Diagnosis of CNS Tumors

**15**

**Chapter 2**

**Abstract**

*IDH*-Mutant Gliomas

*Kensuke Tateishi and Tetsuya Yamamoto*

therapeutic approach for *IDH* mutant tumors.

tumorigenesis and as novel therapeutic targets.

**2. Discovery of** *IDH* **mutations in cancers**

fied at codon 172 in gliomas [4, 7].

cancer metabolism, target therapy

**1. Introduction**

*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

**Keywords:** *IDH* mutation, glioma, 2-hydroxyglutarate, tumor biology,

The WHO 2016 classification integrates molecular and histological features in the diagnosis of gliomas. Among numerous genomic alterations, the *isocitrate dehydrogenase* (*IDH*) mutation is one of the most important genetic alterations found in this kind of tumor. As *IDH* mutation is a ubiquitous mutation in lower grade gliomas, the development of molecular target therapies against *IDH* mutations is expected. Here, we review *IDH*-mutant gliomas, focusing on their role in

The presence of an *isocitrate dehydrogenase* (*IDH*) mutation was first discovered in colorectal cancers [1]. Parsons et al. [2] found mutations of the *IDH1* (2q.33) in 12% of the glioblastomas (GBMs). Other large scale studies validated that *IDH1* and *IDH2* (*IDH*) mutations were found in the majority of secondary GBM and lower grade (WHO grade II and III) gliomas, whereas these were rarely found in adult primary and pediatric GBMs [2–4]. Almost all of the *IDH1* mutations occur at codon 132, >90% of them exhibit a c.395G>A (R132H) substitution, followed by R132C [3, 5, 6]. Although the frequency was low, *IDH2* mutations were also identi-

Besides, *IDH* mutation was found in hematopoietic cancers, including acute myeloid leukemia (AML; 10–15%, *IDH2*) [8, 9], angioimmunoblastic T-cell lymphoma (AITL, 20%) [10], chondrosarcoma (~50%) [11–13], intrahepatic cholangiocarcinoma (15–20%, *IDH1*) [13], and at lower frequency in other hematopoietic

## **Chapter 2** *IDH*-Mutant Gliomas

*Kensuke Tateishi and Tetsuya Yamamoto*

## **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 *isocitrate dehydrogenase* (*IDH*) mutation is one of the most important genetic alterations found in this kind of tumor. As *IDH* mutation is a ubiquitous mutation in lower grade gliomas, the development of molecular target therapies against *IDH* mutations is expected. Here, we review *IDH*-mutant gliomas, focusing on their role in tumorigenesis and as novel therapeutic targets.

## **2. Discovery of** *IDH* **mutations in cancers**

The presence of an *isocitrate dehydrogenase* (*IDH*) mutation was first discovered in colorectal cancers [1]. Parsons et al. [2] found mutations of the *IDH1* (2q.33) in 12% of the glioblastomas (GBMs). Other large scale studies validated that *IDH1* and *IDH2* (*IDH*) mutations were found in the majority of secondary GBM and lower grade (WHO grade II and III) gliomas, whereas these were rarely found in adult primary and pediatric GBMs [2–4]. Almost all of the *IDH1* mutations occur at codon 132, >90% of them exhibit a c.395G>A (R132H) substitution, followed by R132C [3, 5, 6]. Although the frequency was low, *IDH2* mutations were also identified at codon 172 in gliomas [4, 7].

Besides, *IDH* mutation was found in hematopoietic cancers, including acute myeloid leukemia (AML; 10–15%, *IDH2*) [8, 9], angioimmunoblastic T-cell lymphoma (AITL, 20%) [10], chondrosarcoma (~50%) [11–13], intrahepatic cholangiocarcinoma (15–20%, *IDH1*) [13], and at lower frequency in other hematopoietic and solid cancers, such as B-acute lymphoblastic leukemia (B-ALL), esophageal cancer, colorectal cancer, melanoma, prostate carcinoma, and breast adenocarcinoma [1, 4, 14–16].

## **3. Tumorigenesis of** *IDH***-mutant gliomas**

#### **3.1 Genomic characteristics of** *IDH***-mutant glioma**

The discovery of *IDH* mutations allowed the distinction of primary GBM, which is genetically characterized by *TERT* promoter mutation, gene alteration of epidermal growth factor receptor (*EGFR*), phosphatase and tensin homolog (*PTEN*) mutation or deletion, trisomy 7, monosomy 10, and cyclin-dependent kinase inhibitor 2A (*CDKN2A*) homozygous deletion, from secondary GBM (GBM*, IDH-*mutant) [3, 5, 17, 18].

In astrocytic tumors, most of the tumor cells have co-mutations in *IDH1, TP53*, and *ATRX*. Moreover, WHO 2016 [19] defined the presence of *IDH* mutation and codeletion of chromosome1p and 19q as necessary for the diagnosis of oligodendroglial tumors. Also, in oligodendroglial tumors, *TERT* promoter mutation is almost always present (>95%), while *CIC and FUBP1* are commonly (>40%) observed. These genetic abnormalities for astrocytic and oligodendroglial tumors are mutually exclusive [20–24]. Importantly, the *IDH* mutation is the earliest genetic alteration observed; it is commonly retained during tumor progression [25–28], but in a subset of mutants, *IDH1* was either deleted or amplified at tumor recurrence [29], indicating the critical role of *IDH* mutation for tumorigenesis. It has also been shown that *IDH* mutations do not select or create *ATRX* or *TERT* promoter mutations [30].

#### **3.2 Developmental hierarchy in** *IDH***-mutant gliomas**

Two recent large scale single cell RNA-sequencing studies revealed a developmental hierarchy in *IDH1-*mutant gliomas [31, 32]. Accordingly, *IDH1*-mutant astrocytoma and oligodendroglioma shared a similar developmental hierarchy, consisting of three subpopulations of malignant cells: nonproliferative astrocytic and oligodendrocytic cells, proliferative, and undifferentiated neural stem/progenitor cells. In contrast, tumor micro environment (TME) was different in the abundance microglia/macrophage cells between astrocytic and oligodendroglial tumors. TME also differs between astrocytic tumors of different grades. Though TME and genomic alterations are distinctive, evidence indicates the existence of common progenitor cells in *IDH1*-mutant gliomas. In higher grade tumors, undifferentiated glioma stem/progenitor cells were increased [32]. In addition, almost all proliferating cancer cells were composed of subpopulations of undifferentiated cells (stemlike) in oligodendroglioma [31], suggesting a significant role for undifferentiated cells in cell proliferation and malignant progression.

#### **3.3** *IDH***-mutant xenograft model**

Although *IDH1* mutation induced proliferation *in vitro* [33], *IDH1* mutation did not promote xenograft formation [34–36]. Intriguingly, Bardella et al. [37] demonstrated that IDH1R132H overexpression in the murine subventricular zone induced the formation of early gliomagenesis, where stem and transit amplifying/progenitor cell populations were expanded, indicating the pivotal role of *IDH1* mutation in glioma formation. Moreover, Wakimoto et al. demonstrated that "tertiary mutations," such as *PIK3CA* mutation, *PDGFRA* amplification, and *MYC* amplification, promote

**17**

*IDH-Mutant Gliomas*

**Figure 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

*IDH1*-mutant glioma formation in xenograft models. Importantly, tumor harboring tertiary mutations were associated with unfavorable prognosis in *IDH1*-mutant glioma patients [38]. Recently, large genomic analyses demonstrated that malignant progression in *IDH1*-mutant glioma is associated with the *PI3K* pathway and *MYC* activation [39, 40]. Thus, *IDH* mutation induces gliomagenesis, whereas tertiary mutations are

*Genomic alteration and tumor microenvironment in IDH-mutant astrocytic and oligodendroglial tumors.*

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 *IDH* mutation, co-deletion of chromosome1p and 19q, or *ATRX* and *TP53* mutations. Accordingly, gliomas are classified as follows: (1) diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (AA, WHO grade III): *IDH*-mutant, -wildtype, or not otherwise specified (NOS); (2) oligodendroglioma (WHO grade II) or anaplastic oligodendroglioma (WHO grade III): *IDH*-mutant and 1p/19q-codeleted or NOS; (3) oligoastrocytoma (grade II) and anaplastic oligoastrocytoma (WHO grade III): NOS; (4) GBM (WHO grade IV): *IDH*-mutant, -wildtype, or NOS; and (5) diffuse

*IDH*-wildtype GBM (about 90% of cases) is known as primary GBM, while *IDH*-mutant GBM (about 10% of cases) corresponds to secondary GBM [19].

According to some statistical analyses, the *IDH-*mutant GBM or anaplastic astrocytoma patients were more than 20 years younger than those with

critical to promote tumor progression in lower grade gliomas (**Figure 1**).

**4. The 2016 WHO classification**

midline glioma (WHO grade IV): H3K27M-mutant.

**5. Epidemiology of** *IDH***-mutant gliomas**

**5.1 Age distribution of** *IDH***-mutant gliomas**

#### *IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

#### **Figure 1.**

*Brain and Spinal Tumors - Primary and Secondary*

**3. Tumorigenesis of** *IDH***-mutant gliomas**

**3.1 Genomic characteristics of** *IDH***-mutant glioma**

**3.2 Developmental hierarchy in** *IDH***-mutant gliomas**

cells in cell proliferation and malignant progression.

**3.3** *IDH***-mutant xenograft model**

noma [1, 4, 14–16].

*IDH-*mutant) [3, 5, 17, 18].

and solid cancers, such as B-acute lymphoblastic leukemia (B-ALL), esophageal cancer, colorectal cancer, melanoma, prostate carcinoma, and breast adenocarci-

The discovery of *IDH* mutations allowed the distinction of primary GBM, which is genetically characterized by *TERT* promoter mutation, gene alteration of epidermal growth factor receptor (*EGFR*), phosphatase and tensin homolog (*PTEN*) mutation or deletion, trisomy 7, monosomy 10, and cyclin-dependent kinase inhibitor 2A (*CDKN2A*) homozygous deletion, from secondary GBM (GBM*,* 

In astrocytic tumors, most of the tumor cells have co-mutations in *IDH1, TP53*, and *ATRX*. Moreover, WHO 2016 [19] defined the presence of *IDH* mutation and codeletion of chromosome1p and 19q as necessary for the diagnosis of oligodendroglial tumors. Also, in oligodendroglial tumors, *TERT* promoter mutation is almost always present (>95%), while *CIC and FUBP1* are commonly (>40%) observed. These genetic abnormalities for astrocytic and oligodendroglial tumors are mutually exclusive [20–24]. Importantly, the *IDH* mutation is the earliest genetic alteration observed; it is commonly retained during tumor progression [25–28], but in a subset of mutants, *IDH1* was either deleted or amplified at tumor recurrence [29], indicating the critical role of *IDH* mutation for tumorigenesis. It has also been shown that *IDH* mutations do not select or create *ATRX* or *TERT* promoter mutations [30].

Two recent large scale single cell RNA-sequencing studies revealed a developmental hierarchy in *IDH1-*mutant gliomas [31, 32]. Accordingly, *IDH1*-mutant astrocytoma and oligodendroglioma shared a similar developmental hierarchy, consisting of three subpopulations of malignant cells: nonproliferative astrocytic and oligodendrocytic cells, proliferative, and undifferentiated neural stem/progenitor cells. In contrast, tumor micro environment (TME) was different in the abundance microglia/macrophage cells between astrocytic and oligodendroglial tumors. TME also differs between astrocytic tumors of different grades. Though TME and genomic alterations are distinctive, evidence indicates the existence of common progenitor cells in *IDH1*-mutant gliomas. In higher grade tumors, undifferentiated glioma stem/progenitor cells were increased [32]. In addition, almost all proliferating cancer cells were composed of subpopulations of undifferentiated cells (stemlike) in oligodendroglioma [31], suggesting a significant role for undifferentiated

Although *IDH1* mutation induced proliferation *in vitro* [33], *IDH1* mutation did not promote xenograft formation [34–36]. Intriguingly, Bardella et al. [37] demonstrated that IDH1R132H overexpression in the murine subventricular zone induced the formation of early gliomagenesis, where stem and transit amplifying/progenitor cell populations were expanded, indicating the pivotal role of *IDH1* mutation in glioma formation. Moreover, Wakimoto et al. demonstrated that "tertiary mutations," such as *PIK3CA* mutation, *PDGFRA* amplification, and *MYC* amplification, promote

**16**

*Genomic alteration and tumor microenvironment in IDH-mutant astrocytic and oligodendroglial tumors.*

*IDH1*-mutant glioma formation in xenograft models. Importantly, tumor harboring tertiary mutations were associated with unfavorable prognosis in *IDH1*-mutant glioma patients [38]. Recently, large genomic analyses demonstrated that malignant progression in *IDH1*-mutant glioma is associated with the *PI3K* pathway and *MYC* activation [39, 40]. Thus, *IDH* mutation induces gliomagenesis, whereas tertiary mutations are critical to promote tumor progression in lower grade gliomas (**Figure 1**).

## **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 *IDH* mutation, co-deletion of chromosome1p and 19q, or *ATRX* and *TP53* mutations. Accordingly, gliomas are classified as follows: (1) diffuse astrocytoma (WHO grade II) or anaplastic astrocytoma (AA, WHO grade III): *IDH*-mutant, -wildtype, or not otherwise specified (NOS); (2) oligodendroglioma (WHO grade II) or anaplastic oligodendroglioma (WHO grade III): *IDH*-mutant and 1p/19q-codeleted or NOS; (3) oligoastrocytoma (grade II) and anaplastic oligoastrocytoma (WHO grade III): NOS; (4) GBM (WHO grade IV): *IDH*-mutant, -wildtype, or NOS; and (5) diffuse midline glioma (WHO grade IV): H3K27M-mutant.

