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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31827b654d
Review Articles

Mutations in the Isocitrate Dehydrogenase Genes IDH1 and IDH2 in Tumors

Schaap, Frank G. PhD*; French, Pim J. PhD; Bovée, Judith V. M. G. MD, PhD*

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Author Information

*Department of Pathology, Leiden University Medical Center

Department of Neurology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands

Present Address: Frank G. Schaap, Department of Surgery, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

Supported by The Netherlands Organization for Scientific Research (917-76-315).

The authors have no conflicts of interest to disclose.

Reprints: Judith V. M. G. Bovée, MD, PhD, Department of Pathology (L1-Q), Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (e-mail:

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Heterozygous hotspot mutations in isocitrate dehydrogenases (IDH) IDH1 or IDH2 are frequently observed in specific types of cartilaginous tumors, gliomas, and leukemias. Mutant IDH enzyme loses its normal activity to convert isocitrate into α-ketoglutarate (αKG) and instead acquires the ability to reduce αKG to D-2-hydroxyglutarate. Through direct competition with αKG, accumulation of the oncometabolite D-2-hydroxyglutarate in IDH mutated tumors results in inhibition of αKG-dependent dioxygenases involved in DNA and histone demethylation. Apart from epigenetic alterations, perturbations in the tricarboxylic acid cycle (depletion of intermediates) and activation of the intricately linked hypoxia signaling pathway are apparent in IDH mutated cells. As molecular details are being unraveled, the emerging concept is that IDH mutations result in tumor formation by epigenetic alterations that affect gene expression and result in inhibition of cellular differentiation. Activation of hypoxic stress signaling reprograms cellular energy metabolism and promotes anabolic processes and angiogenesis, thus, providing an advantage to promote neoplastic growth.

Tumors show various metabolic aberrations but perhaps the most central to tumor proliferation is the process originally described by Warburg in the 1920s.1 Now termed the “Warburg effect,” cancer cells reprogram their energy metabolism by switching to glycolysis, producing excessive levels of lactate, even under normoxic conditions (aerobic glycolysis). Although the Warburg effect is a common phenomenon in cancer,2 the molecular basis for increased glycolysis and defective respiration has remained largely unknown.3 Although the correlation between certain oncogenes (eg, MYC) or tumor suppressor genes (eg, TP53) and metabolism is only beginning to be explored,4–7 there is a group of tumors and tumor syndromes that carry mutations in metabolic enzymes involved in the tricarboxylic acid (TCA) cycle (Kreb’s cycle). These tumors share striking metabolic abnormalities and the elucidation of the exact mechanism by which these metabolic enzymes contribute to tumorigenesis may shed new light on defective energy metabolism in cancer.

Recurrent somatic mutations in IDH1 encoding isocitrate dehydrogenase (IDH) 1 were first identified through genome-wide sequencing of tumor tissue of patients with glioblastoma multiforme (GBM).8 Mutations in IDH1 were observed in 12 of 105 (11%) tumors and were associated with increased overall survival.8 This initial discovery was soon followed by identification of IDH1 mutations in additional glioma subtypes and uncovering of mutations albeit at a lower frequency in the related IDH2 gene in a subset of brain tumors.9 Frequent mutations in IDH1 or IDH2 have since been observed in 50% to 70% of cartilaginous tumors10 and 20% to 30% of myeloid leukemia,11 and in a small subset of other malignancies (Table 1).

Table 1
Table 1
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Throughout this review, IDH mutation refers to a somatic mutation in either the IDH1 or IDH2 gene. Note that germline mutations have been identified in the IDH3B gene encoding the β-subunit of a third IDH. Somatic IDH mutations are largely confined to single arginine (R) residues in both IDH1 (R132) and IDH2 (R172), with occasional mutation of R140 in IDH2 in myeloid malignancies.11 All presently identified hotspot mutations are single-nucleotide substitutions in the respective arginine codons. Five of 6 possible IDH1 R132 variants (R132C, R132G, R132G, R132L, and R132S) have been identified in cartilaginous tumors and gliomas, with R132C and R132H being the most common variants in the respective tumors (Fig. 1).10–13 Likewise, different substitutions at the R172 position account for the majority of IDH2 hotspot mutations in cartilage tumors and gliomas/acute myeloid leukemia. It is currently unclear if the observed patterns of substitution in different tumor types bear relevance to tumor development or pathogenic progression. Along with heterozygous presentation, the targeting of specific highly conserved arginine residues indicates that mutant IDH enzymes have a gain-of-function. In line with such notion, the IDH1 variant that has thus far resisted uncovering (ie, R132P), is predicted to result in a loss-of-function.29 Somatic mutations in IDH1 are more common and are inversely correlated with mutations in IDH2, indicating that they affect a similar pathway.

