784.

6. Bleeker FE, et al., (2010). The prognostic IDH1 R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol (Berl) 119:487–494, PMID 20127344.

7. Minard KI and McAlister-Henn L, (1999). Dependence of peroxisomal β-oxidation on cytosolic sources of NADPH. J Biol Chem 274:3402–3406, PMID 9920883.

8. Mailloux R J, et al., (2007). The tricarboxylic acid cycle, an ancient metabolic network with a novel twist. PLoS ONE 2:e690, PMID 17668068.

9. 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.

10. Yang ES, et al., (2010). Silencing of cytosolic NADP+-dependent isocitrate dehydrogenase gene enhances ethanol-induced toxicity in HepG2 cells. Arch Pharm Res 33:1065–1071, PMID 20661717.

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. Jo, S.-H. et al. Cellular defense against UVB-induced phototoxicity by cytosolic NADP+-dependent isocitrate dehydrogenase. Biochem. Biophys. Res. Commun. 292, 542–549 (2002). PMID: 11906195

13. Lee, S. M., Huh, T.-L. & Park, J.-W. Inactivation of NADP+-dependent isocitrate dehydrogenase by reactive oxygen species. Biochimie 83, 1057–1065 (2001). PMID: 11879734

14. Batinic-Haberle, I. & Benov, L. T. An SOD mimic protects NADP + -dependent isocitrate dehydrogenase against oxidative inactivation. Free Radic. Res. 42, 618–624 (2008). PMID: 18608518

15. Shechter, I., Dai, P., Huo, L. & Guan, G. IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells. J. Lipid Res. 44, 2169–2180 (2003). PMID: 12923220

16. Joseph, J. W. et al. The Mitochondrial Citrate/Isocitrate Carrier Plays a Regulatory Role in Glucose-stimulated Insulin Secretion. J. Biol. Chem. 281, 35624–35632 (2006). PMID: 17001083

17. Koh, H.-J. et al. Cytosolic NADP + -dependent Isocitrate Dehydrogenase Plays a Key Role in Lipid Metabolism. J. Biol. Chem. 279, 39968–39974 (2004). PMID: 15254034

18. Ronnebaum, S. M. et al. A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion. J. Biol. Chem. 281, 30593–30602 (2006). PMID: 16912049

19. Reitman, Z. J. & Yan, H. Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism. JNCI J. Natl. Cancer Inst. 102, 932–941 (2010). PMID: 20513808

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

21. Sanson, M. et al. Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas. J. Clin. Oncol. 27, 4150–4154 (2009). PMID: 19636000

22. Nobusawa, S., Watanabe, T., Kleihues, P. & Ohgaki, H. IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas. Clin. Cancer Res. 15, 6002–6007 (2009). PMID: 19755387

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

24. 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

25. Pansuriya, T. C. et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat. Genet. 43, 1256–1261 (2011). PMID: 22057234

26. Wang, P. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32, 3091–3100 (2013). PMID: 22824796

27. 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

28. Churi, C. R. et al. Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications. PLOS ONE 9, e115383 (2014). PMID: 25536104

29. Goyal, L. et al. Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma. The Oncologist 20, 1019–1027 (2015). PMID: 26245674

30. Jiao, Y. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat. Genet. 45, 1470–1473 (2013). PMID: 24185509

31. Mardis, E. R. et al. Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome. N. Engl. J. Med. 361, 1058–1066 (2009). PMID: 19657110

32. Xu, Q. et al. Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis. Clin. Cancer Res. 23, 4511–4522 (2017). PMID: 28246275

33. Schnittger, S. et al. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood 116, 5486–5496 (2010). PMID: 20805365

34. Patnaik, M. M. et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic Study of 277 patients. Leukemia 26, 101–105 (2012). PMID: 22033490

35. Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324 (2014). PMID: 25043048

36. Farshidfar, F. et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 18, 2780–2794 (2017). PMID: 28658632

37. Papaemmanuil, E. et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374, 2209–2221 (2016). PMID: 27276561

38. Molenaar, R. J. et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 29, 2134 (2015). PMID: 25836588

39. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). PMID: 19935646

40. Molenaar, R. J., Maciejewski, J. P., Wilmink, J. W. & van Noorden, C. J. F. Wild-type and mutated IDH1/2 enzymes and therapy responses. Oncogene 37, 1949–1960 (2018). PMID: 29367755

41. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891–899 (2004). PMID: 15516961

42. Frezza, C., Tennant, D. A. & Gottlieb, E. IDH1 Mutations in Gliomas: When an Enzyme Loses Its Grip. Cancer Cell 17, 7–9 (2010). PMID: 20129244

43. 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

44. Karpel-Massler, G. et al. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat. Commun. 8, (2017). PMID: 29057925

45. Tateishi, K. et al. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. Cancer Cell 28, 773–784 (2015). PMID: 26678339

46. Chen, F. et al. Oncometabolites D - and L -2-Hydroxyglutarate Inhibit the AlkB Family DNA Repair Enzymes under Physiological Conditions. Chem. Res. Toxicol. 30, 1102–1110 (2017). PMID: 28269980

47. 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

48. Inoue, S. et al. Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2. Cancer Cell 30, 337–348 (2016). PMID: 27424808

49. Noushmehr, H. et al. Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma. Cancer Cell 17, 510–522 (2010). PMID: 20399149