*IDH*-wildtype GBM (about 90% of cases) is known as primary GBM, while *IDH*-mutant GBM (about 10% of cases) corresponds to secondary GBM [19].

## **5. Epidemiology of** *IDH***-mutant gliomas**

#### **5.1 Age distribution of** *IDH***-mutant gliomas**

According to some statistical analyses, the *IDH-*mutant GBM or anaplastic astrocytoma patients were more than 20 years younger than those with

*IDH*-wildtype GBM [4]. In contrast, *IDH*-mutant GBM patients were only 4 years older than those with *IDH1*-mutant grade II and III astrocytoma [41]. This indicates that *IDH*-mutant glioma arises earlier than *IDH*-wildtype glioma (mostly GBM).

#### **5.2 Prognosis of** *IDH***-mutant gliomas**

Parsons et al. [2] initially demonstrated that *IDH1*-mutant GBM patients survived about threefold longer than those with *IDH1*-wildtype GBM. Other groups verified that *IDH1* mutation is a favorable prognostic biomarker in gliomas [4, 42, 43]. In addition to GBM, large amounts of clinical studies indicated that the *IDH* mutation was an independent prognostic factor in grade II and III gliomas [ 4, 28, 43–47]. Notably, the prognosis of *IDH1*-mutant GBM is better than of *IDH1* wildtype AA [48]. Also, a prospective randomized study (NOA-04) revealed that *IDH1* mutation, hypermethylation of the *O<sup>6</sup> -methylguanine DNA-methyltransferase* (*MGMT*) promoter, age, extent of resection, and oligodendroglial histology are independent prognostic factors in anaplastic gliomas [44]. Among them, the impact of *IDH1* mutation conferred a stronger favorable prognosis than 1p/19q co-deletion, *MGMT* promoter methylation, and histology [44]. Collectively, *IDH1* mutation is a convincing prognostic factor in gliomas, irrespective of tumor grade and histology.

#### **5.3 Prognostic classification for gliomas**

Suzuki et al. [28] distinguished lower grade gliomas on the basis of the presence of *IDH1* mutation, *TP53* mutation, and 1p/19q co-deletion. Accordingly, tumors were classified into three groups: type I (*IDH1*-mutant with 1p/19q co-deletion; favorable prognostic group), type II (*IDH1*-mutant with TP53 mutation; intermediate prognostic group), and type III (*IDH1*-wildtype; poor prognostic group). Eckel-Passow et al. [47] classified gliomas into five groups based on the mutation status of *IDH1* and *TERT* promoter and on 1p/19q co-deletion. This group also demonstrated that *TERT* promoter mutations and *ATRX* alterations provided additional information for a tailored prognostic classification [49]. Besides, Arita et al. [50] proposed a classification of grade II–IV gliomas based on the mutations in *IDH* and the hotspot in *TERT* promoter.

Among *IDH*-mutant astrocytic tumors, *CDKN2A/B* homozygous deletion was demonstrated to be an unfavorable prognostic molecular marker [51]. Similarly, another group demonstrated that *PIK3R1* mutation and altered retinoblastoma pathway genes, including *RB1* and *CDKN2A*, were independent predictors of poor survival in astrocytic tumors. In oligodendrogliomas, NOTCH pathway inactivation and PI3K pathway activation were associated with poor prognosis [52, 53]. Collectively, these molecular markers could predict prognosis in glioma patients.

## **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 *IDH3* has been detected in human cancers. If *IDH* is mutated, it blocks normal enzymatic activity and instead produces D-2-hydroxyglutarate (2-HG) from α-KG in an NADPH dependent manner,

**19**

*IDH-Mutant Gliomas*

outcome [65].

*PDGFRA* [67].

*6.2.2 IDH mutation promotes global histone methylation*

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

are required for 2-HG production in glioma cells [58].

**6.2** *IDH***-mutation induced epigenetic alterations**

*6.2.1 IDH-mutation inducible DNA hypermethylator phenotype*

irrespective of the substituted amino acid [54–56]. Compared with *IDH-*wildtype cells, the 2-HG level in *IDH*-mutant cells is 50–100-fold higher [54, 57]. *IDH* mutations are almost always heterozygous, and both mutant and wildtype *IDH1* alleles

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 *IDH1* caused increased 5mC concentrations, instead of decreased 5hmC [37, 61]. *IDH* mutation also promotes methylation of DNA by TET2 inhibition, resulting in a glioma CpG island methylator phenotype (G-CIMP), a specific DNA methylation pattern in *IDH*-mutant tumor cells [61–63]. Indeed, forced overexpression of mutant *IDH* (*IDH1R132H* and *IDH2R172K*) produced high concentrations of 2-HG and increased global 5-mC levels [61]. Similarly, *TET2* mutations, which are mutually exclusive to *IDH* mutations, induce a global hypermethylation signature [61]. Turcan et al. [64] demonstrated that a G-CIMP-like phenotype and G-CIMP positive proneural glioblastomas were formed after the introduction of an *IDH1* mutation into normal human astrocytes (NHA). These data indicate that mutant *IDH* induced TET2 suppression, followed by G-CIMP, in cancer cells. Consistent with *IDH*-mutant glioma patients, glioma patients with G-CIMP are younger at diagnosis and survive longer than those without G-CIMP [62]. Intriguingly, about 10% of G-CIMP tumors were relapsed as G-CIMP low tumors with poor clinical

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 *EGFR* and *NF1* define the classical and mesenchymal subtypes, whereas tumors with an *IDH1* mutation were classified within the proneural group. The proneural group is also accompanied by a *PDGFRA* gene abnormality and the G-CIMP feature [66]. DNA methylation induced by the *IDH1* mutation caused hypermethylation at cohesion and CCCTC-binding factor (CTCF) binding sites and compromised the binding of the insulator protein. As a result, loss of CTCF at a domain permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene

*IDH* mutation is also known to increase histone methylation. Lysine methylation of histone tails modifies chromatin structure and regulates gene expression. By competition with α-KG, 2-HG inhibits histone demethylases including members of the Jumonji transcription factor family (JMJD2A, JMJD2C/KDM4C, and

JHDM1A/FBXL11), resulting in histone hypermethylation [68]. Indeed, hypermethylation in H3K4me1, H3K4me3, H3K9me2, H3K27me2, H3K79me2, H3K27me3, H3K9me3, and H3K36me3 was observed in cells with exogenous 2-HG or mutant *IDH1* induction [60, 63, 64, 69]. Sasaki et al. [63] also demonstrated that *IDH1R132H* knock in mice showed significantly increased early hematopoietic progenitors, histone hypermethylation, and DNA methylation. Interestingly, the elevation of H3K9me3 levels was observed earlier than the DNA methylation

*Brain and Spinal Tumors - Primary and Secondary*

**5.2 Prognosis of** *IDH***-mutant gliomas**

*IDH1* mutation, hypermethylation of the *O<sup>6</sup>*

**5.3 Prognostic classification for gliomas**

in *TERT* promoter.

*IDH*-wildtype GBM [4]. In contrast, *IDH*-mutant GBM patients were only 4 years older than those with *IDH1*-mutant grade II and III astrocytoma [41]. This indicates that *IDH*-mutant glioma arises earlier than *IDH*-wildtype glioma (mostly GBM).

Parsons et al. [2] initially demonstrated that *IDH1*-mutant GBM patients survived about threefold longer than those with *IDH1*-wildtype GBM. Other groups

[4, 42, 43]. In addition to GBM, large amounts of clinical studies indicated that the *IDH* mutation was an independent prognostic factor in grade II and III gliomas [ 4, 28, 43–47]. Notably, the prognosis of *IDH1*-mutant GBM is better than of *IDH1* wildtype AA [48]. Also, a prospective randomized study (NOA-04) revealed that

(*MGMT*) promoter, age, extent of resection, and oligodendroglial histology are independent prognostic factors in anaplastic gliomas [44]. Among them, the impact of *IDH1* mutation conferred a stronger favorable prognosis than 1p/19q co-deletion, *MGMT* promoter methylation, and histology [44]. Collectively, *IDH1* mutation is a convincing prognostic factor in gliomas, irrespective of tumor grade and histology.

Suzuki et al. [28] distinguished lower grade gliomas on the basis of the presence of *IDH1* mutation, *TP53* mutation, and 1p/19q co-deletion. Accordingly, tumors were classified into three groups: type I (*IDH1*-mutant with 1p/19q co-deletion; favorable prognostic group), type II (*IDH1*-mutant with TP53 mutation; intermediate prognostic group), and type III (*IDH1*-wildtype; poor prognostic group). Eckel-Passow et al. [47] classified gliomas into five groups based on the mutation status of *IDH1* and *TERT* promoter and on 1p/19q co-deletion. This group also demonstrated that *TERT* promoter mutations and *ATRX* alterations provided additional information for a tailored prognostic classification [49]. Besides, Arita et al. [50] proposed a classification of grade II–IV gliomas based on the mutations in *IDH* and the hotspot

Among *IDH*-mutant astrocytic tumors, *CDKN2A/B* homozygous deletion was demonstrated to be an unfavorable prognostic molecular marker [51]. Similarly, another group demonstrated that *PIK3R1* mutation and altered retinoblastoma pathway genes, including *RB1* and *CDKN2A*, were independent predictors of poor survival in astrocytic tumors. In oligodendrogliomas, NOTCH pathway inactivation and PI3K pathway activation were associated with poor prognosis [52, 53]. Collectively, these molecular markers could predict prognosis in glioma patients.

**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 *IDH3* has been detected in human cancers. If *IDH* is mutated, it blocks normal enzymatic activity and instead produces D-2-hydroxyglutarate (2-HG) from α-KG in an NADPH dependent manner,

*-methylguanine DNA-methyltransferase*

verified that *IDH1* mutation is a favorable prognostic biomarker in gliomas

**18**

irrespective of the substituted amino acid [54–56]. Compared with *IDH-*wildtype cells, the 2-HG level in *IDH*-mutant cells is 50–100-fold higher [54, 57]. *IDH* mutations are almost always heterozygous, and both mutant and wildtype *IDH1* alleles are required for 2-HG production in glioma cells [58].

## **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 *IDH1* caused increased 5mC concentrations, instead of decreased 5hmC [37, 61]. *IDH* mutation also promotes methylation of DNA by TET2 inhibition, resulting in a glioma CpG island methylator phenotype (G-CIMP), a specific DNA methylation pattern in *IDH*-mutant tumor cells [61–63]. Indeed, forced overexpression of mutant *IDH* (*IDH1R132H* and *IDH2R172K*) produced high concentrations of 2-HG and increased global 5-mC levels [61]. Similarly, *TET2* mutations, which are mutually exclusive to *IDH* mutations, induce a global hypermethylation signature [61]. Turcan et al. [64] demonstrated that a G-CIMP-like phenotype and G-CIMP positive proneural glioblastomas were formed after the introduction of an *IDH1* mutation into normal human astrocytes (NHA). These data indicate that mutant *IDH* induced TET2 suppression, followed by G-CIMP, in cancer cells. Consistent with *IDH*-mutant glioma patients, glioma patients with G-CIMP are younger at diagnosis and survive longer than those without G-CIMP [62]. Intriguingly, about 10% of G-CIMP tumors were relapsed as G-CIMP low tumors with poor clinical outcome [65].

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 *EGFR* and *NF1* define the classical and mesenchymal subtypes, whereas tumors with an *IDH1* mutation were classified within the proneural group. The proneural group is also accompanied by a *PDGFRA* gene abnormality and the G-CIMP feature [66]. DNA methylation induced by the *IDH1* mutation caused hypermethylation at cohesion and CCCTC-binding factor (CTCF) binding sites and compromised the binding of the insulator protein. As a result, loss of CTCF at a domain permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene *PDGFRA* [67].

## *6.2.2 IDH mutation promotes global histone methylation*

*IDH* mutation is also known to increase histone methylation. Lysine methylation of histone tails modifies chromatin structure and regulates gene expression. By competition with α-KG, 2-HG inhibits histone demethylases including members of the Jumonji transcription factor family (JMJD2A, JMJD2C/KDM4C, and JHDM1A/FBXL11), resulting in histone hypermethylation [68]. Indeed, hypermethylation in H3K4me1, H3K4me3, H3K9me2, H3K27me2, H3K79me2, H3K27me3, H3K9me3, and H3K36me3 was observed in cells with exogenous 2-HG or mutant *IDH1* induction [60, 63, 64, 69]. Sasaki et al. [63] also demonstrated that *IDH1R132H* knock in mice showed significantly increased early hematopoietic progenitors, histone hypermethylation, and DNA methylation. Interestingly, the elevation of H3K9me3 levels was observed earlier than the DNA methylation

change in NHA upon IDH1R132H induction [69], suggesting that histone methylation may be an early event in *IDH1*-mutant cancers. The hypermethylation of histones blocks cell differentiation in cancer cells [60, 63, 64, 69]. Using a histone demethylating agent or a specific mutant IDH1 inhibitor, suppressed cell differentiation can be restored [70, 71]. Besides, 2-HG impairs collagen maturation, which leads to basement membrane aberrations that play a part in glioma progression [72]. Taken together, these data show that DNA hypermethylation and histone methylation promote tumorigenesis through a wide range of gene function changes (**Figure 2**).

