Abstract
Isocitrate dehydrogenase (IDH) mutation is one of the most critical genomic alterations in lower grade and secondary glioblastoma patient. More than 90% of IDH mutation is located at codon R132 of IDH1 gene. IDH mutation produces oncometabolite “2-hydroxyglutarate” and induces epigenetic alteration, such as DNA global methylation and histone methylation. As a result, IDH mutation promotes early gliomagenesis. Since IDH mutation is the earliest genomic event and almost always retained during tumor progression, IDH mutation is expected as novel therapeutic target. Herein, we review the clinical characteristics of IDH-mutant gliomas, biological role of IDH mutation for gliomagenesis, and current and future therapeutic approach for IDH mutant tumors.
Keywords
- IDH mutation
- glioma
- 2-hydroxyglutarate
- tumor biology
- cancer metabolism
- target therapy
1. Introduction
The WHO 2016 classification integrates molecular and histological features in the diagnosis of gliomas. Among numerous genomic alterations, the
2. Discovery of IDH mutations in cancers
The presence of an
Besides,
3. Tumorigenesis of IDH -mutant gliomas
3.1 Genomic characteristics of IDH -mutant glioma
The discovery of
In astrocytic tumors, most of the tumor cells have co-mutations in
3.2 Developmental hierarchy in IDH -mutant gliomas
Two recent large scale single cell RNA-sequencing studies revealed a developmental hierarchy in
3.3 IDH -mutant xenograft model
Although
4. The 2016 WHO classification
The 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) integrated phenotypic and genotypic parameters for CNS tumor classification. According to this classification, all diffusely infiltrating gliomas are grouped as diffuse astrocytic and oligodendroglial tumors. These tumors were histologically and genetically classified based on the presence of
5. Epidemiology of IDH -mutant gliomas
5.1 Age distribution of IDH -mutant gliomas
According to some statistical analyses, the
5.2 Prognosis of IDH -mutant gliomas
Parsons et al. [2] initially demonstrated that
5.3 Prognostic classification for gliomas
Suzuki et al. [28] distinguished lower grade gliomas on the basis of the presence of
Among
6. The mechanism of tumorigenesis in IDH1 -mutant gliomas
6.1 IDH mutation drives production of oncometabolite D-2-hydroxyglutarate
In humans, IDH is composed of three types of isozymes (IDH1, IDH2, and IDH3). IDH1 is located in the cytoplasm and peroxisomes, whereas IDH2 and IDH3 are localized in the mitochondria and are involved in the TCA cycle. IDH1 and IDH2 are NADP+ dependent, whereas IDH3 is NAD+ dependent. IDH converts isocitrate into α-ketoglutarate (α-KG). No mutation in
6.2 IDH -mutation induced epigenetic alterations
6.2.1 IDH -mutation inducible DNA hypermethylator phenotype
Since the structure of 2-HG is similar to that of α-KG, 2-HG inhibits a variety of α-KG-dependent dioxygenases [59, 60]. Among them, 10–11 translocation-2 (TET2) induces global demethylation of DNA by catalyzing the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). Forced mutant
The Cancer Genome Atlas (TCGA) performed comprehensive transcriptome analysis. Accordingly, GBM was classified into four groups (classic, mesenchymal, proneural, and neural groups). Aberrations and gene expression of
6.2.2 IDH mutation promotes global histone methylation
6.3 IDH mutation inducible metabolic alterations
In addition to the epigenetic changes,
While several studies demonstrated that the
Cancer cells are known to depend on reductive carboxylation (RC) of glutamine-derived α-KG for
Altered amino acids, glutathione, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were observed in
Importantly, branched-chain amino acid transaminase (BCAT), which catalyzes the α-KG to glutamate conversion, was expressed at lower levels in
7. Role of extensive resection in IDH1 -mutant gliomas
There is a huge amount of evidence showing that surgical resection has a pivotal role in survival benefit of glioma patients. Extensive resection is known to prolong survival in low grade glioma and also in GBM (
In addition, Beiko et al. [97] reported that extensive resection, including nonenhancing area, prolonged survival in
8. Prediction of IDH status
To establish
9. Treatment vulnerability in IDH -mutant gliomas
9.1 Radiotherapy for IDH- mutant gliomas
It has been shown that there is a higher relative sensitivity to radiotherapy and concurrent temozolomide (TMZ) in
9.2 Chemotherapeutic evidence for IDH -mutant gliomas
9.2.1 Temozolomide
Current standard management of GBM consists of surgical tumor resection, following local radiotherapy with temozolomide treatment [125]. Additionally, adjuvant TMZ prolonged survival in anaplastic astrocytoma [126]. Several studies demonstrated
Cytotoxicity of TMZ is provoked by the formation of O6-methylguanine (O6G)-DNA adducts. O6G-DNA adducts induce DNA strand break and apoptosis through the O6G-thymine-mediated mismatch repair pathway [129, 130]. It has also been established that the activation of DNA repairing pathways, including methylguanine methyltransferase (MGMT) repair enzyme, together with mismatch repair (MMR) system proteins deficiency, such as mutation-induced MSH2 and MSH6, result in drug resistance [131, 132, 133].
Some preclinical studies demonstrated that forced
In contrast, TMZ-induced hypermethylation is a critical problem. Long-term TMZ exposure induces MMR inactivation, followed by DNA hypermutation phenotype. Among numerous mutations, gene alterations in RB and AKT-mTOR pathways promoted malignant progression in
9.2.2 Other chemotherapeutic agents
Sulkowski et al. [144] demonstrated that 2-HG inhibits KDM4A and KDM4B, histone demethylases that play a critical role in double strand repair. As a result,
10. Novel therapeutic target in IDH1 -mutant tumors
10.1 Specific IDH inhibitor
In 2013, specific inhibitors for
In
10.2 Other treatment strategies
10.2.1 DNA demethylating agents
In addition to IDH1 inhibitor treatments, other strategies to control
10.2.2 Bcl-2 family inhibitors
Since 2-HG suppresses the activity of cytochrome c oxidase in mitochondrial complex IV, the mitochondrial threshold for apoptosis was decreased after BCL-2 inhibition in
10.2.3 DNA damaging agents
Because PLK1 activation provokes a rapid bypass through the G2 checkpoint after TMZ treatment in
10.2.4 DLL-3 targeting therapy
Since Notch ligand DLL-3 is overexpressed in
10.2.5 Vaccination therapy
Schumacher et al. [165] reported an immunological approach to control
10.2.6 Target for altered metabolism
Mutant
Because of the relationships between
11. Conclusions
In summary, investigations on
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