Isocitrate dehydrogenase (IDH) gene mutations are increasingly being recognized as key genetic prognostic markers for diffuse gliomas, and have been included in a recent (2016) update of diffuse astrocytomas in the WHO classification of brain tumors 7. Somatic mutations of IDH result in enchondromatosis syndromes: Ollier disease and Maffucci syndrome 8.
Isocitrate dehydrogenases are enzymes which catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (α-ketoglutarate). This reaction also produces NADPH (IDH1 and IDH2) or NADH (IDH3) 4,5. Isocitrate dehydrogenase acts at the rate-limiting step of the tricarboxylic acid (TCA; Krebs) cycle.
A number of genes have been identified which code for isoforms of these enzymes, with IDH1 and IDH2 being most relevant in current glioma classification 8.
- located on the long arm of chromosome 2 (2q32)
- encodes for cytosolic isocitrate dehydrogenase
- mutations affect a single amino acid residue 132, in most instances (>85%) resulting in arginine being replaced with histidine and thus denoted R132H 8
- located on the long arm of chromosome 15 (15q21)
- encodes for mitochondrial isocitrate dehydrogenase
- mutations affect a single amino acid residue 172, analogous to the R132 residue in IDH1 8
The terminology can be confusing as although mutation of IDH is seen early in gliomagenesis and is oncogenic it confers a better prognosis than gliomas without the mutation (wild-type) 3. In other words:
- IDH-wild-type = IDH negative = no mutation = poor prognosis
- IDH-mutant = IDH positive = mutation present = better prognosis
Tumors who have mutations of IDH genes are referred to as "IDH-mutant" or in older literature "IDH positive". The majority of low-grade diffuse gliomas (astrocytomas and oligodendrogliomas) are IDH-mutant. A minority of glioblastomas are also IDH-mutant, and it is believed that these usually represent secondary glioblastomas (i.e. GBMs that have arisen from pre-existing low-grade tumors) 2,3. It is important to note that most IDH mutant tumors are also MGMT-methylated (>80%) 9,11.
Tumors with normal IDH genes referred to as "IDH wild-type" or "IDH negative" tend to behave far more aggressively. Prognosis of IDH wild-type low-grade gliomas is similar to that of primary GBM 1.
In most instances, IDH status is obtained by performing immunohistochemistry on surgical biopsy specimens. The majority (90%) IDH mutations in gliomas affect IDH1 with a single amino acid missense mutation at arginine(R)132 replaced by histidine (H); thus denoted as IDH1 R132H. This is the mutation generally tested by immunohistochemistry 7.
If no immunohistochemical reactivity is detected, it is likely but not certain that the tumor is IDH wild-type. This can only be established with formal genotyping, e.g. using pyrosequencing 3,7. In practice, however, this is not always done, both because it is expensive and in some patient groups (e.g. elderly patients with GBM) almost always negative (i.e. almost all GBMs in elderly patients are IDH wild-type). Although no single age cut-off exists, in individuals with a glioblastoma which is IDH1 R132H negative on histochemistry, and who do not have a history of pre-existing lower grade tumor, the chances of detecting an IDH mutation by sequencing is less than 1% 7.
MGMT methylation status is also potentially useful in further reducing the chances that an immunohistochemical IDH1 R132H negative tumor actually harbors a less common mutation. Although the literature is heterogeneous, generally IDH mutated (IDH1 and IDH2) tumors are more likely to also have MGMT methylation (80% for IDH-mt compared to 60% of IDH-wt tumors) 9-11.
Not yet in widespread clinical use, but of tremendous interest, is the assessment of 2-hydroxyglutarate in vivo with MR spectroscopy 3. In tumors with mutated IDH levels of 2-hydroxyglutarate are elevated, which resonates at 2.25 ppm 3,6.
- 1. Brat DJ, Verhaak RG et-al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N. Engl. J. Med. 2015;372 (26): 2481-98. doi:10.1056/NEJMoa1402121 - Free text at pubmed - Pubmed citation
- 2. Yan H, Parsons DW, Jin G et-al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 2009;360 (8): 765-73. doi:10.1056/NEJMoa0808710 - Free text at pubmed - Pubmed citation
- 3. Cohen AL, Holmen SL, Colman H. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 2013;13 (5): 345. doi:10.1007/s11910-013-0345-4 - Free text at pubmed - Pubmed citation
- 4. National Institute of Health (NIH) Genetic Home Reference. IDH1. Read relevant article. Accessed on 24/01/2016
- 5. National Institute of Health (NIH) National Center for Biotechnology Information (NCBI) IDH1 Read relevant article. Accessed on 24/01/2016
- 6. Choi C, Ganji SK, DeBerardinis RJ et-al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat. Med. 2012;18 (4): 624-9. doi:10.1038/nm.2682 - Free text at pubmed - Pubmed citation
- 7. Louis DN, Perry A, Reifenberger G et-al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131 (6): 803-20. doi:10.1007/s00401-016-1545-1 - Pubmed citation
- 8. Cohen AL, Holmen SL, Colman H. IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep. 2013;13 (5): 345. doi:10.1007/s11910-013-0345-4 - Free text at pubmed - Pubmed citation
- 9. Mulholland S, Pearson DM, Hamoudi RA, Malley DS, Smith CM, Weaver JM, Jones DT, Kocialkowski S, Bäcklund LM, Collins VP, Ichimura K. MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations. International journal of cancer. 131 (5): 1104-13. doi:10.1002/ijc.26499 - Pubmed
- 10. Fontana L, Tabano S, Bonaparte E, Marfia G, Pesenti C, Falcone R, Augello C, Carlessi N, Silipigni R, Guerneri S, Campanella R, Caroli M, Sirchia SM, Bosari S, Miozzo M. MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective of IDH Status and Chromosome 10q Deletion. Journal of neuropathology and experimental neurology. doi:10.1093/jnen/nlw052 - Pubmed
- 11. Christensen BC, Smith AA, Zheng S, Koestler DC, Houseman EA, Marsit CJ, Wiemels JL, Nelson HH, Karagas MR, Wrensch MR, Kelsey KT, Wiencke JK. DNA methylation, isocitrate dehydrogenase mutation, and survival in glioma. Journal of the National Cancer Institute. 103 (2): 143-53. doi:10.1093/jnci/djq497 - Pubmed
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