|Year : 2018 | Volume
| Issue : 5 | Page : 129-133
IDH gene mutation in glioma
Leping Liu1, Xuejun Li2
1 Xiangya Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
2 Xiangya Hospital, Xiangya School of Medicine, Central South University; School of Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
|Date of Web Publication||30-Oct-2018|
Prof. Xuejun Li
Xiangya Hospital, Xiangya School of Medicine, Central South University, Changsha 410008, Hunan
Source of Support: None, Conflict of Interest: None
Glioma is one of the most common intracranial malignant tumors. Its development is associated with mutations in the isocitrate dehydrogenase (IDH) gene. IDH plays an important role in the tricarboxylic acid cycle, and when mutated, it can downregulate the expression of α-ketoglutarate and convert it to 2-hydroxypentaric acid (2-HG), activating the HIF-1 pathway to promote the development of glioma. This article briefly describes the role of IDH mutations in glioma development and progression and its relationship with other gene mutations. This information may provide a new perspective toward the treatment, molecular pathological grading, and prognosis of glioma.
Keywords: 2-HG, gene mutation, glioma, HIF-1, isocitrate dehydrogenase
|How to cite this article:|
Liu L, Li X. IDH gene mutation in glioma. Cancer Transl Med 2018;4:129-33
| Introduction|| |
Glioma is the most common primary brain tumor, accounting for 81% of central nervous system malignant tumors, with an incidence of 5 to 8/10 million people, which has been increasing over time and is a serious threat to human health. In 2007, the World Health Organization classified gliomas into Grades I to IV glioma: hair cell astrocytoma (I), diffuse astrocytoma (II), anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic astrocytoma (Grade III), and pleomorphic glioblastoma (Grade IV).
Currently, the standard treatment is surgery, radiotherapy, and chemotherapy. Since malignant gliomas demonstrate invasive growth, a high recurrence rate, and high mortality, the current conventional treatment has difficulty in achieving satisfactory results, and thus the biological treatment approach has become a hot topic of research. With the development of molecular biology, few molecular markers related to the pathogenesis and prognosis of GBM have been identified, such as TP53 mutations,TERT promoter region mutations, EGFRVIII amplification, PTEN deletions, and 1p/19q combined deletions.
There are different molecular markers of gliomas despite similar histological features. Therefore, the discovery of molecular markers is of great significance in molecular subclassification of gliomas and the diagnosis and prognosis of glioma patients. Mutations in the metabolic enzyme gene have an effect on cellular metabolism, and mutations in metabolic enzymes have been observed in several cancer markers. In recent years, mutations in the IDH1 and IDH2 genes, of the isomer citrate dehydrogenase (IDH) gene family, have been shown to be some of the molecular markers that are of great significance in the development of glioma. After mutation of IDH1/2, α KG can be converted to 2-hydroxyglutaric acid (2-HG) that accumulates in cells, and an increase in 2-HG concentration can be detected in the serum of IDH-mutant glioma patients. Since 2-HG content is extremely low in normal tissues, it can serve as a biomarker for glioma diagnosis and prognosis. In this paper, the role of IDH1/2 gene mutations is discussed to reveal their important role in the molecular pathology of glioma.
| IDH Mutations Reported in Gliomas|| |
Parsons et al. identified mutations in the IDH1 gene in 12% of the samples when screening for glioblastoma gene mutations. However, the report from Parsons is only the tip of the iceberg of IDH tumor biology, as many follow-up studies have confirmed and expanded the results of the study. Larger glioma sample groups have reported that up to 70% of the tumors carry IDH1 mutations, and the presence of the mutation has been identified in Grade II and Grade III gliomas and in secondary GBM. Importantly, IDH1 mutations have a high incidence in low-grade gliomas (Grade II gliomas and secondary gliomas), such as diffuse astrocytomas (68%), oligodendrogliomas (69%), oligodendrocytes (78%), and secondary glioblastoma (88%), suggesting IDH1 mutation as an early event in the development of gliomas. It is believed that the IDH1 gene mutation not only occurs in the late stage of the tumor but also exists in the early stage of the disease. Therefore, IDH1 mutations can be important tumorigenic factors in gliomas.
