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 ofform the basis for diffuse astrocytomasadult-type gliomas in the WHO classification of brain tumours ⁷.

Somatic mutations of IDH result in enchondromatosis syndromes: Ollier disease and Maffucci syndrome ⁸.  

Normal function

Isocitrate dehydrogenases are enzymes that catalyse 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. 

• IDH1
  • 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
• IDH2
  • 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

Terminology

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 (wild-type) ³. In other words: 

• IDH-wild-type = IDH negative = no mutation = poor prognosis
• IDH-mutant = IDH positive = mutation present = better prognosis

IDH mutant

Tumours that have mutations of IDH genes are referred to as "IDH-mutant" or in older literature "IDH positive". The majority ofBy definition, essentially all low-grade adult-type 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 tumours) ^2,312. It It is important to note that most IDH mutant tumours are also MGMT-methylated (>80%) ^9,11. 

IDH wild-type

Tumours with normal IDH genes referred to as "IDH wild-type" or "IDH negative" tend to behave far more aggressively. The prognosisAs of IDH wild-type low-grade gliomas is similar to thatthe 5th edition (2021) of primary GBMthe WHO classification, all glioblastomas are now, by definition, IDH-wildtype ¹¹². 

Detection

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 tumour 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 GBMtumours demonstrating necrosis) it is almost always negative (i.e. almost all GBMs in elderly patientsthese are IDH wild-typealmost invariably glioblastoma).

Although no single absolute age cut-off exists, in individuals over the age of 55 years with glioblastoma whicha new diagnosis of glioma that is IDH1 R132H negative on immunohistochemistry, and who do not have a history of pre-existing lower grade tumour, the chances of an IDH mutation being detected by next-generation sequencing is less than 1%low and not considered mandatory ⁷¹².

MGMT methylation status is also potentially useful in further reducing the chances that an immunohistochemical IDH1 R132H negative tumour actually harbours a less common mutation. Although the literature is heterogeneous, generally IDH mutated (IDH1 and IDH2) tumours are more likely to also have MGMT methylation (80% for IDH-mt compared to 60% of IDH-wt tumours)  ^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 tumours with mutated IDH levels of 2-hydroxyglutarate are elevated, which resonates at 2.25 ppm ^3,6.