Figure 1
Figure 1
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Benign and malignant forms of cartilaginous tumors are the most common primary neoplasms affecting the bones.30 Cartilaginous tumors can be classified as central (within the medulla of bone) or peripheral (at the bone surface).31 Enchondromas occur in the medulla of bone either as solitary or multiple lesions. Multiple enchondromas occur within the rare nonhereditary skeletal disorders such as Ollier disease and Maffucci syndrome.32 Osteochondroma is a benign cartilage tumor presenting at the surface of the bone as a cartilage-capped outward-growing lesion of which the stalk is continuous with the underlying marrow. Enchondromas and osteochondromas are thought to arise from deregulated growth plate chondrocytes as they develop nearby the growth plate during periods of bone growth.30 Enchondromas and osteochondromas can undergo malignant transformation to central or peripheral chondrosarcoma, respectively, which is estimated to occur in up to ∼30% of enchondromas in Ollier disease and in 1% to 5% of osteochondromas.31

Chondrosarcoma is the most frequent primary bone sarcoma in adults and constitutes a heterogeneous group of malignant cartilage-forming tumors. Distinct subtypes of chondrosarcoma are recognized of which conventional central chondrosarcoma is most common (∼90%). The long, pelvic, and thoracic bones of adults in the third to sixth decade are principally affected.31,33 In addition to central chondrosarcoma, other subtypes are recognized including peripheral (arising in a benign osteochondroma), dedifferentiated, periosteal, clear cell, and mesenchymal chondrosarcoma. Chondrosarcoma is notoriously resistant to conventional chemotherapy and radiotherapy.33 Conventional chondrosarcoma is histologically classified into 3 grades predicting prognosis.34

A multistep genetic model for the progression from enchondroma (benign) to low-grade and high-grade malignant chondrosarcoma has been gradually elucidated.30 Using gene expression profiling, alterations were found in metabolism in tumors with increased histologic grade.35,36 Glycolysis-associated genes35 and hypoxia pathways37 were significantly higher in high-grade compared with low-grade chondrosarcoma. Indeed, HIF1α expression is found in high-grade chondrosarcomas.37–42 Using kinome profiling, high activity of Src and Akt kinases were identified in chondrosarcoma suggesting that these are important for chondrosarcoma cell survival.43 Both Src and Akt are able to induce HIF1α. The notion that the reprogramming of energy metabolism is an important hallmark of chondrosarcoma development and progression is emphasized by the identification of somatic heterozygous IDH1 (R132C and R132H) or, in rare cases IDH2 (R172S) hotspot mutations.

IDH mutations were found in both syndromic (Ollier disease/Maffucci syndrome; up to 88%) and sporadic central cartilaginous tumors (∼54%).10,12,13 In addition, IDH mutations are present in periosteal chondroma/chondrosarcoma (up to 71%) and in dedifferentiated chondrosarcoma (up to 57%).10,12,14 Moreover, IDH1 mutations were identified in the related disorder metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.44 Heterozygous germline mutations in IDH2 at R140 causes D-2-hydroxyglutaric aciduria, a rare neurometabolic disorder characterized by supraphysiological levels of D-2-hydroxyglutarate (D2HG), in which tumors are absent.45 Although adequate numbers of tumors were not available in all cases, IDH mutations have not been observed in other cartilaginous tumors including osteochondroma/peripheral chondrosarcoma, clear cell chondrosarcoma, mesenchymal chondrosarcoma, extraskeletal myxoid chondrosarcoma, chondromyxoid fibroma, chondroblastoma, soft-tissue chondroma, synovial chondromatosis, and chondroblastic osteosarcoma.10,14,46 The R132C IDH1 mutation is most commonly found in cartilage tumors followed by the R132H IDH1 mutation (Fig. 1). This is important to realize as the commercial antibody against R132H IDH1, which is commonly used in glioma diagnosis, will detect only a small subset of IDH1 mutated cartilage tumors. The striking distribution of IDH mutations suggests distinct tumorigenic modes in enchondroma, central chondrosarcoma, and periosteal tumors. The high mutation frequency and the fact that they are early events suggest a causal rather than a bystander role for IDH mutations in tumorigenesis.