However, compared with other reported genetic lesions, how early does an IDH1 mutation develop in glioma? TP53 is a tumor suppressor gene, which is related to the stability of glioma. TP53 encodes a protein that regulates the cell cycle and avoids cell carcinogenesis, and if its pathway is mutated, this usually leads to poor outcomes and cancer development. Biopsies from 51 patients showed that, in all cases, IDH1 mutations preceded TP53 mutations, indicating a possible involvement of IDH1 mutations in the transformation of glial precursor cells. Subsequent mutations in IDH2 were also found in gliomas, but these mutations were uncommon and were mutually exclusive with IDH1 mutations. At present, all mutations are in arginine residues in IDH1, R132, or IDH2 (R172), which are transformed into histidine.
Recent in vitro studies have shown that the mutated IDH1 protein converts α-ketoglutarate (α-KG) to R (-)-2-hydroxypentaric acid (2-HG) by activating the HIF-1 pathway, leading to tumor development. The activation of this pathway is considered to be one of its carcinogenic pathways. Choi et al. recently reported that 2-HG can be detected in IDH-mutant gliomas using magnetic resonance spectroscopy (MRS), and noninvasive detection of 2-HG can be a valuable diagnostic biomarker. The study by Turcan et al. demonstrated the functional correlation between the IDH mutation and the G-CIMP phenotype, demonstrating that the IDH mutation is the cause of the G-CIMP phenotype. Subsequent studies have shown that IDH mutations are associated with dysregulation of glial differentiation and overall histone methylation in low-grade glioma, and 2-HG inhibits histone demethylation and blocks the differentiation of nontransformed cells., These results indicate that IDH mutants have a variety of biological functions.
Qi et al. analyzed IDH1 and IDH2 states in 53 matched samples and relapsed samples by direct sequencing and anti-IDH1-R132H immunohistochemistry, among which 22 gliomas showed recurrence and malignant progression, but the recurrence of the glioma was unrelated to the presence of an IDH1 mutation. Survival analysis showed that progression-free survival (PFS) and overall survival (OS) were significantly prolonged in IDH1-mutant glioma patients. This study shows that while IDH1/IDH2 is of great significance in the treatment of glioma, the presence of an IDH mutation is not a predictor of malignant progression, but a potential prognostic marker for gliomas.
| The Mechanism of IDH Mutation in Glioma|| |
Leads to activation of the HIF-1α pathway
A large number of experiments have confirmed that the relationship between IDH1 mutation and glioma development is very strong, but the specific mechanism has not yet been determined. IDH1 is present in the cytoplasm and peroxisomes, while IDH2 and IDH3 are present in the mitochondria. Each of them is chained and provides energy in the tricarboxylic acid cycle. Wild-type IDH1 and IDH2 are NADP+-dependent IDH, and they catalyze isocitrate oxidation to decarboxylation to alpha-KG followed by production of NADPH from NADP+.
In normal cells, mitochondrial NADPH plays an important role in the defense against reactive oxygen species (ROS) and in the regulation of NADPH-dependent glutathione reductase. All mutations identified so far are in similar residues, R172 in IDH2 or R132 in IDH1, which are mutated from arginine to histidine. R132 is located in the active site of IDH1 and related studies have shown that the mutation can lead to a decrease in its activity. Although preliminary reports have indicated that mutant IDH exerts negative regulation through heterodimerization with wild-type IDH I and attenuates its activity, recent in vitro studies have shown that mutant IDH1 proteins have acquired the ability to convert α-KG to 2-HG. The function of the enzyme is lost during the positive transformation of isocitric acid to α-KG, leading to tumorigenesis.
