Elsevier

The Lancet Oncology

Volume 12, Issue 1, January 2011, Pages 83-91
The Lancet Oncology

Review
Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma?

https://doi.org/10.1016/S1470-2045(10)70053-XGet rights and content

Summary

The discovery of somatic mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) in glioblastomas was remarkable because the enzyme was not previously identified with any known oncogenic pathway. IDH1 is mutated in up to 75% of grade II and grade III diffuse gliomas. Apart from acute myeloid leukaemia, other tumour types do not carry IDH1 mutations. Mutations in a homologous gene, IDH2, have also been identified, although they are much rarer. Although TP53 mutations and 1p/19q codeletions are mutually exclusive in gliomas, in both of these genotypes IDH1 mutations are common. IDH1 and IDH2 mutations are early events in the development of gliomas. Moreover, IDH1 and IDH2 mutations are a major prognostic marker for overall and progression-free survival in grade II–IV gliomas. Mutated IDH1 has an altered catalytic activity that results in the accumulation of 2-hydroxyglutarate. Molecularly, IDH1 and IDH2 mutations are heterozygous, affect only a single codon, and rarely occur together. Because IDH1 does not belong to a traditional oncogenic pathway and is specifically and commonly mutated in gliomas, the altered enzymatic activity of IDH1 may provide a fundamentally new understanding of diffuse glioma.

Introduction

In 2008, a genome-wide sequencing study identified mutations in a gene encoding isocitrate dehydrogenase (IDH1) in 18 (12%) of 149 samples of glioblastoma multiforme.1 The mutations were most common in young patients with glioblastomas that had progressed from low-grade gliomas to secondary glioblastoma multiforme. Patients with IDH1 mutations were also associated with a longer survival than patients with glioblastomas without IDH1 mutations. Several papers have since identified the IDH1 mutations in other glioma subtypes and in various tumour types (table 1). Functional studies2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 on IDH1 found that IDH1 mutations in the gene are highly glioma specific. Investigations of large numbers of other tumour types showed that acute myeloid leukaemia (AML) was the only cancer other with a high incidence of IDH1 mutations (table 1). IDH1 is the most commonly mutated gene in many types of glioma, with incidences of up to 75% in grade II and grade III glioma (table 1). IDH1 mutations are always heterozygous missense mutations that affect aminoacid residue 132 (figure 1) and are associated with longer survival in patients with glioma than patients with glioma without IDH1 mutations (table 2, figure 2). IDH1 mutations result in a reduced enzymatic activity towards the native substrate, isocitrate, and mutant IDH1 catalyses the formation of 2-hydroxyglutarate from α-ketoglutarate.

In addition to IDH1, mutations in a homologous gene, IDH2, with a different subcellular distribution have been identified in gliomas. IDH2 mutation is much less common than IDH1 mutation; the two rarely occur together, but both seem to be specific to gliomas.5, 6, 11, 24 Inactivating mutations in another gene, IDH3B, have been identified in patients with retinitis pigmentosa, but they do not seem to be associated with tumour formation.25

Section snippets

Structure and function

In human beings, five genes encode for isocitrate dehydrogenase: IDH1, IDH2, IDH3A, IDH3B, and IDH3G. These genes encode three catalytic isozymes: IDH1, IDH2, and IDH3. Both IDH1 and IDH2 function as homodimers whereas IDH3 functions as a heterotetramer composed of two α, one β, and one γ subunit.26 The function of all isocitrate dehydrogenases is to catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate, with oxalosuccinate formed as an intermediate product (figure 1).27 In

Mutation frequency

Diffuse gliomas are the most common primary brain cancer in adults and typically have a poor prognosis.35, 36 On the basis of histology, gliomas are classified into astrocytic tumours (75%) and oligodendroglial tumours (25%). Oligodendroglial tumours comprise both classic oligodendrogliomas and mixed oligoastrocytic tumours.37 Diffuse gliomas are further classified into grade II (or low grade), grade III (anaplastic), and grade IV (gliobastoma multiforme) depending on the presence of malignant

Clinical implications

Histological diagnosis of gliomas is subject to substantial interobserver variation,44 thus IDH1 mutation status can provide an objective marker to identify the glioma subtype. IDH1 mutations are rare in primary glioblastoma multiforme and are common in secondary glioblastoma multiforme; therefore, IDH1 mutation status can distinguish between these two subtypes (sensitivity 71·0–73%, specificity 96%).18 The low incidence of IDH1 mutation in pilocytic astrocytomas also allows clinically relevant

Are IDH1 and IDH2 mutations causal?

Despite the high mutation frequency, whether IDH1 mutations cause disease is unknown. Several observations suggest a causal role for IDH1 and IDH2 in tumorigenesis. The prevalence and nature of somatically acquired mutations does not suggest a bystander mutation.47 Moreover, IDH1 and IDH2 mutations rarely occur together.6 Mutant IDH1 causes an accumulation of 2-hydroxyglutarate, high concentrations of which are associated with brain tumours.16, 48, 49 Specific mutation types segregate into

Mutations of a single codon

All mutations in IDH1 and IDH2 are somatic, missense, heterozygous, and affect codon 132 (IDH1) or codon 172 (IDH2). Moreover, both codons have analogous positions in the isozymes.50, 51, 52 Most mutations are single base transition substitutions: 395G→A for IDH1 (about 90%), and 515G→A for IDH2 (about 60%). These mutations result in an arginine to histidine (R132H) substitution in IDH1 or an arginine to lysine (R172K) substitution in IDH2. The remaining IDH1 mutations are, with the exception

Altered enzymatic activity

Results of studies examining the functional consequences of IDH1 and IDH2 mutant proteins have shown a strong decrease in the isocitrate-dependent production of reduced NADPH production.3, 5, 17 Such a decrease in enzymatic activity suggests that both IDH1 and IDH2 are tumour suppressor genes; however, mutant IDH1 has altered substrate specificity and is more compatible with an oncogenic function.16

A tumour suppressor function of wild-type IDH1 is possible because the mutant protein exerts a

Cellular functions affected by mutant IDH1 and IDH2

Although IDH1 mediates a reaction identical to that which happens in the tricarboxylic-acid cycle, IDH1 does not play a direct part in the reaction because it is localised in the cytosol. Thus, IDH1 does not seem to mediate the Warburg effect (the observation that even under normoxic conditions tumour cells preferentially use glycolysis over aerobic respiration).65 Other tumour-associated mutations in metabolic enzymes have been described in hereditary phaeochromocytoma-paraganglioma syndrome,

Conclusion

The incidence of IDH1 mutation is very high in most diffuse gliomas, but not in primary glioblastomas, and to a lesser extent in AML. Mutations in the homologous IDH2 gene also occur albeit with a much lower incidence than IDH1. These mutations are early events in gliomagenesis, and arise both in TP53 mutated astrocytomas and in 1p and 19q codeleted oligodendrogliomas. IDH1 is a strong prognostic marker for overall survival and progression-free survival in gliomas, suggesting that future

Search strategy and selection criteria

Information for this review was obtained by PubMed searches, and references from relevant articles, in December, 2009, using the search terms “IDH1”, “IDH2”, “IDPC”, “glioma”, “isocitrate dehydrogenase”, “NADP”, “2-hydroxyglurate”, and “2-hydroxyglutaric aciduria”. Only articles published in English were used with no date restrictions.

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