Noncanonical (Non-R132H) IDH-Mutated Gliomas

Abstract

Mutations in IDH1 or IDH2 confer a significant survival advantage compared to their isocitrate dehydrogenase (IDH) wild-type counterparts and, as such, are the most significant prognostic factors in this group. The mutations in the IDH1 gene are heterozygous and almost always involve only a single residue (arginine 132), which is replaced by histidine in roughly 90% of tumors. Regardless, the non-p.R132H (noncanonical) mutations in the IDH1 gene were also documented in around 20% of mutated glioma. The noncanonical IDH mutations have distinguishing radiological and histological features. The existence of such tumors seems to be associated with a genetic predisposition to cancer development.

1. Introduction

1.1 The 2020 WHO classification of adult gliomas

According to the latest World Health Organization (WHO) classification of CNS tumors, all isocitrate dehydrogenase (IDH)-mutant tumors were classified as either IDH-mutant oligodendrogliomas or astrocytomas and graded as WHO grade 2, 3, or 4 [1]. This classification recognized a grade 4 IDH-mutant astrocytoma and tumors harboring CDKN2A/B homozygous deletion. We favor using the term cancerous glioma to the previous term “Low-Grade Glioma (LGG),” since the current 2020 WHO classification presented major changes that advance the role of molecular diagnostics in CNS tumor classification. With the new classification, there are three groups of adult-type gliomas (Figure 1).

Figure 1.

The 2020 WHO classification of adult gliomas.

Group 1 is the astrocytoma with IDH mutation, group 2 is astrocytoma with no IDH mutation (IDH wild-type), and group 3 is oligodendroglioma, which carries the IDH mutation and 1p/19q co-deletion. Other significant molecular profile findings include IDH1, IDH2, ATRX, TP53, and CDKN2A/B. Group 1 is further classified based on the histopathological grade into 2, 3, and 4. The second group is the astrocytoma with IDH wild-type status, where only one histological grade is given (grade 4) due to the nature of the disease and it is prognosis. A third group is oligodendrogliomas which are characterized by the 1p/19q co-deletion which is unique for this group and considered to be a positive prognostic marker for this particular group [2, 3].

2. IDH mutation in glioma

IDH1 mutations are very recurring in World Health Organization (WHO) grade II astrocytomas, anaplastic astrocytomas WHO grade III, low-grade/anaplastic oligodendrogliomas, and secondary glioblastomas (representing 80%, 64%, 66–80%, and 83%, respectively) [4, 5, 6, 7]. Several studies have consistently reported a positive association between the IDH1 mutations and the better prognosis for patients with malignant gliomas [7, 8, 9, 10, 11]. Yet, for the adult cancerous glioma or (LGGs) vague results have been published so far. Metellus et al. studied a small series of 47 LGGs (85% oligodendroglial and 15% astrocytic tumors) and deduced that IDH1 mutations were positive prognostic values and associated with more prolonged overall survival (OS) and progression-free survival (PFS) [12]. Dubbink et al. analyzed a retrospective series of 49 low-grade astrocytomas for IDH1/2 mutations and found a highly significant correlation between OS and IDH1 status [13]. A more considerable series by Sanson and his colleagues with 100 LGGs (88% oligodendroglial tumors and 12% astrocytomas WHO-II) concluded that IDH1 is a prognostic marker and associated with longer OS only but not with PFS [9]. An association between IDH1 mutation status and OS was also noted in a cohort of 139 LGGs consisting of 61 oligodendroglial and 78 astrocytic tumors [5]. Contrariwise, additional investigations on patients with LGGs did not report any correlation between IDH1 mutation and OS [14, 15, 16]. These studies were associated with low hazard ratio (HR); however, a meta-analysis reported later (included the later studies) showed a positive HR between the IDH mutation status and death (with less mortality rate in IDH-mutated glioma compared to the wild-type) [17].

2.1 Biological impact of IDH mutation

In adults, mutations in IDH1 or IDH2 confer a significant survival benefit compared to their IDH wild-type counterparts and as such are the most important prognostic factor in this group [9]. Glioma-specific mutations in IDH1 always affect the amino acid arginine in position 132 of the amino acid sequence which belongs to an evolutionary highly conserved region located at the binding site for isocitrate [8]. The role of IDH1 mutations in tumor biology currently is intensely studied. Mutations inactivate enzyme activity and confer the novel function of catalyzing the conversion of alpha-ketoglutarate (αKG) to D-2-hydroxyglutarate (2HG) [5]. The downstream effects of mutant IDH include decreased cellular NADPH and αKG levels, HIF1a stabilization, increased production of 2HG, which competitively inhibits αKG-dependent enzymes such as histone methyltransferases and 5-methylcytosine hydroxylases [18, 19, 20, 21, 22], as shown in (Figure 2).