In addition to participating in metabolism, α-KG has other important roles. Prolyl hydroxylase (PHD) is a dioxygenase that catalyzes many reactions using α-KG as a substrate, such as repairing alkylated DNA, sensing oxygen levels, and responding to hypoxia. HIF-1 is involved in the regulation of gene expression in the hypoxic environment, and its activation is involved in angiogenesis, cell survival, glucose metabolism, and transcription of invasive genes, all of which can increase the mortality of cancer patients. When α-KG levels are reduced and 2-HG levels increase, HIF-1α accumulates and activates HIF-1, leading to tumorigenesis. In addition, P53-induced (II) collagen-prolyl-4-hydroxylase, another member of the PHD family, produces an anti-angiogenic collagen fragment that is regulated by the 2-HG allogene in mutant IDH cells. As [Figure 1] shows, through these two mechanisms, 2-HG competitively inhibits PHD enzymes and has the potential to promote tumor angiogenesis.
|Figure 1: The picture shows the mutation of IDH in the tricarboxylic acid cycle and the pathway that leads to tumorigenesis after the mutation|
Click here to view
IDH is the first generation of metabolic enzymes, and its genetic and biochemical changes have been incorporated into tumor biology. 2-HG can be used as an important biomarker for tumors with IDH1/2 mutations. Choi et al. recently reported that 2-HG can be detected using MRS in IDH-mutant gliomas, and the presence of highly elevated levels of 2-HG (10–100 times) can identify tumors with IDH1/2 mutations. In the absence of a 1P/19Q codeletion, the largest range of IDH-mutant gliomas in surgical resection can provide patients with a more significant survival benefit. Noninvasive imaging methods to detect IDH-mutant tumors can provide clinicians with more personalized surgical strategies.
Modifying the histones and influencing the methylation level of DNA
DNA methylation and histone methylation are important mechanisms for regulating gene expression and cell differentiation and establishing the balance between methyltransferase and demethylase activity maintains methylation levels. α-KG is a substrate for these enzymes, including histone demethylation enzyme-1 (JHDM1), jumonji histone demethylase (JMJD2), Jmj C domain, and 5 mC hydroxylase, the TET family. The inhibitory effect of 2-HG is weak, its affinity to the enzyme active site is only 1% of α-HG, and a small amount of 2-HG cannot inhibit the activity of histone demethylation enzyme effectively. However, when the IDH gene mutation occurs in vivo, the activity of histone demethylase can be inhibited by downregulating the expression of α-KG and upregulating the expression of 2-HG.
High levels of 2-HG also inhibit 5-methylpyrimidine hydroxylase, causing DNA hypermethylation. Thus, the mutant IDH can affect local or systemic methylation patterns through competitive inhibition of histone demethylase of 2-HG, altering the expression of oncogenes, tumor suppressor genes, or other critical and metabolic pathway components. It is worth noting that IDH1 mutations are associated with promoter methylation of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT removes the O6-methylguanine DNA adduct produced by TMZ by transferring the methyl adduct to its own cysteine, and thus the glioblastoma patients with MGMT methylation have a favorable prognosis. In addition, α-KG-dependent metabolic enzymes can also be inhibited by 2-HG, such as JLP1, and by a-KG-dependent dioxygenase, which is involved in sulfonate catabolism. Thus, mutant IDH can affect the adaptation of cells to environmental and nutritional stress. Structural similarities between D-2-HG and glutamate indicate that 2-HG can affect excitotoxicity by activating glutamate receptors (N-methyl-D-aspartate-MNDA receptors) in neurons. The relevant experiments show that the activation of NMDA receptors with 2-HG in the brains of rats can interfere with intracellular calcium homeostasis and cause the production of ROS. IDH is an important NADPH-producing enzyme and inactivation of its positive response or an increase in reverse function through somatic mutations can alter the cell's NADPH/NADP+ ratio, resulting in mitochondrial dysfunction. Importantly, NADPH prevents oxidative stress through the production of glutathione, and without its formation, there can be damage to DNA and free radical formation. Other metabolic nodules, such as pentose phosphate, that are regulated by NADPH/NADP+ ratios, may also be affected, leading to metabolic changes and cellular stress. The TCGA group has recently reported a large number of hypermethylations in GBM, known as the CpG island methylation phenotype (G-CIMP), which are associated with IDH1 gene mutations. G-CIMP can identify different glioma subtypes, indicating that IDH1 mutations play an important role in epigenetic changes of genes.
