Citation, DOI & article data
Isocitrate dehydrogenase (IDH) gene mutations are increasingly being recognized as key genetic prognostic markers for diffuse gliomas, and form the basis for diffuse adult-type gliomas in the WHO classification of brain tumors 7.
Isocitrate dehydrogenases are enzymes that 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 cycle (also known as Krebs cycle).
A number of genes have been identified that 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 because although mutation of IDH 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
Tumors that have mutations of IDH genes are referred to as "IDH-mutant" or in older literature "IDH positive". By definition, essentially all low-grade adult-type diffuse gliomas (astrocytomas and oligodendrogliomas) are IDH-mutant 12. It is important to note that most IDH-mutant tumors are also MGMT-methylated (>80%) 9,11.
As of the 5th edition (2021) of the WHO classification, all glioblastomas are now, by definition, IDH-wildtype 12.
In most instances, IDH status is obtained by performing immunohistochemistry on surgical biopsy specimens. The majority (90%) of 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-wildtype. 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 tumors demonstrating necrosis) it is almost always negative (i.e. these are almost invariably glioblastoma).
Although no single absolute age cut-off exists, in individuals over the age of 55 years with a new diagnosis of glioma that is IDH1 R132H negative on immunohistochemistry, the chances of an IDH mutation being detected by next-generation sequencing is low and not considered mandatory 12.
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-mutant compared to 60% of IDH-wildtype 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.
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- 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
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- 9. Mulholland S, Pearson D, Hamoudi R et al. MGMT CpG Island is Invariably Methylated in Adult Astrocytic and Oligodendroglial Tumors with IDH1 or IDH2 Mutations. Int J Cancer. 2012;131(5):1104-13. doi:10.1002/ijc.26499 - Pubmed
- 10. Fontana L, Tabano S, Bonaparte E et al. MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective of IDH Status and Chromosome 10q Deletion. J Neuropathol Exp Neurol. 2016;75(8):791-800. doi:10.1093/jnen/nlw052 - Pubmed
- 11. Christensen B, Smith A, Zheng S et al. DNA Methylation, Isocitrate Dehydrogenase Mutation, and Survival in Glioma. J Natl Cancer Inst. 2011;103(2):143-53. doi:10.1093/jnci/djq497 - Pubmed
- 12. Brat D, Reuss D, Deimling A, Huse JR, Astrocytoma, IDH-mutant. In: WHO Classification of Tumours Editorial Board. Central nervous system tumours. Lyon (France): International Agency for Research on Cancer; 2021. . (WHO classification of tumours series, 5th ed.; vol. 6). https://publications.iarc.fr/601