#### **6.3** *IDH* **mutation inducible metabolic alterations**

In addition to the epigenetic changes, *IDH1* mutation is known to alter hypoxia inducible factor 1α (HIF-1α) activity. Under oxidative conditions, α-KG-dependent prolyl hydroxylases (PHDs), which form the Egl nine homolog (EglN) families, induce HIF-1α hydroxylation. Hydroxylated protein is then bound by the von Hippel-Lindau tumor suppressor protein (VHL), ubiquitylated, and degraded via proteasome. In contrast, under hypoxia, the hydroxylation reaction is inhibited and HIF-1α is upregulated. HIF-1α then activates the transcription of several genes to mediate a switch from oxidative to glycolytic metabolism and induces angiogenesis by regulating the expression of vascular endothelial growth factor (VEGF) [73, 74]. Koivunen et al. [33] demonstrated that *IDH1* mutation attenuates HIF-1α through the activation of HIF prolyl 4-hydroxylase (EGLN), enhancing the proliferation and soft agar growth of NHA.

While several studies demonstrated that the *IDH1* mutation induced aerobic glycolysis via HIF-1α activity [59, 75], other group reported that HIF-1α responsive genes, including lactate dehydrogenase (LDHA) were downregulated; silenced LDHA was associated with increased methylation of the LDHA promoter [76]. Another group showed that *IDH1* mutation reduces pyruvate flux to lactate and suppresses monocarboxylate transporters MCT1 and MCT4, which mediate lactate transmembrane transport [77]. *IDH* mutation also alters pyruvate metabolism, including pyruvate dehydrogenase and pyruvate carboxylase enzymes, resulting in anaplerosis of the TCA cycle [78, 79].

Cancer cells are known to depend on reductive carboxylation (RC) of glutamine-derived α-KG for *de novo* lipogenesis under hypoxia [80]. It is worth noticing

**21**

*IDH-Mutant Gliomas*

gliomas [87].

wildtype GBM.

maximal resection should be considered.

**8. Prediction of** *IDH* **status**

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

that the RC pathway is inhibited by *IDH* mutation [55]. Under hypoxia, *IDH1* muta-

Altered amino acids, glutathione, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were observed in *IDH*-mutant cells [82, 83]. Glutamate dehydrogenase (GDH)1 and GDH2 were overexpressed in *IDH1*-mutant tumors, and the orthotopic growth of an *IDH1*-mutant glioma is inhibited by a double GDH1/2 knockdown [84]. Another group demonstrated that GDH2 was critical for IDH1-mutation induced metabolic alterations and IDH1-mutant glioma growth [85]. The presence of 2-HG also inhibited ATP synthase and mTOR signaling [41]. Importantly, branched-chain amino acid transaminase (BCAT), which catalyzes the α-KG to glutamate conversion, was expressed at lower levels in *IDH1*-mutant gliomas than in *IDH1-*wildtype [86, 87]. As a result, the glutamate level was decreased, and cell proliferation and invasiveness were suppressed in *IDH*-mutant

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 (*IDH1-*wildtype) [88–91]. In *IDH1* mutant gliomas, an MRI study demonstrated that *IDH1*-mutant tumors were rarely located in high risk areas of the brain and show unilateral patterns of growth, sharp tumor margins, and less contrast enhancement [92, 93]. Indeed, radiographic atlas revealed *IDH1*-mutant gliomas were frequently located at frontal lobe [94]. A diffusion-tensor imaging study demonstrated that *IDH*-mutant GBM has a less invasive phenotype than *IDH-*wildtype GBM [95]. Intriguingly, patients with *IDH1* wildtype gliomas had a reduced neurocognitive function and lower performance score than those with *IDH1*-mutant gliomas [96]. In addition, lesion volume was not associated with neurocognitive function for patients with *IDH1*-mutant tumors, but associated for those with *IDH1*-wildtype tumors [96]. Consequently, *IDH1*-mutant gliomas may be relatively less invasive to the surrounding eloquent area than *IDH*-

In addition, Beiko et al. [97] reported that extensive resection, including nonenhancing area, prolonged survival in *IDH1*-mutant anaplastic astrocytoma and glioblastoma. They also mentioned, since *IDH1*-mutant gliomas were predominantly located at frontal lobe, that maximal resection was relatively amenable. Another group independently demonstrated that gross total resection extended survival in grade III *IDH1*-mutant gliomas without 1p/19q co-deletion [98]. In contrast, survival advantage was controversial in grade II astrocytoma [99, 100]. These results suggest that for *IDH1*-mutant gliomas, especially grade III astrocytoma,

To establish *IDH* status-based treatment strategies, including surgery, advanced

preoperative or intraoperative molecular analysis is important. Magnetic resonance spectroscopy (MRS) can be used to detect 2-HG and glutamate changes [101–107]. A recent MRS study demonstrated that 2-HG peaks rapidly decrease in accordance with tumor regression, whereas they increase with tumor progression in *IDH*-mutant gliomas [108], suggesting that 2-HG concentration, measured by MRS, may be a reliable approach to evaluate disease states in *IDH*-mutant gliomas.

tion upregulated the contribution of glutamine to lipogenesis [81, 56].

**7. Role of extensive resection in** *IDH1***-mutant gliomas**

**Figure 2.** *Biological role of IDH mutation to induce gliomagenesis.*

#### *IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

*Brain and Spinal Tumors - Primary and Secondary*

**6.3** *IDH* **mutation inducible metabolic alterations**

changes (**Figure 2**).

and soft agar growth of NHA.

anaplerosis of the TCA cycle [78, 79].

*Biological role of IDH mutation to induce gliomagenesis.*

change in NHA upon IDH1R132H induction [69], suggesting that histone methylation may be an early event in *IDH1*-mutant cancers. The hypermethylation of histones blocks cell differentiation in cancer cells [60, 63, 64, 69]. Using a histone demethylating agent or a specific mutant IDH1 inhibitor, suppressed cell differentiation can be restored [70, 71]. Besides, 2-HG impairs collagen maturation, which leads to basement membrane aberrations that play a part in glioma progression [72]. Taken together, these data show that DNA hypermethylation and histone methylation promote tumorigenesis through a wide range of gene function

In addition to the epigenetic changes, *IDH1* mutation is known to alter hypoxia inducible factor 1α (HIF-1α) activity. Under oxidative conditions, α-KG-dependent prolyl hydroxylases (PHDs), which form the Egl nine homolog (EglN) families, induce HIF-1α hydroxylation. Hydroxylated protein is then bound by the von Hippel-Lindau tumor suppressor protein (VHL), ubiquitylated, and degraded via proteasome. In contrast, under hypoxia, the hydroxylation reaction is inhibited and HIF-1α is upregulated. HIF-1α then activates the transcription of several genes to mediate a switch from oxidative to glycolytic metabolism and induces angiogenesis by regulating the expression of vascular endothelial growth factor (VEGF) [73, 74]. Koivunen et al. [33] demonstrated that *IDH1* mutation attenuates HIF-1α through the activation of HIF prolyl 4-hydroxylase (EGLN), enhancing the proliferation

While several studies demonstrated that the *IDH1* mutation induced aerobic glycolysis via HIF-1α activity [59, 75], other group reported that HIF-1α responsive genes, including lactate dehydrogenase (LDHA) were downregulated; silenced LDHA was associated with increased methylation of the LDHA promoter [76]. Another group showed that *IDH1* mutation reduces pyruvate flux to lactate and suppresses monocarboxylate transporters MCT1 and MCT4, which mediate lactate transmembrane transport [77]. *IDH* mutation also alters pyruvate metabolism, including pyruvate dehydrogenase and pyruvate carboxylase enzymes, resulting in

Cancer cells are known to depend on reductive carboxylation (RC) of glutamine-derived α-KG for *de novo* lipogenesis under hypoxia [80]. It is worth noticing

**20**

**Figure 2.**

that the RC pathway is inhibited by *IDH* mutation [55]. Under hypoxia, *IDH1* mutation upregulated the contribution of glutamine to lipogenesis [81, 56].

Altered amino acids, glutathione, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were observed in *IDH*-mutant cells [82, 83]. Glutamate dehydrogenase (GDH)1 and GDH2 were overexpressed in *IDH1*-mutant tumors, and the orthotopic growth of an *IDH1*-mutant glioma is inhibited by a double GDH1/2 knockdown [84]. Another group demonstrated that GDH2 was critical for IDH1-mutation induced metabolic alterations and IDH1-mutant glioma growth [85]. The presence of 2-HG also inhibited ATP synthase and mTOR signaling [41].

Importantly, branched-chain amino acid transaminase (BCAT), which catalyzes the α-KG to glutamate conversion, was expressed at lower levels in *IDH1*-mutant gliomas than in *IDH1-*wildtype [86, 87]. As a result, the glutamate level was decreased, and cell proliferation and invasiveness were suppressed in *IDH*-mutant gliomas [87].

## **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 (*IDH1-*wildtype) [88–91]. In *IDH1* mutant gliomas, an MRI study demonstrated that *IDH1*-mutant tumors were rarely located in high risk areas of the brain and show unilateral patterns of growth, sharp tumor margins, and less contrast enhancement [92, 93]. Indeed, radiographic atlas revealed *IDH1*-mutant gliomas were frequently located at frontal lobe [94]. A diffusion-tensor imaging study demonstrated that *IDH*-mutant GBM has a less invasive phenotype than *IDH-*wildtype GBM [95]. Intriguingly, patients with *IDH1* wildtype gliomas had a reduced neurocognitive function and lower performance score than those with *IDH1*-mutant gliomas [96]. In addition, lesion volume was not associated with neurocognitive function for patients with *IDH1*-mutant tumors, but associated for those with *IDH1*-wildtype tumors [96]. Consequently, *IDH1*-mutant gliomas may be relatively less invasive to the surrounding eloquent area than *IDH*wildtype GBM.

In addition, Beiko et al. [97] reported that extensive resection, including nonenhancing area, prolonged survival in *IDH1*-mutant anaplastic astrocytoma and glioblastoma. They also mentioned, since *IDH1*-mutant gliomas were predominantly located at frontal lobe, that maximal resection was relatively amenable. Another group independently demonstrated that gross total resection extended survival in grade III *IDH1*-mutant gliomas without 1p/19q co-deletion [98]. In contrast, survival advantage was controversial in grade II astrocytoma [99, 100]. These results suggest that for *IDH1*-mutant gliomas, especially grade III astrocytoma, maximal resection should be considered.

#### **8. Prediction of** *IDH* **status**

To establish *IDH* status-based treatment strategies, including surgery, advanced preoperative or intraoperative molecular analysis is important. Magnetic resonance spectroscopy (MRS) can be used to detect 2-HG and glutamate changes [101–107]. A recent MRS study demonstrated that 2-HG peaks rapidly decrease in accordance with tumor regression, whereas they increase with tumor progression in *IDH*-mutant gliomas [108], suggesting that 2-HG concentration, measured by MRS, may be a reliable approach to evaluate disease states in *IDH*-mutant gliomas.

In addition, several MR techniques, including diffusion tensor imaging and MR methods for determining relative cerebral blood volume, have been proposed to detect mutant *IDH1* noninvasively [109–111]. Moreover, T2-FLAIR mismatch sign was found as a highly specific imaging marker for *IDH*-mutant astrocytoma [112–114]. Intraoperative technologies to assess *IDH1* mutation have also been established [115–117]. These advanced technologies may allow the development of tailored surgical strategies for *IDH*-mutant gliomas. Other group demonstrated that urinary 2-HG is increased in patients with *IDH1-*mutant gliomas [118]. These findings indicate the possibility of application of indirectly assessed 2-HG as a clinical biomarker.

## **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 *IDH1*-mutant GBM patients than in those with *IDH1-*wildtype GBM [119], although there is no prospective clinical evidence of radiation therapy to extend survival in glioma patients with *IDH1* mutation. As described above, *IDH* mutation inhibits NADPH and glutamate production, resulting in reduced glutathione levels and increased reactive oxygen species (ROS) [120–123]. Conversely, radiosensitivity in *IDH1*-mutant tumors was diminished by IDH1 inhibitor [124]. These findings support selective vulnerability to radiation therapy in *IDH*-mutant gliomas.

## **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 *IDH1*-mutation as a predictive biomarker for TMZ sensitivity in low grade gliomas and secondary GBM [127, 128].

Cytotoxicity of TMZ is provoked by the formation of O6 -methylguanine (O6 G)- DNA adducts. O6 G-DNA adducts induce DNA strand break and apoptosis through the O6 G-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 [131–133]. *MGMT* promoter methylation is highly methylated in *IDH1*-mutant gliomas, particularly oligodendrogliomas, compared with *IDH*-wildtype [43].

Some preclinical studies demonstrated that forced *IDH* mutation sensitized cells to chemotherapy by increased ROS [134–136]. Conversely, forced *IDH1* mutation revealed that *IDH1* mutation-induced temozolomide (TMZ) resistance and rapid G2 cell cycle arrest through increased RAD-51-mediated homologous recombination (HR) [137, 138]. Importantly, among DNA adducts, O6 G represents less than 10%, while the majority of TMZ-induced DNA lesions are N7 -methylguanine (60–80%) and N3 -methyladenine (10–20%) adducts, which are immediately repaired through poly(ADP-ribose)polymerase (PARP)-dependent base excision repair (BER) [129, 139, 140]. We have recently shown that there are lower steady state NAD+ levels in *IDH1*-mutant gliomas [141],

**23**

*IDH-Mutant Gliomas*

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

*9.2.2 Other chemotherapeutic agents*

**10.1 Specific IDH inhibitor**

refractory AML patients [150, 151].

and that TMZ immediately induces NAD+ consumption through PARP activationmediated BER in *IDH1*-mutant gliomas [142]. Besides, Lu et al. [143] reported that the PARP associated DNA repair pathway was extensively compromised in *IDH1*-mutant cells due to decreased NAD+ availability, thus, cells were sensitive to TMZ, suggesting that deregulated NAD+ metabolism may be related with chemosensitivity. Taken together, these studies show that *IDH* mutation may increase susceptibility to chemotherapy; however, it remains unclear if *IDH* mutation itself promotes TMZ sensitivity. 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 *IDH1*-mutant gliomas [27].

of hematopoietic stem cells in acute myeloid leukemia [145].