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Gliomas, the most common type of brain tumors, can be classified into 4 clinicopathologic grades. GBM [World Health Organization (WHO) grade IV astrocytoma] is the most frequent and most malignant brain tumor having one of the worst prognosis among human tumor types. They can develop de novo (primary GBM, >90% of cases) or progress from lower-grade gliomas (secondary GBM). Despite indistinguishable pathology, primary and secondary GBM affect patients of different age and have distinct patterns of genetic abnormalities. EGFR amplification/overexpression and deletion of CDKN2A and PTEN mutation are commonly encountered in primary GBM, a malignancy mainly affecting the elderly.47 Secondary GBM, which manifests in younger subjects, typically lack these genetic alterations but do carry TP53 mutations.

The finding of recurring mutations in the IDH1 or IDH2 genes was first made in a GBM cohort.8 IDH mutations are predominantly present in secondary GBM (up to 50% to 88%) and its precursor lesions (WHO grade II/III diffuse/anaplastic astrocytomas; up to 70% to 90%), as well as in WHO grade II/III oligodendrogliomas and oligoastrocytomas (up to 79% to 94%) but are infrequently encountered in primary GBM (3% to 16%) or other brain tumors.9,16,48–50 IDH mutation is considered an early event in the development of astrocytomas and oligodendrogliomas.48 Moreover, IDH mutated gliomas have a distinct epigenetic profile characterized by hypermethylation of CpG islands (CpG island methylator phenotype).51

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Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults, and its incidence increases with age. Recurrent chromosomal translocations and somatic mutations are recognized in the pathogenesis of AML with specific cytogenetic aberrations having prognostic value. Mutations in the IDH1 or IDH2 genes are frequently found in cytogenetically normal AML (up to 15% to 30%), and are also recognized in other myeloid leukemias (myelodysplastic syndrome and myeloproliferative neoplasms; up to 5% to 20%).11,52 Unlike other tumors, mutations in the IDH2 gene are quite common in AML and have a comparable or higher frequency as compared with IDH1 mutations. Not only are IDH2 mutations more common in AML, the spectrum of mutations is also unique. It is the only tumor type with mutations at the R140 position. Notably, this position is also mutated in patients with IDH2 mutated D2HG aciduria.45 IDH mutation appears as an early event in myeloid malignancies and may drive tumorigenesis. Global hypermethylation is characteristic of AML, and signatures based on promoter methylation status can classify AML in biologically distinct clusters.53 In IDH mutated AML, aberrant methylation is most striking in promoter regions and CpG islands neighboring the transcription start sites of genes, resulting predominantly in suppressive effects on gene transcription.54 Mutations in IDH and TET2 (a determinant of epigenetic status) are mutually exclusive in AML indicating that these mutations affect the same pathway.

Alterations of the epigenome are hallmarks for many types of tumors, and aberrations of the methylation landscape have been noted in IDH mutated cartilaginous tumors, gliomas, and leukemias. Compelling evidence is available that these epigenetic changes are the direct consequence of mutant IDH enzyme activity.55–58

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IDH catalyzes the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (αKG) and CO2, one of the reactions in the TCA cycle. In addition, they catalyze the reductive carboxylation of αKG to form isocitrate, an essential step in glutamine-dependent lipogenesis under hypoxic conditions and in tumor cells with defective mitochondria.59,60 Humans have 3 distinct IDHs that are encoded by 5 separate genes. IDH1 and IDH2 are homodimeric enzymes that utilize NADP+ as a cofactor and localize to the cytoplasm and peroxisomes (IDH1) and mitochondria (IDH2).61 IDH3 is a heterotetrameric mitochondrial enzyme that employs NAD+ as a cofactor.

The exact mechanism by which mutations in metabolic enzymes cause cancer is so far unknown. Recent evidence points to an important role for epigenetic changes.55,56,62 Hotspot mutations in IDH1 and IDH2 lead to the formation of a neoenzyme that catalyzes the NADPH-dependent reduction of αKG to the otherwise trace metabolite D2HG (also referred to as R2HG).63–65 In IDH mutated tumors, one wild-type allele is retained. Dimeric IDH enzyme composed of a wild-type and mutant subunit effectively converts isocitrate to D2HG.29 Tissue levels of D2HG are up to 100-fold higher in IDH mutated gliomas,65 as well as in IDH mutated cartilage tumors.12 Moreover, levels are markedly elevated in serum of patients with IDH mutated AML.63 Importantly, D2HG could be detected noninvasively in patients with IDH mutated gliomas by magnetic resonance spectroscopy.66,67 Note that accumulation of D2HG and/or its stereoisomer L2HG is also observed in the inherited 2-hydroxyglutaric acidurias,68 with excess L2HG being associated with elevated risk for gliomas. More severe clinical manifestation in patients with D-2-hydroxyglutaric aciduria may, however, preclude observation of tumors.

