Gliomas are the most common type of primary brain tumors and are grouped into four grades according to the WHO criteria Citation[1]. Gliomas include several specific histological subtypes; the most common are astrocytomas, oligodendrogliomas and ependymomas. Glioblastomas (GBMs; WHO grade IV), the most malignant type of glioma, may develop very rapidly de novo (primary GBM) in elderly patients or develop more slowly from low grade diffuse (WHO grade II) or anaplastic astrocytoma (WHO grade III; secondary GBM) in younger patients Citation[2].
IDH1 & IDH2
Recent genome-wide mutational analysis has revealed somatic mutations of the cytosolic NADP+-dependent IDH1 gene at 2q33 in approximately 12% of GBMs Citation[3]. IDH catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, leading to production of the reduced form of NADP in the tricarboxylic acid cycle. The mutations affected the amino acid arginine in position 132 of the amino acid sequence, which is evolutionarily highly conserved and is located in the binding site of isocitrate Citation[4]. Wild-type arginine in position 132 was replaced by histidine (R132H) in the vast majority of the cases Citation[3]. IDH1 protein is present in the cytosol, whereas IDH2 protein is one of the mitochondrial IDH forms. The IDH2 gene is homologous to the IDH1 gene that uses NADP+ as an electron receptor. Gliomas without IDH1 mutations often had mutations at the analogous amino acid (R172) of the IDH2 gene Citation[5]. Both IDH1 and IDH2 mutations reduced enzymatic activity of the encoded protein Citation[5].
IDH1 & IDH2 mutations are early events in gliomagenesis
Recent analyses showed IDH1 mutations were more frequent in secondary GBMs than primary GBMs Citation[5–9]. Similarly, IDH1 mutations were very common (≥70%) in diffuse or anaplastic astrocytomas, oligodendrogliomas and anaplastic oligodendrogliomas Citation[6–10]. On the other hand, IDH2 mutations were only found in WHO grade II or III gliomas without IDH1 mutations Citation[5]. By contrast, IDH1 mutations have only been found in a few cases of other CNS tumors. Furthermore, IDH1 mutations have been identified in a subset of acute myeloid leukemia cases but not in other cancer types Citation[11–13].
IDH1 and IDH2 mutations are commonly found in both astrocytomas and oligodendrogliomas, but the pattern of other genetic alterations is different. The majority of low-grade diffuse astrocytomas have both TP53 and IDH1 mutations, whereas most oligodendrogliomas show both IDH1 mutations and 1p/19q codeletion Citation[10]. Therefore, IDH1 and IDH2 mutations are very early events in gliomagenesis and may affect common glial precursors. The pattern of other genetic alterations in gliomas with IDH mutations is entirely different from that in gliomas without IDH mutations. Alterations of PTEN, EGFR or CDKN2A/CDKN2B are frequently found in GBMs with wild-type IDH1 and IDH2, but in only 5% of cases of anaplastic astrocytoma and GBM with IDH mutation. Similarly, 1p/19q codeletion was rarely found in oligodendroglial tumors without IDH mutation Citation[5,6,8,10].
IDH mutation as a favorable prognostic factor in glioma patients
Clinically, an IDH1 mutation is strongly correlated with good prognosis in patients with gliomas Citation[5,9,14]. Median overall survival in GBM patients with IDH mutations was significantly longer than that in GBM patients with wild-type IDH1 and IDH2Citation[5]. Mutations of IDH are also associated with improved prognosis in patients with anaplastic astrocytomas Citation[5,9]. Multivariate analysis has confirmed that IDH1 mutation is an independent favorable prognostic marker in GBMs and anaplastic gliomas after adjustment for other genomic profiles and treatment modality Citation[14,15].
2-HG levels are elevated in gliomas with IDH1 mutations
Although the biological function of IDH mutation is not fully understood, IDH mutations are always monoallelic and do not result in simple loss of function. IDH1 mutation impairs the enzyme’s affinity for its substrate and dominantly inhibits wildtype IDH1 activity through the formation of catalytically inactive heterodimers Citation[16]. Consequently, R132H mutation disrupts the function of IDH1 to convert isocitrate to α-ketoglutarate. More recently, IDH1 mutations were found to result in an ability of the enzyme to catalyze the reduced NADP-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG) Citation[17]. 2-HG levels were remarkably elevated in human malignant gliomas with IDH1 mutations Citation[17]. Structural studies demonstrated that replacement of arginine 132 by histidine results in shifting of residues in the active site to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert α-ketoglutarate to 2-HG.
Accumulation of 2-HG is found in patients with the inherited metabolic disorder 2-hydroxyglutaric aciduria. This disease is caused by a deficiency in the enzyme 2-HG dehydrogenase, which converts 2-HG to α-ketoglutarate Citation[18]. Patients with 2-HG dehydrogenase deficiencies have an increased risk of developing brain tumors Citation[19]. The effect of IDH1 mutation on cellular metabolism requires more investigation, but reduction of α-ketoglutarate by 2-HG or mutant IDH1 results in a lower level of prolyl hydroxylases and promotes the accumulation of hypoxia-inducible factor 1α. Alterations in hypoxia-inducible factor 1α may result from mutant IDH1 protein expression. In addition to IDH mutations in gliomas, mutations of other metabolic enzymes, such as fumarate hydratase and succinate dehydrogenase, occur in paraganglioma and leiomyoma, respectively Citation[20]. Energy is produced predominantly by aerobic glycolysis in the cytosol of most cancer cells, rather than by mitochondrial oxidative phosphorylation as in normal differentiated cells, a phenomenon termed the ‘Warburg effect’. Aerobic glycolysis may provide cancer cells with a growth advantage by supplying the necessary metabolites to incorporate into the biomass and produce a new cell. Aerobic glycolysis may also be important for glioma progression. Both PI3K and tyrosine kinase signaling are involved with growth control and glycolysis. PI3K activation by PTEN mutation and/or tyrosine kinase activation by EGFR alteration are frequently found in primary GBMs. However, PTEN mutations and EGFR alterations are rarely found in anaplastic astrocytoma and GBM patients with IDH mutation, suggesting that the mechanism of cellular metabolism in glioma might depend on the IDH status.
Mutations in IDH seem to play an important role in the formation of specific subtypes of gliomas. Detection of IDH mutations is easier to perform and interpret than the determination of 1p/19q codeletion and MGMT promoter methylation. Such information could be useful to improve the diagnostic and therapeutic strategies for gliomas. Furthermore, measurement of 2-HG production will identify patients with IDH1 mutant brain tumors. Of course, further analysis of IDH1 and IDH2 in glioma model systems will be necessary to clarify the genetic mechanisms involved in the initiation and malignant progression of this disease. In addition, extensive genetic profiling of gliomas may allow the molecular classification of gliomas to replace the histological classification in the near future. Patients with IDH1 mutation may benefit from treatment modalities designed to inhibit the mutant IDH1 expression. Inhibition of 2-HG production might also have therapeutic potential in the treatment of gliomas.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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