**10. Novel therapeutic target in** *IDH1***-mutant tumors**

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, *IDH1* mutation suppresses HR and induces PARP inhibitor sensitivity. Additionally, *IDH1* mutant downregulates the DNA double strand break sensor ATM by altering histone methylation, resulting in impaired DNA repair. As a result, *IDH1* mutation causes DNA damage susceptibility to radiation and daunorubicin and reduces self-renewal

In 2013, specific inhibitors for *IDH1* and *IDH2* mutations were discovered [70, 146]. In *IDH2-*mutant AML cells, an IDH2R140Q inhibitor induced both histone and DNA demethylation [147]. These effects reversed blocked cell differentiation and resulted in cytotoxicity *in vitro* [146, 147]. It is interesting to note that histone hypermethylation is more rapidly reversed than DNA hypermethylation [147]. In *IDH1*-mutant AML cells, differentiation and DNA demethylation were also induced by a next generation IDH1 inhibitor [148]. Since the *IDH2* mutation is crucial for proliferation and maintenance of leukemia cells [149], an IDH inhibitor may be used as a novel and efficient chemotherapeutic agent against *IDH-*mutant AML cells. Indeed, clinical trials demonstrated durable response for *IDH1/2*-mutant

In *IDH1-*mutant glioma cells, Rohle et al. [70] reported that a specific IDH1 inhibitor, AGI-5198, blocked 2-HG production, histone demethylation, cell differentiation, and inhibited cell growth in endogenous *IDH1*-mutant glioma cells. Other group demonstrated that BAY 1436032, a pan inhibitor of IDH1 mutation, promoted mild cytotoxic effects *in vivo* [152]. In contrast, we established that, even with a long-term IDH1 inhibitor treatment, 2-HG depletion does not induce demethylation of global-DNA and histones, cell differentiation, nor cytotoxicity [141]. Studies using another IDH1 inhibitor also revealed minimal cytotoxicity despite a rapid decrease in 2-HG levels in glioma cells [153, 154]. Similarly, treatment with an IDH1 inhibitor did not contribute to cytotoxicity, and the CpG island methylation status as well as histone trimethylation levels were largely retained in malignant glioma and chondrosarcoma [155, 156]. Intriguingly, in immortalized human astrocytes with an inducible IDH1R132H expression system, a specific IDH1 inhibitor induced demethylation and inhibited tumorigenesis when forced expression was prior or concomitant to inhibitor treatment, but these effects were

#### *IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

*Brain and Spinal Tumors - Primary and Secondary*

**9. Treatment vulnerability in** *IDH***-mutant gliomas**

**9.2 Chemotherapeutic evidence for** *IDH***-mutant gliomas**

Cytotoxicity of TMZ is provoked by the formation of O6

grade gliomas and secondary GBM [127, 128].

**9.1 Radiotherapy for** *IDH-***mutant gliomas**

therapy in *IDH*-mutant gliomas.

*9.2.1 Temozolomide*

DNA adducts. O6

*IDH*-wildtype [43].

Importantly, among DNA adducts, O6

of TMZ-induced DNA lesions are N7

the O6

biomarker.

In addition, several MR techniques, including diffusion tensor imaging and MR methods for determining relative cerebral blood volume, have been proposed to detect mutant *IDH1* noninvasively [109–111]. Moreover, T2-FLAIR mismatch sign was found as a highly specific imaging marker for *IDH*-mutant astrocytoma [112–114]. Intraoperative technologies to assess *IDH1* mutation have also been established [115–117]. These advanced technologies may allow the development of tailored surgical strategies for *IDH*-mutant gliomas. Other group demonstrated that urinary 2-HG is increased in patients with *IDH1-*mutant gliomas [118]. These findings indicate the possibility of application of indirectly assessed 2-HG as a clinical

It has been shown that there is a higher relative sensitivity to radiotherapy and concurrent temozolomide (TMZ) in *IDH1*-mutant GBM patients than in those with *IDH1-*wildtype GBM [119], although there is no prospective clinical evidence of radiation therapy to extend survival in glioma patients with *IDH1* mutation. As described above, *IDH* mutation inhibits NADPH and glutamate production, resulting in reduced glutathione levels and increased reactive oxygen species (ROS) [120–123]. Conversely, radiosensitivity in *IDH1*-mutant tumors was diminished by IDH1 inhibitor [124]. These findings support selective vulnerability to radiation

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 *IDH1*-mutation as a predictive biomarker for TMZ sensitivity in low

G-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 [131–133]. *MGMT* promoter methylation is highly methylated in *IDH1*-mutant gliomas, particularly oligodendrogliomas, compared with

Some preclinical studies demonstrated that forced *IDH* mutation sensitized cells to chemotherapy by increased ROS [134–136]. Conversely, forced *IDH1* mutation revealed that *IDH1* mutation-induced temozolomide (TMZ) resistance and rapid G2 cell cycle arrest through increased RAD-51-mediated homologous recombination (HR) [137, 138].

(10–20%) adducts, which are immediately repaired through poly(ADP-ribose)polymerase (PARP)-dependent base excision repair (BER) [129, 139, 140]. We have recently shown that there are lower steady state NAD+ levels in *IDH1*-mutant gliomas [141],

G-DNA adducts induce DNA strand break and apoptosis through

G represents less than 10%, while the majority



G)-


**22**

and that TMZ immediately induces NAD+ consumption through PARP activationmediated BER in *IDH1*-mutant gliomas [142]. Besides, Lu et al. [143] reported that the PARP associated DNA repair pathway was extensively compromised in *IDH1*-mutant cells due to decreased NAD+ availability, thus, cells were sensitive to TMZ, suggesting that deregulated NAD+ metabolism may be related with chemosensitivity. Taken together, these studies show that *IDH* mutation may increase susceptibility to chemotherapy; however, it remains unclear if *IDH* mutation itself promotes TMZ sensitivity.

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 *IDH1*-mutant gliomas [27].

## *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, *IDH1* mutation suppresses HR and induces PARP inhibitor sensitivity. Additionally, *IDH1* mutant downregulates the DNA double strand break sensor ATM by altering histone methylation, resulting in impaired DNA repair. As a result, *IDH1* mutation causes DNA damage susceptibility to radiation and daunorubicin and reduces self-renewal of hematopoietic stem cells in acute myeloid leukemia [145].

## **10. Novel therapeutic target in** *IDH1***-mutant tumors**

## **10.1 Specific IDH inhibitor**

In 2013, specific inhibitors for *IDH1* and *IDH2* mutations were discovered [70, 146]. In *IDH2-*mutant AML cells, an IDH2R140Q inhibitor induced both histone and DNA demethylation [147]. These effects reversed blocked cell differentiation and resulted in cytotoxicity *in vitro* [146, 147]. It is interesting to note that histone hypermethylation is more rapidly reversed than DNA hypermethylation [147]. In *IDH1*-mutant AML cells, differentiation and DNA demethylation were also induced by a next generation IDH1 inhibitor [148]. Since the *IDH2* mutation is crucial for proliferation and maintenance of leukemia cells [149], an IDH inhibitor may be used as a novel and efficient chemotherapeutic agent against *IDH-*mutant AML cells. Indeed, clinical trials demonstrated durable response for *IDH1/2*-mutant refractory AML patients [150, 151].

In *IDH1-*mutant glioma cells, Rohle et al. [70] reported that a specific IDH1 inhibitor, AGI-5198, blocked 2-HG production, histone demethylation, cell differentiation, and inhibited cell growth in endogenous *IDH1*-mutant glioma cells. Other group demonstrated that BAY 1436032, a pan inhibitor of IDH1 mutation, promoted mild cytotoxic effects *in vivo* [152]. In contrast, we established that, even with a long-term IDH1 inhibitor treatment, 2-HG depletion does not induce demethylation of global-DNA and histones, cell differentiation, nor cytotoxicity [141]. Studies using another IDH1 inhibitor also revealed minimal cytotoxicity despite a rapid decrease in 2-HG levels in glioma cells [153, 154]. Similarly, treatment with an IDH1 inhibitor did not contribute to cytotoxicity, and the CpG island methylation status as well as histone trimethylation levels were largely retained in malignant glioma and chondrosarcoma [155, 156]. Intriguingly, in immortalized human astrocytes with an inducible IDH1R132H expression system, a specific IDH1 inhibitor induced demethylation and inhibited tumorigenesis when forced expression was prior or concomitant to inhibitor treatment, but these effects were

not observed if the treatment was delayed [157]. These results indicate that 2-HG depletion or blocked mutant *IDH1* might be insufficient to control tumor growth and reprogramming of epigenomic alterations in progressed *IDH1-*mutant gliomas. Indeed, preliminary results indicate that the 6-month progression-free survival of *IDH1*-mutant glioma, chondrosarcoma, and cholangiocarcinoma is 25, 56, and 43%, respectively, suggesting that the potential of the IDH1 inhibitor may be weaker in *IDH1*-mutant gliomas than in other cancers [158].

#### **10.2 Other treatment strategies**

### *10.2.1 DNA demethylating agents*

In addition to IDH1 inhibitor treatments, other strategies to control *IDH1* mutant tumor cells have been proposed. Because the *IDH1* mutation promotes proliferation by blocking DNA demethylation, treatment with DNA demethylating agents reverses DNA methylation and inhibits proliferation in *IDH1*-mutant cells [71, 159]. Intriguingly, treatment with both the DNA demethylating agent 5-azacytidine (5-Aza) and TMZ demonstrated extensively prolonged survival in an *IDH1*-mutant orthotopic xenograft model [160].

### *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 *IDH1* and *IDH2-*mutant AML [161]. Similarly, another Bcl-2 family member, the Bcl-xL inhibitor, induced apoptosis in *IDH*-mutant cells, including endogenous *IDH1*-mutant glioma cells [162]. Together, inhibition of Bcl-2 family members may be targetable to control growth in *IDH*-mutant cells.

#### *10.2.3 DNA damaging agents*

Because PLK1 activation provokes a rapid bypass through the G2 checkpoint after TMZ treatment in *IDH1*-mutant tumors, combination treatments with TMZ and a PLK1 inhibitor significantly suppressed tumor growth in an *IDH1*-mutant *in vivo* model [138]. In tumors with ATRX mutation-associated alternative lengthening telomeres (ALT), ATR inhibitor is highly sensitive [163], implying that such inhibition may be useful for treatments of *IDH1*-mutant astrocytic tumors with positive ALT. *IDH1* mutation blocked HR, so-called "BRCA ness" phenotype provided specific sensitivity for PARP inhibitor both *in vitro* and *in vivo* [144].

#### *10.2.4 DLL-3 targeting therapy*

Since Notch ligand DLL-3 is overexpressed in *IDH*-mutant gliomas, anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), is a potent therapeutic agent for *IDH*-mutant gliomas [164].

#### *10.2.5 Vaccination therapy*

Schumacher et al. [165] reported an immunological approach to control *IDH1* mutant cells. They showed that an epitope derived from the *IDH1*-mutant amino acid sequence is presented in HLA class II molecules of antigen-presenting cells, which elicit a strong immune response via CD4 + T cells. In addition, they showed that constitutive stimulation with synthetic peptides having the *IDH1-*mutation

**25**

*IDH-Mutant Gliomas*

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

tor result in enhanced toxicity in *IDH-*mutant tumors.

due to decreased NAD+ availability, thus sensitive to TMZ.

*10.2.6 Target for altered metabolism*

radiation [86].

novel therapeutic targets.

development in *IDH-*mutant glioma patients.

**11. Conclusions**

sequence developed an immune response that eradicated *IDH1* mutated tumors in a mouse model with human HLA molecules. Thus, vaccine therapy targeting for *IDH1-*mutation is expected to develop for future clinical trial [165, 166]. Moreover, *IDH1-*mutation caused downregulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system including immune cells, such as macrophages [167]. Additionally, tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) were expressed at low levels in *IDH1-*mutant gliomas [168]. In contrast, Kohanbash et al. [153] demonstrated reduced expression of cytotoxic T lymphocyte-associated genes and IFN-gamma inducible chemokines in *IDH1-*mutant cells; these results were reversed by specific IDH1 inhibitor. Therefore, combination treatments with vaccine immunotherapy and IDH1 inhibi-

*IDH1* mutation induced altered metabolism is also expected as a novel therapeutic target. Based on the fact that the main carbon source for α-KG and 2-HG synthesis in *IDH1*-mutant cells is glutamine from glutaminolysis, a suitable target therapy would be the use of glutaminase (GLS) inhibitor or anti-diabetic drug metformin via the inhibition of mitochondrial complex I in the electron transport system [83, 169–171]. Since reduced glutamate blocks glutathione synthesis, inhibition of glutaminase specifically sensitizes *IDH*-mutant glioma cells to oxidative stress and

Mutant *IDH1* alters steady state levels of NAD+ through inhibiting NAPRT1, one rate limiting enzyme for NAD+ biosynthesis. Therefore, inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another rate limiting enzyme, induced high cytotoxicity in *IDH1*-mutant patient-derived glioma cells [141]. Since TMZ rapidly consumes NAD+ through PARP activation, combination treatments with TMZ and NAMPT inhibitor further enhanced NAD+ depletion-mediated cytotoxicity in *IDH1-*mutant cancers [142]. Similarly, Lu et al. [143] reported that the PARPassociated DNA repair pathway was extensively compromised in *IDH1*-mutant cells

Because of the relationships between *IDH1* mutation and *MYC* activation [38, 40, 172], target therapy to regulate *MYC*, by using bromodomain and extra-terminal (BET) inhibitors, CDK7 or MYC-induced glycolysis may be used for *IDH*-mutant gliomas [40, 173–175]. Given the results of these studies, *IDH1* mutation-specific biological alterations and metabolic feature may be expected as

In summary, investigations on *IDH* mutations enabled distinctive tumor classification and may allow the development of specific therapeutic strategies. Further preclinical and clinical studies are warranted to overcome the outcomes of cancer

#### *IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

*Brain and Spinal Tumors - Primary and Secondary*

*IDH1*-mutant gliomas than in other cancers [158].