The above studies suggest that the possible pathogenesis of glioma is that IDH1 or IDH2 mutations lead to a loss of isocitrate oxidative decarboxylation and reduction of α-HG to 2-HG to stabilize HIF-1α (and PHD activity is inhibited in IDH1-mutated cell lines), altering DNA and histone methylation patterns, leading to the accumulation of ROS-driven tumors. It is obvious that this metabolic pathway is an important tumorigenic pathway in gliomas.
| The Relationship between IDH Gene Mutations and Other Gene Mutations|| |
Studies of glioma biology over the past 25 years have found hundreds of molecular changes in Grade II, III, and IV gliomas, and three changes are particularly noteworthy because they occur early in glioma formation, are prevalent in glioma, or are strongly associated with OS. The first identified change is the 1p/19q chromosome deletion, which is associated with the oligodendrocyte histological type and is sensitive to chemotherapies using alkylating agents. This is followed by IDH mutations, which are not limited to specific histopathological types of gliomas but are associated with specific types of tumor cell metabolism. The third is a mutation in the TERT promoter, which encodes telomerase. However, TERT promoter mutations were observed in the most aggressive class IV astrocytomas and in minimal invasive Grade II oligodendrogliomas, both of which resulted in increased telomerase activity and telomere elongation, indicating that the terminal granule maintenance may be a necessary prerequisite for brain tumor formation. TERT promoter mutations are mutually exclusive with TP53 mutations but occur simultaneously with deletions of the 1p/19q chromosome. In addition, certain germline polymorphisms are associated with specific histological types of gliomas, particularly in relation to tumor-specific mutations, such as those that affect IDH. For example, a single-nucleotide polymorphism (SNP) on chromosome 8q24 (rs55705857 in dbSNP) is associated with IDH-mutant gliomas, increases up to 6 times in IDH-mutant gliomas and is associated with PFS in patients treated with captopril, lomustine, and vincristine.
Eckel-Passow et al. 27 grouped the gliomas based on the above three mutations and determined whether these groups have specific clinical characteristics, are enriched with specific acquired somatic cells, or are correlated with germline variants. In 615 Grade II/III gliomas, 29% had all three changes (i.e., triple positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple negative, and 10% and 5% had other combinations. In 472 cases of Grade IV gliomas, fewer than 1% were triple positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple negative, and 74% had only TERT mutations. In patients with gliomas with only IDH mutations, the mean age at diagnosis was the lowest (37 years) and they had an intermediate prognosis. The mean age of the patients with only TERT mutations was the highest (59 years) and they had the lowest survival rate. This group also evaluated the association between the five glioma groups and the nine factors known to be associated with gliomas. These groups had different ages of onset, OS, and association with germline variants, implying that they are characterized by different pathogenesis pathways.
Researchers evaluating IDH mutations, EGFR amplification, and TERT mutations have proposed a new prognostication model for glioma patients. In the case of TERT mutations or EGFR amplification, the prognosis of patients is poor and the intermediate survival time is approximately 12 to 16 months. In the absence of changes in EGFR, the prognosis is better. IDH wild-type have an intermediate survival period of more than 2 years and those with an IDH mutation of more than 3 years.
Furnari et al. found that in 30 cases of glioblastoma patients, IDH mutations and 1p/19q deletions both occurred at a high frequency. In diffuse astrocytoma, the TP53 and IDH mutation relationship is more obvious, while in Grade II–III glioma, MGMT promoter methylation and IDH mutations are more closely correlated. IDH mutations and 1p/19q codeletion are independent prognostic factors for patients with Grade III gliomas. IDH mutations can increase the risk of survival in patients with Grade III glioma without 1q/19q deletions, but for Grade II glioma or glioblastomas, there was no obvious correlation. Thus, IDH mutations are more useful in predicting the outcomes of non-1p/19q-deficient Grade III gliomas. In summary, the combination of multiple glioma molecular marker analysis for glioma research, prognosis, and diagnosis is of great significance.
