IDH-mutant glioma
see IDH2 mutation
Isocitrate dehydrogenase (IDH) mutations are disease-defining mutations in IDH-mutant astrocytomas and Oligodendroglioma IDH-mutant and 1p/19q-codeleted. In more than 80% of these tumors, point mutations in IDH type 1 (IDH1) lead to the expression of the tumor-specific protein IDH1R132H. IDH1R132H harbors a major histocompatibility complex class II (MHCII)-restricted neoantigen that was safely and successfully targeted in a first-in-human clinical phase 1 trial evaluating an IDH1R132H 20-mer peptide vaccine (IDH1-vac) in newly diagnosed astrocytomas concomitant to the standard of care (SOC).
High-grade gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH wild type counterparts. Accurate determination of the IDH genotype preoperatively may have both prognostic and diagnostic values.
Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma.
Tumor histology, size and IDH-mutation status are important predictors for prolonged overall survival in patients with low-grade glioma LGG and may provide a reliable tool for standardizing future treatment strategies 1).
Prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation 2).
(EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.
Gliomas, the most common primary brain tumors, are characterized by isocitrate dehydrogenase 1 mutation (IDH1-M). High mutation frequency of IDH1 indicates it's promoting role in tumorgenesis. However, the observation that patients with IDH1-M have better survival comparing with patients with IDH1 wild-type (IDH1-W) suggests that this alteration has other significant beneficial features for patients.
Magnetic resonance imaging
Treatment
Outcome
IDH mutant high-grade glioma
see IDH mutant high-grade glioma
Diffuse astrocytoma IDH mutant.
Gemistocytic astrocytoma IDH-mutant
Anaplastic astrocytoma IDH mutant
Oligodendroglioma IDH mutant and 1p/19 q codeleted
Anaplastic Oligodendroglioma IDH mutant and 1p/19 q codeleted
Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct subtype, reflected in the World Health Organization Classification of Tumors of the Central Nervous System 2016 revised diagnostic criteria.
IDH1 and IDH2 mutations stratify individuals into molecular subtypes with distinct clinical outcomes – the mutations are associated with lower-grade astrocytomas, oligodendrogliomas (grade II/III) and secondary gliomas with better overall survival, progression-free survival and chemosensitivity than glioblastomas that are wild type for both genes 3) 4) 5).
IDH mutant gliomas are comprised of the majority of grade II-III gliomas and nearly all secondary glioblastomas. These progressive gliomas arise from mutations in IDH1 or IDH2 that pathologically produces D-2-hydroxyglutarate (2HG). 2-HG interferes with cell reactions using alpha ketoglutarate leading to a hypermethylated genome and epigenetic dysregulation of gene expression initiating tumorigenesis 6).
Tumor location predilection for isocitrate dehydrogenase (IDH) mutant tumors was found in both glioblastoma and lower-grade glioma cohorts, each showing a concordant predominance in the frontal lobe adjacent to the rostral extension of the lateral ventricles (permutation-adjusted p=0.021 for the glioblastoma and 0.013 for the lower-grade glioma cohort). Apart from that, the VLSM analysis did not reveal a significant association of the tumor location with any other key molecular alteration in both cohorts (permutation-adjusted p>0.05, each).
A study highlights the unique properties of IDH-mutations and underpins the hypothesis that the rostral extension of the lateral ventricles is a potential location for the cell of origin in IDH-mutant gliomas 7).
Gliomas are the most frequent intrinsic tumours of the central nervous system and encompass two principle subgroups: diffuse gliomas and gliomas showing a more circumscribed growth pattern ('non-diffuse gliomas'). In the revised 4th edition of the World Health Organization Classification of Tumors of the Central Nervous System published in 2016, classification of especially diffuse gliomas has fundamentally changed: for the first time a large subset of these tumours is now defined based on presence/absence of IDH mutation and 1p19q codeletion. Following this approach, the diagnosis of anaplastic oligoastrocytoma can be expected to largely disappear 8).
A study published online in Neuro-Oncology in December 2013 demonstrated that IDH-mutant malignant astrocytomas are more amenable to complete surgical resection of enhancing tumour (93% complete resections in the IDH-mutant group versus 67% in the IDH wildtype group). In contrast with IDH wild-type grade III and IV astrocytomas, which didn’t show significant benefit from further resection of non-enhancing tumour, the IDH-mutant grade III and IV astrocytoma group showed a survival benefit with maximal resection of both enhancing and non-enhancing tumour.
IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there may be distinguishable subtypes. We analyzed 170 WHO grade II to IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of the TCGA was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas: AA), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas: AO). Of the 88 IDH-wild type Glioblastomas, 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival (OS) compared to 19q-intact AAs (p=0.001). This tendency was observed in the TCGA Lower Grade Glioma dataset. In contrast, there was no difference in OS between the 19q-loss Glioblastoma and 19q-intact Glioblastoma (p=0.4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas 9).