*IDH1*-mutant orthotopic xenograft model [160].

**10.2 Other treatment strategies**

*10.2.1 DNA demethylating agents*

*10.2.2 Bcl-2 family inhibitors*

*10.2.3 DNA damaging agents*

*10.2.4 DLL-3 targeting therapy*

*10.2.5 Vaccination therapy*

therapeutic agent for *IDH*-mutant gliomas [164].

not observed if the treatment was delayed [157]. These results indicate that 2-HG depletion or blocked mutant *IDH1* might be insufficient to control tumor growth and reprogramming of epigenomic alterations in progressed *IDH1-*mutant gliomas. Indeed, preliminary results indicate that the 6-month progression-free survival of *IDH1*-mutant glioma, chondrosarcoma, and cholangiocarcinoma is 25, 56, and 43%, respectively, suggesting that the potential of the IDH1 inhibitor may be weaker in

In addition to IDH1 inhibitor treatments, other strategies to control *IDH1* mutant tumor cells have been proposed. Because the *IDH1* mutation promotes proliferation by blocking DNA demethylation, treatment with DNA demethylating agents reverses DNA methylation and inhibits proliferation in *IDH1*-mutant cells [71, 159]. Intriguingly, treatment with both the DNA demethylating agent 5-azacytidine (5-Aza) and TMZ demonstrated extensively prolonged survival in an

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 *IDH1* and *IDH2-*mutant AML [161]. Similarly, another Bcl-2 family member, the Bcl-xL inhibitor, induced apoptosis in *IDH*-mutant cells, including endogenous *IDH1*-mutant glioma cells [162]. Together, inhibition of Bcl-2 family

Because PLK1 activation provokes a rapid bypass through the G2 checkpoint after TMZ treatment in *IDH1*-mutant tumors, combination treatments with TMZ and a PLK1 inhibitor significantly suppressed tumor growth in an *IDH1*-mutant *in vivo* model [138]. In tumors with ATRX mutation-associated alternative lengthening telomeres (ALT), ATR inhibitor is highly sensitive [163], implying that such inhibition may be useful for treatments of *IDH1*-mutant astrocytic tumors with positive ALT. *IDH1* mutation blocked HR, so-called "BRCA ness" phenotype provided specific sensitivity for PARP inhibitor both *in vitro* and *in vivo* [144].

Since Notch ligand DLL-3 is overexpressed in *IDH*-mutant gliomas, anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), is a potent

Schumacher et al. [165] reported an immunological approach to control *IDH1* mutant cells. They showed that an epitope derived from the *IDH1*-mutant amino acid sequence is presented in HLA class II molecules of antigen-presenting cells, which elicit a strong immune response via CD4 + T cells. In addition, they showed that constitutive stimulation with synthetic peptides having the *IDH1-*mutation

members may be targetable to control growth in *IDH*-mutant cells.

**24**

sequence developed an immune response that eradicated *IDH1* mutated tumors in a mouse model with human HLA molecules. Thus, vaccine therapy targeting for *IDH1-*mutation is expected to develop for future clinical trial [165, 166]. Moreover, *IDH1-*mutation caused downregulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system including immune cells, such as macrophages [167]. Additionally, tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) were expressed at low levels in *IDH1-*mutant gliomas [168]. In contrast, Kohanbash et al. [153] demonstrated reduced expression of cytotoxic T lymphocyte-associated genes and IFN-gamma inducible chemokines in *IDH1-*mutant cells; these results were reversed by specific IDH1 inhibitor. Therefore, combination treatments with vaccine immunotherapy and IDH1 inhibitor result in enhanced toxicity in *IDH-*mutant tumors.

## *10.2.6 Target for altered metabolism*

*IDH1* mutation induced altered metabolism is also expected as a novel therapeutic target. Based on the fact that the main carbon source for α-KG and 2-HG synthesis in *IDH1*-mutant cells is glutamine from glutaminolysis, a suitable target therapy would be the use of glutaminase (GLS) inhibitor or anti-diabetic drug metformin via the inhibition of mitochondrial complex I in the electron transport system [83, 169–171]. Since reduced glutamate blocks glutathione synthesis, inhibition of glutaminase specifically sensitizes *IDH*-mutant glioma cells to oxidative stress and radiation [86].

Mutant *IDH1* alters steady state levels of NAD+ through inhibiting NAPRT1, one rate limiting enzyme for NAD+ biosynthesis. Therefore, inhibition of nicotinamide phosphoribosyltransferase (NAMPT), another rate limiting enzyme, induced high cytotoxicity in *IDH1*-mutant patient-derived glioma cells [141]. Since TMZ rapidly consumes NAD+ through PARP activation, combination treatments with TMZ and NAMPT inhibitor further enhanced NAD+ depletion-mediated cytotoxicity in *IDH1-*mutant cancers [142]. Similarly, Lu et al. [143] reported that the PARPassociated DNA repair pathway was extensively compromised in *IDH1*-mutant cells due to decreased NAD+ availability, thus sensitive to TMZ.

Because of the relationships between *IDH1* mutation and *MYC* activation [38, 40, 172], target therapy to regulate *MYC*, by using bromodomain and extra-terminal (BET) inhibitors, CDK7 or MYC-induced glycolysis may be used for *IDH*-mutant gliomas [40, 173–175]. Given the results of these studies, *IDH1* mutation-specific biological alterations and metabolic feature may be expected as novel therapeutic targets.

## **11. Conclusions**

In summary, investigations on *IDH* mutations enabled distinctive tumor classification and may allow the development of specific therapeutic strategies. Further preclinical and clinical studies are warranted to overcome the outcomes of cancer development in *IDH-*mutant glioma patients.

*Brain and Spinal Tumors - Primary and Secondary*

## **Author details**

Kensuke Tateishi\* and Tetsuya Yamamoto Department of Neurosurgery, Yokohama City University, Yokohama, Japan

\*Address all correspondence to: ktate12@yokohama-cu.ac.jp

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**27**

*IDH-Mutant Gliomas*

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**26**

**Author details**

provided the original work is properly cited.

Kensuke Tateishi\* and Tetsuya Yamamoto

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Neurosurgery, Yokohama City University, Yokohama, Japan

\*Address all correspondence to: ktate12@yokohama-cu.ac.jp

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*IDH-Mutant Gliomas*

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Mutational landscape and clonal architecture in grade II and III gliomas. Nature Genetics. 2015;**47**(5):458-468

#### *IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

*Brain and Spinal Tumors - Primary and Secondary*

cancers. International Journal of Cancer.

[22] Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA,

Fontebasso AM, et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathologica. 2012;**124**(5):615-625

[23] Arita H, Narita Y, Fukushima S, Tateishi K, Matsushita Y, Yoshida A, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathologica.

[24] Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proceedings of the National Academy of Sciences of the United States of America.

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[27] Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;**343**(6167):189-193

[28] Suzuki H, Aoki K, Chiba K, Sato Y,

Shiozawa Y, Shiraishi Y, et al.

2013;**126**(2):267-276

2013;**110**(15):6021-6026

2009;**174**(4):1149-1153

2012;**108**(3):403-410

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[16] Li-Chang HH, Kasaian K, Ng Y, Lum A, Kong E, Lim H, et al. Retrospective review using targeted deep sequencing reveals mutational differences between gastroesophageal junction and gastric carcinomas. BMC

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2009;**125**(2):353-355

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2012;**3**(10):1194-1203

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**28**

Mutational landscape and clonal architecture in grade II and III gliomas. Nature Genetics. 2015;**47**(5):458-468

[29] Mazor T, Chesnelong C, Pankov A, Jalbert LE, Hong C, Hayes J, et al. Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. Proceedings of the National Academy of Sciences of the United States of America. 2017;**114**(40):10743-10748

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[31] Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;**539**(7628):309-313

[32] Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, et al. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science. 2017;**355**(6332)

[33] Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;**483**(7390):484-488

[34] Piaskowski S, Bienkowski M, Stoczynska-Fidelus E, Stawski R, Sieruta M, Szybka M, et al. Glioma cells showing IDH1 mutation cannot be propagated in standard cell culture conditions. British Journal of Cancer. 2011;**104**(6):968-970

[35] Luchman HA, Stechishin OD, Dang NH, Blough MD, Chesnelong C, Kelly JJ, et al. An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro-Oncology. 2012;**14**(2):184-191

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[37] Bardella C, Al-Dalahmah O, Krell D, Brazauskas P, Al-Qahtani K, Tomkova M, et al. Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer Cell. 2016;**30**(4):578-594

[38] Wakimoto H, Tanaka S, Curry WT, Loebel F, Zhao D, Tateishi K, et al. Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas. Clinical Cancer Research. 2014;**20**(11):2898-2909

[39] Kamoun A, Idbaih A, Dehais C, Elarouci N, Carpentier C, Letouze E, et al. Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas. Nature Communications. 2016;**7**:11263

[40] Bai H, Harmanci AS, Erson-Omay EZ, Li J, Coskun S, Simon M, et al. Integrated genomic characterization of IDH1-mutant glioma malignant progression. Nature Genetics. 2016;**48**(1):59-66

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[46] Minniti G, Scaringi C, Arcella A, Lanzetta G, Di Stefano D, Scarpino S, et al. IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy. Journal of Neuro-Oncology. 2014;**118**(2):377-383

[47] Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. The New England Journal of Medicine. 2015;**372**(26):2499-2508

[48] Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the

unfavorable prognostic effect of higher age: Implications for classification of gliomas. Acta Neuropathologica. 2010;**120**(6):707-718

[49] Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H, et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: Additional prognostic roles of ATRX and TERT. Acta Neuropathologica. 2017;**133**(6):1001-1016

[50] Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H, et al. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathologica Communications. 2016;**4**(1):79

[51] Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F, et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathologica. 2018;**136**(1):153-166

[52] Halani SH, Yousefi S, Vega JV, Rossi MR, Zhao Z, Amrollahi F, et al. Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways. NPJ Precision Oncology. 2018;**2**:24

[53] Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T, et al. Prognostic relevance of genetic alterations in diffuse lowergrade gliomas. Neuro-Oncology. 2018;**20**(1):66-77

[54] Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;**462**(7274):739-744

[55] Leonardi R, Subramanian C, Jackowski S, Rock CO. Cancer-associated isocitrate dehydrogenase mutations inactivate

**31**

*IDH-Mutant Gliomas*

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carboxylation. The Journal of Biological Chemistry. 2012;**287**(18):14615-14620

BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer

[63] Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012;**488**(7413):656-659

[64] Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;**483**(7390):479-483

[65] de Souza CF, Sabedot TS, Malta TM, Stetson L, Morozova O, Sokolov A, et al. A distinct DNA methylation shift in a subset of glioma CpG island methylator phenotypes during tumor recurrence. Cell Reports. 2018;**23**(2):637-651

[66] Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell.

[67] Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature.

[68] Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Reports. 2011;**12**(5):463-469

[69] Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature.

2012;**483**(7390):474-478

2010;**17**(1):98-110

2016;**529**(7584):110-114

Cell. 2010;**17**(5):510-522

[56] Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X,

et al. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial

metabolism. Cancer Research.

[57] Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell.

[58] Jin G, Reitman ZJ, Duncan CG,

[59] Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;**324**(5924):

[60] Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutaratedependent dioxygenases. Cancer Cell.

[61] Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer

[62] Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman

Spasojevic I, Gooden DM, Rasheed BA, et al. Disruption of wild-type IDH1 suppresses D-2 hydroxyglutarate production in IDH1 mutated gliomas. Cancer Research.

2014;**74**(12):3317-3331

2010;**17**(3):225-234

2013;**73**(2):496-501

261-265

2011;**19**(1):17-30

Cell. 2010;**18**(6):553-567

NADPH-dependent reductive

*IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

*Brain and Spinal Tumors - Primary and Secondary*

unfavorable prognostic effect of higher age: Implications for classification of gliomas. Acta Neuropathologica.

[49] Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Hansen H, et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: Additional prognostic roles of ATRX and TERT. Acta Neuropathologica.

[50] Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H, et al. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathologica Communications.

[51] Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F, et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathologica. 2018;**136**(1):153-166

[52] Halani SH, Yousefi S, Vega JV, Rossi MR, Zhao Z, Amrollahi F, et al. Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways. NPJ Precision

[53] Aoki K, Nakamura H, Suzuki H, Matsuo K, Kataoka K, Shimamura T,

et al. Prognostic relevance of genetic alterations in diffuse lowergrade gliomas. Neuro-Oncology.

