Isocitrate dehydrogenase (IDH)
Isocitrate dehydrogenase (IDH) gene mutations are increasingly being recognised 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 tumours 7. Somatic mutations of IDH result in enchondromatosis syndromes: Ollier's disease and Maffucci syndrome 8.
Isocitrate dehydrogenases are enzymes which catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate (a.k.a. 2-ketoglutarate). This reaction also produces NADPH (IDH1 and IDH2) or NADH (IDH3) 4,5.
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 IDH1 is seen early in gliomagenesis and is oncogenic it confers a better prognosis than gliomas without the mutation (wildtype) 3. In other words:
- IDH-wildtype = IDH negative = no mutation = poor prognosis
- IDH-mutant = IDH positive = mutation present = better prognosis
Tumours 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 preexisting low grade tumours) 2,3.
Tumours with normal IDH genes referred to as "IDH-wildtype" or "IDH negative" tend to behave far more aggressively. Prognosis of IDH-wildtype 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 or by formal genotyping 3,7.
Not yet in widespread clinical use, but of tremendous interest, is the assessment of 2-hydroxyglutarate in vivo with MR spectroscopy 3. In tumours with mutated IDH levels of 2-hydroxyglutarate are elevated, which resonates at 2.25ppm 3,6.
- WHO classification of CNS tumours
- WHO grading of CNS tumours
- VASARI MRI feature set
- diffuse astrocytoma grading
- grade I:
- grade II:
- grade III
- anaplastic astrocytoma
- anaplastic oligodendroglioma
- grade IV:
- glioblastoma vs cerebral metastasis
- radiation-induced gliomas
- gliomatosis cerebri (growth pattern)
- specific locations
- treatment response
- Stupp protocol
- glioma treatment response assessment in clinical trials
- multicentric glioblastoma
- multifocal glioblastoma
- prognostic genetic markers
- 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