| Treatment Strategy|| |
Understanding the metabolic processes of IDH mutations promoting tumor growth can provide researchers with new ideas for treating gliomas, thereby developing targeted drugs that benefit clinical patients. Since the enzyme encoded by the IDH gene acts as a catalytic isoenzyme and is closely related to the energy-generating tricarboxylic acid cycle, mutations in the IDH gene may interfere with intracellular DNA methylation, amino acid concentration, and enzyme activity. At present, a specific antibody against mIDH1R132H, the expression product of the IDH1 gene mutation, has been commercialized. It can be used to label, identify, and judge the prognosis of glioma by immunohistochemistry. In addition to better classification and prognosis, IDH mutations may provide new targets for the development of new drugs. So far, only a few studies of dehydrogenase inhibitors are reported, and only the inositol monophosphate dehydrogenase inhibitors have entered clinical development., Other clinical examples include gossypol, which is a polyphenolic hormone that inhibits dehydrogenase, and although its low efficiency and poor performance impedes its clinical use, its chemical scaffold can provide a starting point for pharmacochemical design or can be used as an inhibitor binding model for other drug-like chemical scaffolds; for example, the substituted 2,3-dihydroxy-1-naphthoic acid can bind lactate dehydrogenase A dinucleotide pockets with good potency. When designing inhibitors of the enzyme's active site, especially for NADPH competitive inhibitors, they tend to inadvertently inhibit other NADPH-using enzymes. For example, nonspecific inhibition of wild-type IDH1 and IDH2 in the heart or liver will significantly reduce its therapeutic effect, so drugs used in clinical treatment have to have a high degree of selectivity. A dual-ligand inhibitor, such as an inhibitor that spans both cofactors and substrate sites, exhibits good selectivity in oxidoreductases, indicating that highly specific inhibitors of IDH mutations are possible in theory.
With the deepening of the understanding of tumor angiogenesis, anti-angiogenesis therapy for glioma treatment provides a new strategy. CD105 is a specific marker of endothelial cell proliferation. CD105MVD is significantly increased in HIF-1α and COX-2 positive groups, which increases in correlation with increase in CD105MVD. Huang et al.33 have confirmed that the effect of COX-2 on VEGF is accomplished by upregulating the expression of HIF-1α by its product PGE2, thereby promoting new tumor angiogenesis. There are drugs that have a role in regulating VEGF. Bevacizumab is a monoclonal antibody targeting VEGF, and although the US FDA has approved this drug for use against recurrent glioblastoma and for interstitial glioma treatment, it cannot extend the OS of newly diagnosed glioma patients, and there are still no available conventional first-line drugs for the treatment of new gliomas.,
| Discussion|| |
IDH1 is the first mutated gene to be found in glioma using genomic approaches, and it is an important metabolic enzyme in the Krebs cycle. IDH mutations can lead to the activation of the HIF-1 pathway, which provides a useful idea for the development of therapeutic glioma drugs. The α-KG analogs can inhibit HIF-1α activity and block the activation of this pathway, and thus researchers can develop drugs that, like α-KG analogs, inhibit proliferation of tumor cells. The presence of IDH mutations poses both advantages and disadvantages for glioma patients. The advantage is that the patients with IDH mutations have a good prognosis, but the disadvantage is that it also promotes glioma deterioration. IDH1 gene mutation detection has been carried out in domestic organizations and genomic methods can be used to detect and predict the outcome of glioma by combined detection of multiple molecular markers. IDH has great potential for clinical application, and we believe that with the further development of molecular genetics and immunology technology, we will have a deeper understanding of IDH gene mutations. For preclinical studies, alternative treatment strategies based on metabolic load, chemosensitivity, and telomere maintenance mechanisms for gliomas with IDH mutations will be important.
We thank Dr. Feiyifan Wang for thoughtful discussions and comments on the manuscript.
Financial support and sponsorship
This work was supported financially by grants from the National Natural Science Foundation of China (81472594 & 81770781).
Conflicts of interest
There are no conflicts of interest.
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