D2HG is considered an oncometabolite and inhibits αKG-dependent dioxygenases like TET2, by direct competition with αKG.57,58 This results in inhibition of DNA demethylation, causing hypermethylation of CpG dinucleotides that may impact on gene transcription and genome stability.69,70 TET2 normally alters the epigenetic status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5 hmC). It is currently unresolved whether 5 hmC represents a distinct epigenetic mark or an intermediate in DNA demethylation.71 Loss of 5 hmC is associated with tumor development and malignant transformation.72,73

IDH1 mutations induce a hypermethylated phenotype in leukemias, gliomas, and enchondromas.13,56–58 D2HG also inhibits other αKG-dependent oxygenases74,75 such as the Jumonji-domain histone demethylases, thereby increasing histone methylation as well.55 Thus, D2HG affects histone methylation and thereby gene activity. Monoallelic expression of mutant IDH1 in an isogenic colon cancer cell line or expression of mutant IDH1 in immortalized primary human astrocytes was sufficient to induce global DNA and histone hypermethylation, consistent with inhibition of DNA and histone demethylation by accumulating D2HG.56,76 Epigenetic changes due to mutant IDH protein were demonstrated to result in impairment of hematopoietic differentiation in leukemia.57,62 Moreover, IDH1 mutation was recently shown to result in repression of adipocytic and neural differentiation, which correlated with changes in histone methylation.55 Thus, epigenetic changes induced by IDH mutations subsequently affect differentiation.

In addition, mutations affecting metabolic enzymes may give tumor cells a growth advantage through activation of hypoxic response pathways mediated by HIF1α. The hypoxia response is a common feature of solid tumors and reprograms cellular energy metabolism (reduced aerobic adenosine triphosphate production and increased anaerobic glycolysis) and activates pathways involved in synthesis of amino acids, lipids (glutamine-dependent lipogenesis), and nucleotides. To meet their growth rate, tumor cells have increased anabolic demands especially building blocks for protein, lipid, and nucleic acids. HIF1α is a key factor in the cellular response to hypoxia, causing upregulation of glucose transport and glycolysis.77,78 Prolyl hydroxylases are αKG-dependent dioxygenases that tag HIF1α for proteasomal degradation under normoxic conditions. Through direct competition with the cosubstrate in this reaction (αKG), D2HG may stabilize HIF1α allowing nuclear translocation, heterodimerization and transcription of HIF1α target genes.

The link between D2HG and HIF1α is controversial. Initial findings indicated that mutant IDH stabilizes HIF1α through αKG-antagonistic action of D2HG on HIF prolyl hydroxylases.58,79 It was recently shown that while the L2HG enantiomer indeed inhibited HIF prolyl hydroxylases, the D2HG enantiomer produced by mutated IDH stimulated their activity leading to diminished HIF1α levels.80 This is consistent with previous findings in cartilaginous tumors that HIF1α expression is not an early event, only being found in high-grade chondrosarcoma,37 implying no direct role for IDH mutations, which are an early event. Thus, it is so far unclear whether stabilization of HIF1α contributes to tumorigenesis in IDH mutated cartilage tumors. Adding to the debate, knock-in mice expressing mutant Idh1 in the brain displayed elevated Hif1α protein levels and upregulated Hif1α-dependent transcription in the brain.81

Other substrates/products affected by mutation of IDH may contribute to tumor formation.82 Abrogated formation of NADPH in the normal IDH reaction and consumption of NADPH in the neomorphic reaction may disrupt the NADP+/NADPH balance and accordingly antioxidant defense pathways in IDH mutated cells. Reduced NADPH levels, as reflected by a modest increase in NADP+/NADPH ratio, were noted in knock-in mice expressing mutant Idh1 in the brain, but this was unexpectedly accompanied by reduced levels of reactive oxygen species.81 Furthermore, the reduction of αKG to D2HG by mutant IDH, depletes αKG and downstream TCA cycle intermediates (succinate, fumarate, and malate) independent whether the mutation occurs in the cytoplasmic (IDH1) or mitchondrial (IDH2) enzyme.82 Functioning as a pathway integrating multiple metabolic pathways, the perturbation of TCA cycle function by mutant IDH results in among others increased amino acid levels, enabling anabolic routes.82