[54] Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;**462**(7274):739-744

[55] Leonardi R, Subramanian

CO. Cancer-associated isocitrate dehydrogenase mutations inactivate

C, Jackowski S, Rock

Oncology. 2018;**2**:24

2018;**20**(1):66-77

2010;**120**(6):707-718

2017;**133**(6):1001-1016

2016;**4**(1):79

[43] Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. Journal of Clinical Oncology.

[44] Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine,

lomustine, and vincristine or temozolomide. Journal of Clinical Oncology. 2009;**27**(35):5874-5880

[45] Killela PJ, Pirozzi CJ, Healy P, Reitman ZJ, Lipp E, Rasheed BA, et al. Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas. Oncotarget. 2014;**5**(6):1515-1525

[46] Minniti G, Scaringi C, Arcella A, Lanzetta G, Di Stefano D, Scarpino S, et al. IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy. Journal of Neuro-Oncology. 2014;**118**(2):377-383

[47] Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. The New England Journal of Medicine.

[48] Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the

2015;**372**(26):2499-2508

[42] Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clinical Cancer Research.

2009;**15**(19):6002-6007

2009;**27**(25):4150-4154

**30**

NADPH-dependent reductive carboxylation. The Journal of Biological Chemistry. 2012;**287**(18):14615-14620

[56] Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, et al. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Research. 2014;**74**(12):3317-3331

[57] Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;**17**(3):225-234

[58] Jin G, Reitman ZJ, Duncan CG, Spasojevic I, Gooden DM, Rasheed BA, et al. Disruption of wild-type IDH1 suppresses D-2 hydroxyglutarate production in IDH1 mutated gliomas. Cancer Research. 2013;**73**(2):496-501

[59] Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;**324**(5924): 261-265

[60] Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutaratedependent dioxygenases. Cancer Cell. 2011;**19**(1):17-30

[61] Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;**18**(6):553-567

[62] Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;**17**(5):510-522

[63] Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012;**488**(7413):656-659

[64] Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;**483**(7390):479-483

[65] de Souza CF, Sabedot TS, Malta TM, Stetson L, Morozova O, Sokolov A, et al. A distinct DNA methylation shift in a subset of glioma CpG island methylator phenotypes during tumor recurrence. Cell Reports. 2018;**23**(2):637-651

[66] Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;**17**(1):98-110

[67] Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016;**529**(7584):110-114

[68] Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Reports. 2011;**12**(5):463-469

[69] Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;**483**(7390):474-478

[70] Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013;**340**(6132):626-630

[71] Turcan S, Fabius AW, Borodovsky A, Pedraza A, Brennan C, Huse J, et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget. 2013;**4**(10):1729-1736

[72] Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, et al. D-2 hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes & Development. 2012;**26**(18):2038-2049

[73] Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. The Journal of Clinical Investigation. 2013;**123**(9):3664-3671

[74] Semenza GL. Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harbor Symposia on Quantitative Biology. 2011;**76**:347-353

[75] Nie Q, Guo P, Guo L, Lan J, Lin Y, Guo F, et al. Overexpression of isocitrate dehydrogenase-1R(1)(3)(2)H enhances the proliferation of A172 glioma cells via aerobic glycolysis. Molecular Medicine Reports. 2015;**11**(5):3715-3721

[76] Chesnelong C, Chaumeil MM, Blough MD, Al-Najjar M, Stechishin OD, Chan JA, et al. Lactate dehydrogenase A silencing in IDH mutant gliomas. Neuro-Oncology. 2014;**16**(5):686-695

[77] Viswanath P, Najac C, Izquierdo-Garcia JL, Pankov A, Hong C, Eriksson P, et al. Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters. Oncotarget. 2016;**7**(23):34942-34955

[78] Izquierdo-Garcia JL, Cai LM, Chaumeil MM, Eriksson P, Robinson AE, Pieper RO, et al. Glioma cells with the IDH1 mutation modulate metabolic fractional flux through pyruvate carboxylase. PLoS ONE. 2014;**9**(9):e108289

[79] Izquierdo-Garcia JL, Viswanath P, Eriksson P, Cai L, Radoul M, Chaumeil MM, et al. IDH1 mutation induces reprogramming of pyruvate metabolism. Cancer Research. 2015;**75**(15):2999-3009

[80] Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2012;**481**(7381):380-384

[81] Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, et al. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. The Journal of Biological Chemistry. 2014;**289**(34):23318-23328

[82] Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**(8):3270-3275

[83] Ohka F, Ito M, Ranjit M, Senga T, Motomura A, Motomura K, et al. Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumour Biology. 2014;**35**(6):5911-5920

[84] Chen R, Nishimura MC, Kharbanda S, Peale F, Deng Y, Daemen A, et al. Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma. Proceedings of

**33**

*IDH-Mutant Gliomas*

Diplas BH, Hansen LJ, Carpenter AB, et al. Adaptive evolution of the GDH2 allosteric domain promotes gliomagenesis by resolving IDH1(R132H)-induced metabolic liabilities. Cancer Research.

2018;**78**(1):36-50

[86] McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA, et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell.

2018;**175**(1):101-116 e25

2013;**19**(7):901-908

2001;**95**(2):190-198

2008;**26**(8):1338-1345

2011;**115**(1):3-8

[87] Tonjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nature Medicine.

[88] Lacroix M, Abi-Said D, Fourney DR,

[89] Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S, et al. Role of extent of resection in the longterm outcome of low-grade hemispheric gliomas. Journal of Clinical Oncology.

[90] Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of Neurosurgery.

[91] Marko NF, Weil RJ, Schroeder JL, Lang FF, Suki D, Sawaya RE. Extent

Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. Journal of Neurosurgery.

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

of resection of glioblastoma revisited: Personalized survival modeling facilitates more accurate survival prediction and supports a maximumsafe-resection approach to surgery. Journal of Clinical Oncology.

[92] Qi S, Yu L, Li H, Ou Y, Qiu X, Ding Y, et al. Isocitrate dehydrogenase mutation is associated with tumor location and magnetic resonance imaging characteristics in astrocytic neoplasms. Oncology Letters.

[93] Darlix A, Deverdun J, Menjot de Champfleur N, Castan F, Zouaoui S, Rigau V, et al. IDH mutation and 1p19q codeletion distinguish two radiological patterns of diffuse low-grade gliomas. Journal of Neuro-

Oncology. 2017;**133**(1):37-45

[94] Ellingson BM, Lai A, Harris RJ, Selfridge JM, Yong WH, Das K, et al. Probabilistic radiographic atlas of glioblastoma phenotypes. AJNR. American Journal of

Neuroradiology. 2013;**34**(3):533-540

dehydrogenase wild-type glioblastomas: A diffusion-tensor imaging study. Radiology. 2017;**283**(1):215-221

[96] Wefel JS, Noll KR, Rao G, Cahill DP. Neurocognitive function varies by IDH1 genetic mutation status in patients with malignant glioma prior to surgical resection. Neuro-Oncology.

[97] Beiko J, Suki D, Hess KR, Fox BD, Cheung V, Cabral M, et al. IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with

2016;**18**(12):1656-1663

[95] Price SJ, Allinson K, Liu H, Boonzaier NR, Yan JL, Lupson VC, et al. Less invasive phenotype found in isocitrate dehydrogenase-mutated glioblastomas than in isocitrate

2014;**32**(8):774-782

2014;**7**(6):1895-1902

[85] Waitkus MS, Pirozzi CJ, Moure CJ,

the National Academy of Sciences of the United States of America. 2014;**111**(39):14217-14222

#### *IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

the National Academy of Sciences of the United States of America. 2014;**111**(39):14217-14222

*Brain and Spinal Tumors - Primary and Secondary*

[78] Izquierdo-Garcia JL, Cai LM, Chaumeil MM, Eriksson P, Robinson AE, Pieper RO, et al. Glioma cells with the IDH1 mutation modulate metabolic fractional flux through pyruvate carboxylase. PLoS ONE.

[79] Izquierdo-Garcia JL, Viswanath P,

Chaumeil MM, et al. IDH1 mutation induces reprogramming of pyruvate metabolism. Cancer Research.

[80] Metallo CM, Gameiro PA, Bell EL,

[81] Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, et al. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. The Journal of Biological Chemistry. 2014;**289**(34):23318-23328

[82] Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proceedings of the National Academy of Sciences of the United States of America.

[83] Ohka F, Ito M, Ranjit M, Senga T, Motomura A, Motomura K, et al. Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumour Biology. 2014;**35**(6):5911-5920

[84] Chen R, Nishimura MC, Kharbanda S, Peale F, Deng Y, Daemen A, et al. Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma. Proceedings of

2011;**108**(8):3270-3275

Eriksson P, Cai L, Radoul M,

Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature.

2015;**75**(15):2999-3009

2012;**481**(7381):380-384

2014;**9**(9):e108289

[71] Turcan S, Fabius AW, Borodovsky A, Pedraza A, Brennan C, Huse J, et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget.

[72] Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, et al. D-2 hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes & Development. 2012;**26**(18):2038-2049

[73] Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. The Journal of Clinical Investigation.

[74] Semenza GL. Regulation of

Reports. 2015;**11**(5):3715-3721

[76] Chesnelong C, Chaumeil MM, Blough MD, Al-Najjar M, Stechishin OD, Chan JA, et al. Lactate dehydrogenase A silencing in IDH mutant gliomas. Neuro-Oncology. 2014;**16**(5):686-695

[77] Viswanath P, Najac C, Izquierdo-Garcia JL, Pankov A, Hong C, Eriksson P,

et al. Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters. Oncotarget. 2016;**7**(23):34942-34955

metabolism by hypoxia-inducible factor 1. Cold Spring Harbor Symposia on Quantitative Biology. 2011;**76**:347-353

[75] Nie Q, Guo P, Guo L, Lan J, Lin Y, Guo F, et al. Overexpression of isocitrate dehydrogenase-1R(1)(3)(2)H enhances the proliferation of A172 glioma cells via aerobic glycolysis. Molecular Medicine

2013;**123**(9):3664-3671

[70] Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science.

2013;**340**(6132):626-630

2013;**4**(10):1729-1736

**32**

[85] Waitkus MS, Pirozzi CJ, Moure CJ, Diplas BH, Hansen LJ, Carpenter AB, et al. Adaptive evolution of the GDH2 allosteric domain promotes gliomagenesis by resolving IDH1(R132H)-induced metabolic liabilities. Cancer Research. 2018;**78**(1):36-50

[86] McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA, et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell. 2018;**175**(1):101-116 e25

[87] Tonjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nature Medicine. 2013;**19**(7):901-908

[88] Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. Journal of Neurosurgery. 2001;**95**(2):190-198

[89] Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S, et al. Role of extent of resection in the longterm outcome of low-grade hemispheric gliomas. Journal of Clinical Oncology. 2008;**26**(8):1338-1345

[90] Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. Journal of Neurosurgery. 2011;**115**(1):3-8

[91] Marko NF, Weil RJ, Schroeder JL, Lang FF, Suki D, Sawaya RE. Extent

of resection of glioblastoma revisited: Personalized survival modeling facilitates more accurate survival prediction and supports a maximumsafe-resection approach to surgery. Journal of Clinical Oncology. 2014;**32**(8):774-782

[92] Qi S, Yu L, Li H, Ou Y, Qiu X, Ding Y, et al. Isocitrate dehydrogenase mutation is associated with tumor location and magnetic resonance imaging characteristics in astrocytic neoplasms. Oncology Letters. 2014;**7**(6):1895-1902

[93] Darlix A, Deverdun J, Menjot de Champfleur N, Castan F, Zouaoui S, Rigau V, et al. IDH mutation and 1p19q codeletion distinguish two radiological patterns of diffuse low-grade gliomas. Journal of Neuro-Oncology. 2017;**133**(1):37-45

[94] Ellingson BM, Lai A, Harris RJ, Selfridge JM, Yong WH, Das K, et al. Probabilistic radiographic atlas of glioblastoma phenotypes. AJNR. American Journal of Neuroradiology. 2013;**34**(3):533-540

[95] Price SJ, Allinson K, Liu H, Boonzaier NR, Yan JL, Lupson VC, et al. Less invasive phenotype found in isocitrate dehydrogenase-mutated glioblastomas than in isocitrate dehydrogenase wild-type glioblastomas: A diffusion-tensor imaging study. Radiology. 2017;**283**(1):215-221

[96] Wefel JS, Noll KR, Rao G, Cahill DP. Neurocognitive function varies by IDH1 genetic mutation status in patients with malignant glioma prior to surgical resection. Neuro-Oncology. 2016;**18**(12):1656-1663

[97] Beiko J, Suki D, Hess KR, Fox BD, Cheung V, Cabral M, et al. IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with

maximal surgical resection. Neuro-Oncology. 2014;**16**(1):81-91

[98] Kawaguchi T, Sonoda Y, Shibahara I, Saito R, Kanamori M, Kumabe T, et al. Impact of gross total resection in patients with WHO grade III glioma harboring the IDH 1/2 mutation without the 1p/19q co-deletion. Journal of Neuro-Oncology. 2016;**129**(3):505-514

[99] Wijnenga MMJ, French PJ, Dubbink HJ, Dinjens WNM, Atmodimedjo PN, Kros JM, et al. The impact of surgery in molecularly defined low-grade glioma: An integrated clinical, radiological, and molecular analysis. Neuro-Oncology. 2018;**20**(1):103-112

[100] Patel T, Bander ED, Venn RA, Powell T, Cederquist GY, Schaefer PM, et al. The role of extent of resection in IDH1 wild-type or mutant low-grade gliomas. Neurosurgery. 2018;**82**(6):808-814

[101] Andronesi OC, Kim GS, Gerstner E, Batchelor T, Tzika AA, Fantin VR, et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Science Translational Medicine. 2012;**4**(116):116ra4