50. 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

51. Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012). PMID: 22343889

52. Losman, J.-A. & Kaelin, W. G. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013). PMID: 23630074

53. Tönjes, M. et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19, 901–908 (2013). PMID: 23793099

54. Molenaar, R. J. et al. Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198. Cancer Res. 75, 4790–4802 (2015). PMID: 26363012

55. Shi, J. et al. Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumor Biol. 36, 655–662 (2015). PMID: 25283382

56. Molenaar, R. J., Radivoyevitch, T., Maciejewski, J. P., van Noorden, C. J. & Bleeker, F. E. The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim. Biophys. Acta BBA-Rev. Cancer 1846, 326–341 (2014). PMID: 24880135

57. Gilbert, M. R. et al. Autophagy and oxidative stress in gliomas with IDH1 mutations. Acta Neuropathol. (Berl.) 127, 221–233 (2014). PMID: 24150401

58. Ohgaki, H. & Kleihues, P. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci. 100, 2235–2241 (2009). PMID: 19737147

59. Watanabe, T., Nobusawa, S., Kleihues, P. & Ohgaki, H. IDH1 Mutations Are Early Events in the Development of Astrocytomas and Oligodendrogliomas. Am. J. Pathol. 174, 1149–1153 (2009). PMID: 19246647

60. Watanabe, T., Vital, A., Nobusawa, S., Kleihues, P. & Ohgaki, H. Selective acquisition of IDH1 R132C mutations in astrocytomas associated with Li-Fraumeni syndrome. Acta Neuropathol. (Berl.) 117, 653–656 (2009). PMID: 19340432

61. The Cancer Genome Atlas Research Network. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N. Engl. J. Med. 372, 2481–2498 (2015). PMID: 26061751

62. 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

63. Marcucci, G. et al. IDH1 and IDH2 Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J. Clin. Oncol. 28, 2348–2355 (2010). PMID: 20368543

64. Feng, J.-H. et al. Prognostic significance of IDH1 mutations in acute myeloid leukemia: a meta-analysis. Am. J. Blood Res. 2, 254 (2012). PMID: 23226625

65. Cuyàs, E. et al. Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype. Oncotarget 6, (2015). PMID: 25980580

66. Molenaar, R. J. et al. Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1 -mutated or IDH2 -mutated solid tumours. BMJ Open 7, e014961 (2017). PMID: 28601826

67. Seltzer, M. J. et al. Inhibition of Glutaminase Preferentially Slows Growth of Glioma Cells with Mutant IDH1. Cancer Res. 70, 8981–8987 (2010). PMID: 21045145

68. Elhammali, A. et al. A High-Throughput Fluorimetric Assay for 2-Hydroxyglutarate Identifies Zaprinast as a Glutaminase Inhibitor. Cancer Discov. 4, 828–839 (2014). PMID: 24740997

69. Emadi, A. et al. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp. Hematol. 42, 247–251 (2014). PMID: 24333121

70. Mohrenz, I. V. et al. Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. Apoptosis 18, 1416–1425 (2013). PMID: 23801081

71. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012). PMID: 22101433

72. Calvert, A. E. et al. Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. Cell Rep. 19, 1858–1873 (2017). PMID: 28564604

73. Konopleva, M. et al. 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 (2016). PMID: 27520294

74. 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

75. Boutzen, H. et al. Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia. J. Exp. Med. 213, 483–497 (2016). PMID: 26951332

76. Zarei, M. et al. Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells. Cancer Res. 77, 4460–4471 (2017). PMID: 28652247

77. Kim, S. Y., Yoo, Y. H. & Park, J.-W. Silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase gene enhances glioma radiosensitivity. Biochem. Biophys. Res. Commun. 433, 260–265 (2013). PMID: 23500467

78. Wang, J.-B., Dong, D.-F., Wang, M.-D. & Gao, K. IDH1 Overexpression Induced Chemotherapy Resistance and IDH1 Mutation Enhanced Chemotherapy Sensitivity in Glioma Cells in Vitro and in Vivo. Asian Pac. J. Cancer Prev. 15, 427–432 (2014). PMID: 24528069

79. Wang, P. et al. Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep. 13, 2353–2361 (2015). PMID: 26686626

80. Buckner, J. C. et al. Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N. Engl. J. Med. 374, 1344–1355 (2016). PMID: 27050206

81. SongTao, Q. et al. IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci. 103, 269–273 (2012). PMID: 22034964

82. 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

83. Lu, Y. et al. Chemosensitivity of IDH1-Mutated Gliomas Due to an Impairment in PARP1-Mediated DNA Repair. Cancer Res. 77, 1709–1718 (2017). PMID: 28202508

84. Popovici-Muller, J. et al. Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med. Chem. Lett. 3, 850–855 (2012). PMID: 24900389

85. Popovici-Muller, J. et al. Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Med. Chem. Lett. 9, 300–305 (2018). PMID: 29670690

86. Rohle, D. et al. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. Science 340, 626–630 (2013). PMID: 23558169

87. Li, L. et al. Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells. PLOS ONE 10, e0133813 (2015). PMID: 26368816

88. Birendra, K. C. & DiNardo, C. D. Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120. Clin. Lymphoma Myeloma Leuk. 16, 460–465 (2016). PMID: 27245312

Notes

*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.