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In addition to mutations in IDH, 2 other tumor syndromes were previously identified to be caused by mutations in a metabolic enzyme (Table 2). Inactivating germline mutations were found in subunits of mitochondrial complex II, the succinate dehydrogenase subunit D, C, and B genes in patients with head and neck paragangliomas and pheochromocytomas.83 Head and neck paragangliomas are tumors of the parasympathetic paraganglia and are closely related to the sympathetic paragangliomas of the adrenal gland (pheochromocytomas) and abdominal paraganglia. Although head and neck paragangliomas are generally benign tumors, sympathetic paragangliomas can be metastatic and associated with hypertension. Paragangliomas are composed of 2 cell types, the chief cells and the sustentacular cells. Succinate dehydrogenase subunit D was the first tumor suppressor gene encoding a mitochondrial protein and metabolic enzyme.84 Indeed, these tumors show a mitochondrial deficiency.85 Gene expression profiles indicate a hypoxic transcriptional profile in succinate dehydrogenase (SDH) mutated paragangliomas including expression of HIF1α,86 emphasizing that aberrant energy metabolism is a hallmark of paragangliomas.

Table 2
Table 2
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These discoveries were followed by the identification of inactivating germline mutations of another TCA cycle gene, fumarate hydratase (FH), which were shown to cause autosomal dominant hereditary leiomyomas and type 2 papillary renal cell carcinoma syndrome, including benign cutaneous and uterine leiomyomas and renal cell cancer.87,88 Strikingly, although uterine leiomyomas are quite common, hereditary leiomyomas and type 2 papillary renal cell carcinoma syndrome is extremely rare. Biallelic inactivation in nonsyndromic leiomyomas and leiomyosarcomas is also very rare (<1%).89

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In 2000, Hanahan and Weinberg90 published an influential review in which they formulated 6 hallmarks of cancer, sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, and the activation of invasion and metastasis. On the basis of conceptual progress over the last decade, their recent update added 2 “emerging hallmarks” to this list, the reprogramming of energy metabolism and evasion of immune destruction.2 Cancer cells reprogram their energy metabolism by switching to glycolysis and producing excessive levels of lactate, even under normoxic conditions (aerobic glycolysis). This is the basis for the widely used tumor imaging technique [18F]deoxyglucose-positron emission tomography.

A common theme of the tumors arising from mutation in IDH, SDH, or FH, is the accumulation of metabolites (D2HG, succinate, and fumarate) that perturb TCA cycle function and affect HIF1α stability.3,65 Although metabolic alterations in these tumors can be explained through activation of the hypoxia response pathway, the molecular events that result in initial accumulation of undifferentiated cells is far from clear. It is now evident that IDH mutation results in global changes in DNA and histone methylation that affect the cellular transcriptome. Knock-in mice expressing mutant IDH1 in the hematopoietic compartment recapitulated the changes to the epigenome and displayed accumulation of hematopoietic precursors.62 Knock-in mice expressing mutant IDH1 in the brain showed perinatal lethality because of perturbed collagen maturation and basement membrane dysfunction resulting in central nervous system hemorrhage.81 Knock-in mice surviving into adulthood were devoid of gliomas, which may relate to their markedly reduced lifespan. Thus, it remains to be determined if IDH mutation is sufficient to initiate and drive tumorigenesis, although the observation that these mice develop liver tumors suggests that Idh1 mutations are sufficient to drive tumor formation. Further studies in knock-in mice are expected to yield valuable insight into the molecular pathways involved in inhibition of differentiation and further processes affected by IDH mutation. IDH mutations occur early in tumorigenesis and are retained (at least in some tumors) during progression to malignant stages, making mutated IDH an attractive therapeutical target. It will be interesting to learn whether the active site of mutant IDH can be distinguished from the native enzyme and is amenable to pharmaceutical inhibition.

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Back to Top | Article Outline

epigenome; hypoxic signaling; IDH mutation; tumor metabolism

© 2013 Lippincott Williams & Wilkins, Inc.


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