[102] Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nature Medicine. 2012;**18**(4):624-629

[103] Lazovic J, Soto H, Piccioni D, Lou JR, Li S, Mirsadraei L, et al. Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation. Neuro-Oncology. 2012;**14**(12):1465-1472

[104] Andronesi OC, Rapalino O, Gerstner E, Chi A, Batchelor TT, Cahill DP, et al. Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate. The Journal of Clinical Investigation. 2013;**123**(9):3659-3663

[105] de la Fuente MI, Young RJ, Rubel J, Rosenblum M, Tisnado J, Briggs S, et al. Integration of 2-hydroxyglutarateproton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma. Neuro-Oncology. 2016;**18**(2):283-290

[106] Emir UE, Larkin SJ, de Pennington N, Voets N, Plaha P, Stacey R, et al. Noninvasive quantification of 2-hydroxyglutarate in human gliomas with IDH1 and IDH2 mutations. Cancer Research. 2016;**76**(1):43-49

[107] Nagashima H, Tanaka K, Sasayama T, Irino Y, Sato N, Takeuchi Y, et al. Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma. Neuro-Oncology. 2016;**18**(11):1559-1568

[108] Choi C, Raisanen JM, Ganji SK, Zhang S, McNeil SS, An Z, et al. Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma. Journal of Clinical Oncology. 2016;**34**(33):4030-4039

[109] Tan WL, Huang WY, Yin B, Xiong J, Wu JS, Geng DY. Can diffusion tensor imaging noninvasively detect IDH1 gene mutations in astrogliomas? A retrospective study of 112 cases. AJNR. American Journal of Neuroradiology. 2014;**35**(5):920-927

[110] Kickingereder P, Sahm F, Radbruch A, Wick W, Heiland S, Deimling A, et al. IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome

**35**

*IDH-Mutant Gliomas*

2015;**5**:16238

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

of the United States of America. 2014;**111**(30):11121-11126

[117] Shankar GM, Francis JM, Rinne ML, Ramkissoon SH, Huang FW, Venteicher AS, et al. Rapid intraoperative molecular characterization of glioma. JAMA Oncology. 2015;**1**(5):662-667

[118] Fathi AT, Nahed BV, Wander SA, Iafrate AJ, Borger DR, Hu R, et al. Elevation of urinary 2-hydroxyglutarate in IDH-mutant glioma. The Oncologist.

[119] Tran AN, Lai A, Li S, Pope WB, Teixeira S, Harris RJ, et al. Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro-Oncology.

2016;**21**(2):214-219

2014;**16**(3):414-420

2014;**2014**:198697

2015;**116**(3):381-387

[120] Li S, Chou AP, Chen W, Chen R, Deng Y, Phillips HS, et al. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro-Oncology. 2013;**15**(1):57-68

[121] Wang XW, Labussiere M, Valable S, Peres EA, Guillamo JS, Bernaudin M, et al. IDH1(R132H) mutation increases U87 glioma cell sensitivity to radiation therapy in hypoxia. BioMed Research International.

[122] Kessler J, Guttler A, Wichmann H, Rot S, Kappler M, Bache M, et al. IDH1(R132H) mutation causes a less aggressive phenotype and

radiosensitizes human malignant glioma cells independent of the oxygenation status. Radiotherapy and Oncology.

[123] Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, et al. The prognostic IDH1( R132 ) mutation is associated with reduced NADP+-dependent IDH activity in

[111] Yamashita K, Hiwatashi A, Togao O, Kikuchi K, Hatae R, Yoshimoto K, et al. MR imaging-based analysis of glioblastoma multiforme: Estimation of IDH1 mutation status. AJNR. American

[112] Juratli TA, Tummala SS, Riedl A, Daubner D, Hennig S, Penson T, et al. Radiographic assessment of contrast enhancement and T2/ FLAIR mismatch sign in lower grade gliomas: Correlation with molecular groups. Journal of Neuro-Oncology.

[113] Broen MPG, Smits M, Wijnenga MMJ, Dubbink HJ, Anten M, Schijns O, et al. The T2-FLAIR mismatch sign as an imaging marker for non-enhancing IDH-mutant, 1p/19q-intact lower-grade glioma: A validation study. Neuro-Oncology. 2018;**20**(10):1393-1399

[114] Patel SH, Poisson LM, Brat DJ, Zhou Y, Cooper L, Snuderl M, et al. T2-FLAIR mismatch, an imaging biomarker for IDH and 1p/19q status in lower-grade gliomas: A TCGA/TCIA project. Clinical Cancer Research.

2017;**23**(20):6078-6085

2014;**120**(6):1288-1297

[116] Santagata S, Eberlin LS, Norton I, Calligaris D, Feldman DR, Ide JL, et al. Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery. Proceedings of the National Academy of Sciences

[115] Kanamori M, Kikuchi A, Watanabe M, Shibahara I, Saito R, Yamashita Y, et al. Rapid and sensitive intraoperative detection of mutations in the isocitrate dehydrogenase 1 and 2 genes during surgery for glioma. Journal of Neurosurgery.

signature which is non-invasively predictable with rCBV imaging in human glioma. Scientific Reports.

Journal of Neuroradiology.

2016;**37**(1):58-65

2019;**141**(2):327-335

#### *IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

signature which is non-invasively predictable with rCBV imaging in human glioma. Scientific Reports. 2015;**5**:16238

*Brain and Spinal Tumors - Primary and Secondary*

DP, et al. Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate. The Journal of Clinical Investigation.

[105] de la Fuente MI, Young RJ, Rubel J, Rosenblum M, Tisnado J, Briggs S, et al. Integration of 2-hydroxyglutarateproton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma. Neuro-

[106] Emir UE, Larkin SJ, de Pennington N, Voets N, Plaha P, Stacey R, et al. Noninvasive quantification of

2-hydroxyglutarate in human gliomas with IDH1 and IDH2 mutations. Cancer

[107] Nagashima H, Tanaka K, Sasayama T, Irino Y, Sato N, Takeuchi Y, et al. Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma. Neuro-Oncology.

[108] Choi C, Raisanen JM, Ganji SK, Zhang S, McNeil SS, An Z, et al. Prospective longitudinal analysis of 2-hydroxyglutarate magnetic

resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma.

[109] Tan WL, Huang WY, Yin B, Xiong J, Wu JS, Geng DY. Can diffusion tensor imaging noninvasively detect IDH1 gene mutations in astrogliomas? A retrospective study of 112 cases. AJNR. American Journal of Neuroradiology. 2014;**35**(5):920-927

Journal of Clinical Oncology. 2016;**34**(33):4030-4039

[110] Kickingereder P, Sahm F, Radbruch A, Wick W, Heiland S, Deimling A, et al. IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome

2013;**123**(9):3659-3663

Oncology. 2016;**18**(2):283-290

Research. 2016;**76**(1):43-49

2016;**18**(11):1559-1568

[98] Kawaguchi T, Sonoda Y, Shibahara I,

[99] Wijnenga MMJ, French PJ, Dubbink HJ, Dinjens WNM, Atmodimedjo PN, Kros JM, et al. The impact of surgery in molecularly defined low-grade glioma: An integrated clinical, radiological, and molecular analysis. Neuro-Oncology.

[100] Patel T, Bander ED, Venn RA, Powell T, Cederquist GY, Schaefer PM, et al. The role of extent of resection in IDH1 wild-type or mutant low-grade gliomas. Neurosurgery.

[101] Andronesi OC, Kim GS, Gerstner E, Batchelor T, Tzika AA, Fantin VR, et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Science Translational Medicine.

[102] Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nature Medicine. 2012;**18**(4):624-629

[103] Lazovic J, Soto H, Piccioni D, Lou JR, Li S, Mirsadraei L, et al. Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation. Neuro-Oncology. 2012;**14**(12):1465-1472

[104] Andronesi OC, Rapalino O, Gerstner E, Chi A, Batchelor TT, Cahill

maximal surgical resection. Neuro-

Saito R, Kanamori M, Kumabe T, et al. Impact of gross total resection in patients with WHO grade III glioma harboring the IDH 1/2 mutation without the 1p/19q co-deletion. Journal of Neuro-Oncology. 2016;**129**(3):505-514

Oncology. 2014;**16**(1):81-91

2018;**20**(1):103-112

2018;**82**(6):808-814

2012;**4**(116):116ra4

**34**

[111] Yamashita K, Hiwatashi A, Togao O, Kikuchi K, Hatae R, Yoshimoto K, et al. MR imaging-based analysis of glioblastoma multiforme: Estimation of IDH1 mutation status. AJNR. American Journal of Neuroradiology. 2016;**37**(1):58-65

[112] Juratli TA, Tummala SS, Riedl A, Daubner D, Hennig S, Penson T, et al. Radiographic assessment of contrast enhancement and T2/ FLAIR mismatch sign in lower grade gliomas: Correlation with molecular groups. Journal of Neuro-Oncology. 2019;**141**(2):327-335

[113] Broen MPG, Smits M, Wijnenga MMJ, Dubbink HJ, Anten M, Schijns O, et al. The T2-FLAIR mismatch sign as an imaging marker for non-enhancing IDH-mutant, 1p/19q-intact lower-grade glioma: A validation study. Neuro-Oncology. 2018;**20**(10):1393-1399

[114] Patel SH, Poisson LM, Brat DJ, Zhou Y, Cooper L, Snuderl M, et al. T2-FLAIR mismatch, an imaging biomarker for IDH and 1p/19q status in lower-grade gliomas: A TCGA/TCIA project. Clinical Cancer Research. 2017;**23**(20):6078-6085

[115] Kanamori M, Kikuchi A, Watanabe M, Shibahara I, Saito R, Yamashita Y, et al. Rapid and sensitive intraoperative detection of mutations in the isocitrate dehydrogenase 1 and 2 genes during surgery for glioma. Journal of Neurosurgery. 2014;**120**(6):1288-1297

[116] Santagata S, Eberlin LS, Norton I, Calligaris D, Feldman DR, Ide JL, et al. Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery. Proceedings of the National Academy of Sciences

of the United States of America. 2014;**111**(30):11121-11126

[117] Shankar GM, Francis JM, Rinne ML, Ramkissoon SH, Huang FW, Venteicher AS, et al. Rapid intraoperative molecular characterization of glioma. JAMA Oncology. 2015;**1**(5):662-667

[118] Fathi AT, Nahed BV, Wander SA, Iafrate AJ, Borger DR, Hu R, et al. Elevation of urinary 2-hydroxyglutarate in IDH-mutant glioma. The Oncologist. 2016;**21**(2):214-219

[119] Tran AN, Lai A, Li S, Pope WB, Teixeira S, Harris RJ, et al. Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro-Oncology. 2014;**16**(3):414-420

[120] Li S, Chou AP, Chen W, Chen R, Deng Y, Phillips HS, et al. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro-Oncology. 2013;**15**(1):57-68

[121] Wang XW, Labussiere M, Valable S, Peres EA, Guillamo JS, Bernaudin M, et al. IDH1(R132H) mutation increases U87 glioma cell sensitivity to radiation therapy in hypoxia. BioMed Research International. 2014;**2014**:198697

[122] Kessler J, Guttler A, Wichmann H, Rot S, Kappler M, Bache M, et al. IDH1(R132H) mutation causes a less aggressive phenotype and radiosensitizes human malignant glioma cells independent of the oxygenation status. Radiotherapy and Oncology. 2015;**116**(3):381-387

[123] Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, et al. The prognostic IDH1( R132 ) mutation is associated with reduced NADP+-dependent IDH activity in

glioblastoma. Acta Neuropathologica. 2010;**119**(4):487-494

[124] Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, et al. Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Research. 2015;**75**(22):4790-4802

[125] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine. 2005;**352**(10):987-996

[126] van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: A phase 3, randomised, openlabel intergroup study. Lancet. 2017;**390**(10103):1645-1653

[127] Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;**75**(17):1560-1566

[128] SongTao Q, Lei Y, Si G, YanQing D, HuiXia H, XueLin Z, et al. IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Science. 2012;**103**(2):269-273

[129] Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nature Reviews. Cancer. 2012;**12**(2):104-120

[130] Fan CH, Liu WL, Cao H, Wen C, Chen L, Jiang G. O6-methylguanine DNA methyltransferase as a

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[131] Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England Journal of Medicine. 2005;**352**(10):997-1003

[132] Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Research. 2006;**66**(8):3987-3991

[133] Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clinical Cancer Research. 2007;**13**(7):2038-2045

[134] Fu Y, Huang R, Zheng Y, Zhang Z, Liang A. Glioma-derived mutations in isocitrate dehydrogenase 2 beneficial to traditional chemotherapy. Biochemical and Biophysical Research Communications. 2011;**410**(2):218-223

[135] Mohrenz IV, Antonietti P, Pusch S, Capper D, Balss J, Voigt S, et al. Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. Apoptosis. 2013;**18**(11):1416-1425

[136] Shi J, Sun B, Shi W, Zuo H, Cui D, Ni L, et al. Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumour Biology. 2015;**36**(2):655-662

[137] Ohba S, Mukherjee J, See WL, Pieper RO. Mutant IDH1-driven cellular transformation increases RAD51 mediated homologous recombination

**37**

*IDH-Mutant Gliomas*

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

Science Translational Medicine.

[145] Inoue S, Li WY, Tseng A, Beerman I, Elia AJ, Bendall SC, et al. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell.

[146] Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science.

[147] Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C, et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition.

[148] Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, et al. New IDH1 mutant inhibitors

2017;**9**(375)

2016;**30**(2):337-348

2013;**340**(6132):622-626

Blood. 2015;**125**(2):296-303

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[152] Pusch S, Krausert S, Fischer V, Balss J, Ott M, Schrimpf D, et al.

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2014;**14**(3):329-341

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[138] Koncar RF, Chu Z, Romick-Rosendale LE, Wells SI, Chan TA, Qi X,

et al. PLK1 inhibition enhances temozolomide efficacy in IDH1 mutant gliomas. Oncotarget. 2017;**8**(9):15827-15837

[139] Trivedi RN, Almeida KH, Fornsaglio JL, Schamus S, Sobol RW. The role of base excision repair in the sensitivity and resistance to temozolomide-mediated cell death. Cancer Research. 2005;**65**(14):6394-6400

[140] Yoshimoto K, Mizoguchi M, Hata N, Murata H, Hatae R, Amano T, et al. Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma. Frontiers in Oncology.

[141] Tateishi K, Wakimoto H, Iafrate AJ, Tanaka S, Loebel F, Lelic N, et al. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. Cancer

[142] Tateishi K, Higuchi F, Miller J, Koerner MVA, Lelic N, Shankar GM, et al. The alkylating chemotherapeutic temozolomide induces metabolic stress in IDH1-mutant cancers and potentiates NAD+ depletion-mediated cytotoxicity. Cancer Research. 2017;**77**(15):4102-4115

[143] Lu Y, Kwintkiewicz J, Liu Y, Tech K, Frady LN, Su YT, et al. Chemosensitivity of IDH1 mutant gliomas due to an impairment in PARP1 mediated DNA repair. Cancer Research.

[144] Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations

suppresses homologous recombination and induces PARP inhibitor sensitivity.

2017;**77**(7):1709-1718

Cell. 2015;**28**(6):773-784

2012;**2**:186

*IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

and temozolomide resistance. Cancer Research. 2014;**74**(17):4836-4844

*Brain and Spinal Tumors - Primary and Secondary*

promising target for the treatment of temozolomide-resistant gliomas. Cell

[131] Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England Journal of Medicine.

[132] Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Research.

[133] Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, et al. Loss of the mismatch repair protein MSH6 in human

glioblastomas is associated with tumor progression during temozolomide treatment. Clinical Cancer Research.

[134] Fu Y, Huang R, Zheng Y, Zhang Z, Liang A. Glioma-derived mutations in isocitrate dehydrogenase 2

beneficial to traditional chemotherapy. Biochemical and Biophysical Research Communications. 2011;**410**(2):218-223

[135] Mohrenz IV, Antonietti P, Pusch

[136] Shi J, Sun B, Shi W, Zuo H, Cui D, Ni L, et al. Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumour

S, Capper D, Balss J, Voigt S, et al. Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. Apoptosis.

2013;**18**(11):1416-1425

Biology. 2015;**36**(2):655-662

[137] Ohba S, Mukherjee J, See WL, Pieper RO. Mutant IDH1-driven cellular transformation increases RAD51 mediated homologous recombination

Death & Disease. 2013;**4**:e876

2005;**352**(10):997-1003

2006;**66**(8):3987-3991

2007;**13**(7):2038-2045

glioblastoma. Acta Neuropathologica.

[124] Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, et al. Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Research.

2010;**119**(4):487-494

2015;**75**(22):4790-4802

2005;**352**(10):987-996

[125] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine.

[126] van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: A phase 3, randomised, openlabel intergroup study. Lancet. 2017;**390**(10103):1645-1653

[127] Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology.

[128] SongTao Q, Lei Y, Si G, YanQing D,

secondary glioblastoma. Cancer Science.

HuiXia H, XueLin Z, et al. IDH mutations predict longer survival and response to temozolomide in

[129] Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nature Reviews. Cancer.

[130] Fan CH, Liu WL, Cao H, Wen C, Chen L, Jiang G. O6-methylguanine

DNA methyltransferase as a

2010;**75**(17):1560-1566

2012;**103**(2):269-273

2012;**12**(2):104-120

**36**

[138] Koncar RF, Chu Z, Romick-Rosendale LE, Wells SI, Chan TA, Qi X, et al. PLK1 inhibition enhances temozolomide efficacy in IDH1 mutant gliomas. Oncotarget. 2017;**8**(9):15827-15837

[139] Trivedi RN, Almeida KH, Fornsaglio JL, Schamus S, Sobol RW. The role of base excision repair in the sensitivity and resistance to temozolomide-mediated cell death. Cancer Research. 2005;**65**(14):6394-6400

[140] Yoshimoto K, Mizoguchi M, Hata N, Murata H, Hatae R, Amano T, et al. Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma. Frontiers in Oncology. 2012;**2**:186

[141] Tateishi K, Wakimoto H, Iafrate AJ, Tanaka S, Loebel F, Lelic N, et al. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. Cancer Cell. 2015;**28**(6):773-784

[142] Tateishi K, Higuchi F, Miller J, Koerner MVA, Lelic N, Shankar GM, et al. The alkylating chemotherapeutic temozolomide induces metabolic stress in IDH1-mutant cancers and potentiates NAD+ depletion-mediated cytotoxicity. Cancer Research. 2017;**77**(15):4102-4115

[143] Lu Y, Kwintkiewicz J, Liu Y, Tech K, Frady LN, Su YT, et al. Chemosensitivity of IDH1 mutant gliomas due to an impairment in PARP1 mediated DNA repair. Cancer Research. 2017;**77**(7):1709-1718

[144] Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.

Science Translational Medicine. 2017;**9**(375)

[145] Inoue S, Li WY, Tseng A, Beerman I, Elia AJ, Bendall SC, et al. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell. 2016;**30**(2):337-348

[146] Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013;**340**(6132):622-626

[147] Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, Gliser C, et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood. 2015;**125**(2):296-303

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[149] Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P, et al. Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell. 2014;**14**(3):329-341

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[155] Suijker J, Oosting J, Koornneef A, Struys EA, Salomons GS, Schaap FG, et al. Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines. Oncotarget. 2015;**6**(14):12505-12519

[156] Turcan S, Makarov V, Taranda J, Wang Y, Fabius AWM, Wu W, et al. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nature Genetics. 2018;**50**(1):62-72

[157] Johannessen TA, Mukherjee J, Viswanath P, Ohba S, Ronen SM, Bjerkvig R, et al. Rapid conversion of mutant IDH1 from driver to passenger in a model of human gliomagenesis. Molecular Cancer Research. 2016;**14**(10):976-983

[158] Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discovery Medicine. 2016;**21**(117):373-380

[159] Borodovsky A, Salmasi V, Turcan S, Fabius AW, Baia GS, Eberhart CG, et al.

5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. Oncotarget. 2013;**4**(10):1737-1747

[160] Yamashita AS, da Costa Rosa M, Borodovsky A, Festuccia WT, Chan T, Riggins GJ. Demethylation and epigenetic modification with 5-azacytidine reduces IDH1 mutant glioma growth in combination with temozolomide. Neuro-Oncology. 2018

[161] Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nature Medicine. 2015;**21**(2):178-184

[162] Karpel-Massler G, Ishida CT, Bianchetti E, Zhang Y, Shu C, Tsujiuchi T, et al. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nature Communications. 2017;**8**(1):1067

[163] Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015;**347**(6219):273-277

[164] Spino M, Kurz SC, Chiriboga L, Serrano J, Zeck B, Sen N, et al. Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma. Clinical Cancer Research. 2019;**25**(4):1261-1271

[165] Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014;**512**(7514):324-327

[166] Pellegatta S, Valletta L, Corbetta C, Patane M, Zucca I, Riccardi Sirtori F, et al. Effective immuno-targeting of the IDH1 mutation R132H in a murine

**39**

*IDH-Mutant Gliomas*

2017;**31**(8):774-786

2010;**70**(22):8981-8987

2014;**42**(4):247-251

2015;**6**(14):12279-12296

2015;**3**:4

*DOI: http://dx.doi.org/10.5772/intechopen.84543*

in MYCN-driven cancer. Cell. 2014;**159**(5):1126-1139

2014;**26**(6):909-922

[174] Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell.

[175] Tateishi K, Iafrate AJ, Ho Q, Curry WT, Batchelor TT, Flaherty KT, et al. Myc-driven glycolysis is a therapeutic target in glioblastoma. Clinical Cancer Research. 2016;**22**(17):4452-4465

model of intracranial glioma. Acta Neuropathologica Communications.

[167] Amankulor NM, Kim Y, Arora S, Kargl J, Szulzewsky F, Hanke M, et al. Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes & Development.

[168] Berghoff AS, Kiesel B, Widhalm G, Wilhelm D, Rajky O, Kurscheid S, et al. Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro-Oncology. 2017;**19**(11):1460-1468

[169] Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Research.

[170] Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Experimental Hematology.

[171] Cuyas E, Fernandez-Arroyo S, Corominas-Faja B, Rodriguez-Gallego E, Bosch-Barrera J, Martin-Castillo B, et al. Oncometabolic mutation IDH1 R132H confers a metforminhypersensitive phenotype. Oncotarget.

[172] Odia Y, Orr BA, Bell WR, Eberhart CG, Rodriguez FJ. cMYC expression in infiltrating gliomas: Associations with IDH1 mutations, clinicopathologic features and outcome. Journal of Neuro-

Oncology. 2013;**115**(2):249-259

[173] Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, et al. CDK7 inhibition suppresses super-enhancerlinked oncogenic transcription

*IDH-Mutant Gliomas DOI: http://dx.doi.org/10.5772/intechopen.84543*

model of intracranial glioma. Acta Neuropathologica Communications. 2015;**3**:4

*Brain and Spinal Tumors - Primary and Secondary*

5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. Oncotarget. 2013;**4**(10):1737-1747

[160] Yamashita AS, da Costa Rosa M,

Borodovsky A, Festuccia WT, Chan T, Riggins GJ. Demethylation and epigenetic modification with 5-azacytidine reduces IDH1 mutant glioma growth in combination with temozolomide. Neuro-Oncology. 2018

[161] Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase

1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nature Medicine. 2015;**21**(2):178-184

[162] Karpel-Massler G, Ishida CT, Bianchetti E, Zhang Y, Shu C, Tsujiuchi

[163] Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive

[164] Spino M, Kurz SC, Chiriboga L, Serrano J, Zeck B, Sen N, et al. Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma. Clinical Cancer Research. 2019;**25**(4):1261-1271

[165] Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature.

[166] Pellegatta S, Valletta L, Corbetta C, Patane M, Zucca I, Riccardi Sirtori F, et al. Effective immuno-targeting of the IDH1 mutation R132H in a murine

to ATR inhibitors. Science. 2015;**347**(6219):273-277

2014;**512**(7514):324-327

T, et al. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nature Communications. 2017;**8**(1):1067

Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathologica. 2017;**133**(4):629-644

[153] Kohanbash G, Carrera DA,

et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. The Journal of Clinical Investigation.

[154] Davis MI, Gross S, Shen M, Straley KS, Pragani R, Lea WA, et al. Biochemical, cellular, and biophysical characterization of a potent inhibitor of mutant isocitrate dehydrogenase IDH1. The Journal of Biological Chemistry.

2017;**127**(4):1425-1437

2014;**289**(20):13717-13725

2015;**6**(14):12505-12519

2018;**50**(1):62-72

[155] Suijker J, Oosting J, Koornneef A, Struys EA, Salomons GS, Schaap FG, et al. Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines. Oncotarget.

[156] Turcan S, Makarov V, Taranda J, Wang Y, Fabius AWM, Wu W, et al. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nature Genetics.

[157] Johannessen TA, Mukherjee J, Viswanath P, Ohba S, Ronen SM, Bjerkvig R, et al. Rapid conversion of mutant IDH1 from driver to passenger in a model of human gliomagenesis.

[158] Fujii T, Khawaja MR, DiNardo CD,

[159] Borodovsky A, Salmasi V, Turcan S, Fabius AW, Baia GS, Eberhart CG, et al.

Molecular Cancer Research.

Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discovery Medicine.

2016;**14**(10):976-983

2016;**21**(117):373-380

Shrivastav S, Ahn BJ, Jahan N, Mazor T,

**38**

[167] Amankulor NM, Kim Y, Arora S, Kargl J, Szulzewsky F, Hanke M, et al. Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes & Development. 2017;**31**(8):774-786

[168] Berghoff AS, Kiesel B, Widhalm G, Wilhelm D, Rajky O, Kurscheid S, et al. Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro-Oncology. 2017;**19**(11):1460-1468

[169] Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Research. 2010;**70**(22):8981-8987

[170] Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Experimental Hematology. 2014;**42**(4):247-251

[171] Cuyas E, Fernandez-Arroyo S, Corominas-Faja B, Rodriguez-Gallego E, Bosch-Barrera J, Martin-Castillo B, et al. Oncometabolic mutation IDH1 R132H confers a metforminhypersensitive phenotype. Oncotarget. 2015;**6**(14):12279-12296

[172] Odia Y, Orr BA, Bell WR, Eberhart CG, Rodriguez FJ. cMYC expression in infiltrating gliomas: Associations with IDH1 mutations, clinicopathologic features and outcome. Journal of Neuro-Oncology. 2013;**115**(2):249-259

[173] Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, et al. CDK7 inhibition suppresses super-enhancerlinked oncogenic transcription

in MYCN-driven cancer. Cell. 2014;**159**(5):1126-1139

[174] Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014;**26**(6):909-922

[175] Tateishi K, Iafrate AJ, Ho Q, Curry WT, Batchelor TT, Flaherty KT, et al. Myc-driven glycolysis is a therapeutic target in glioblastoma. Clinical Cancer Research. 2016;**22**(17):4452-4465

**41**

Section 3

Spinal Tumors