Figure 2.

Biological role of IDH1 mutation [22].

3. Noncanonical IDH-mutant gliomas

3.1 Overview and prevalence

Mutations in the IDH1 gene are heterozygous and almost always affect only a single residue (arginine 132), which is replaced by histidine in roughly 90% of tumors [4, 9, 23, 24, 25]. Nonetheless, non-p.R132H mutations in the IDH1 gene (e.g. p.R132C) have been documented to accumulate at higher frequencies in histological subtypes of glioma [5] in astrocytomas of Li-Fraumeni patients [26] and in patients with AML [27]. Visani and his co-authors found that around 19% of grade II or III tumors harbored a noncanonical IDH mutation, while in GBM they recognized only the IDH1-R132H mutation [28].

Blass et al. [24] sequenced 685 primary brain tumors to analyze the genomic region spanning wild-type R132 of IDH1. They recognized 221 somatic IDH1 mutations with higher frequency in secondary glioblastomas followed by oligoastrocytomas, oligodendrogliomas, and diffuse astrocytomas (88%, 78%, 69%, and 68% respectively). Exclusively one wild-type allele was detected, and all the mutations were heterozygous. Mutation in codon 132 of IDH1 was detected only and 205 mutations were of the R132H type. Nevertheless, they also encountered leading to R132C, R132S, R132G, R132L, and R132V (eight, four, two, one, and one mutation, respectively), as shown in Figure 3. There was no apparent association of the rare mutation types with a distinct tumor entity, although six of the eight R132C mutations were seen in astrocytomas.

Figure 3.

Type of 221 IDH1 mutations in brain tumors in Blass et al.’s study [24].

Hartmann and his colleagues analyzed 1010 human gliomas for mutations in codons 132 and 172 in the genes for IDH1 and IDH2, respectively [5]. Their series consisted of 1010 diffuse gliomas including diffuse astrocytomas WHO grade II (227), anaplastic astrocytomas WHO grade III (228), anaplastic oligoastrocytomas (177), anaplastic oligodendrogliomas WHO grade III (174), oligodendrogliomas WHO grade II (128), and oligoastrocytomas WHO grade II (76). R132H was the dominant amino acid sequence alteration accounting for 92.7% of the detected mutations followed by R132C, R132S, R132G, and R132L. The type and distribution of the mutations are given in Figure 4.

Figure 4.

Type of 716 IDH1 and 31 IDH2 mutations and frequency among mutations in 1010 WHO grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas analyzed by Hartmann et al. [5].

The disparities in the literature regarding the low frequencies of R132S, R132G, and R132L may be due to dissimilarities in sample size and different types of tumors examined. Franceschi and his colleagues lately reviewed 390 patients with an R132H-IDH1 mutation and 34 patients with a non-R132H mutation [29]. Likened to patients with the R132H-IDH1 mutation, patients with non-R132H mutations were discovered to have less frequent 1p19q co-deletion. In addition, they were also younger than those with noncanonical IDH1 mutation (p < 0.001). Improved overall survival was correlated to the extent of surgical resection, 1p19 co-deletion existence, and the presence of non-R132H mutation [29].

The prognostic impact of non-R132 mutation is still under study and not fully defined.

Since most mutations affect the same hot spot region of IDH1-R132H, it was naturally presumed that the associated clinical outcomes are similar to that of IDH1-R132H mutated tumors, as implied by the difficulty in culling clinical data for specific noncanonical mutations from documented series. Restricted data are available in the literature concerning the prognosis, overall survival, and role of adjuvant therapies (radiotherapy and/or chemotherapy) in patients with noncanonical IDH mutations. Moreover, the literature also lacks studies that distinguish the IDH-mutant astrocytomas and oligodendrogliomas. The issue with combining the two different groups is that the oligodendrogliomas are characterized by the 1p19q co-deletion with the positive prognostic marker for this group. This might have an influence on the overall conclusion of these studies.

Figure 5a-d displaying a Scopus review of documents that cited the “noncanonical IDH” OR “non-R132” mutated glioma in the title or abstract. There were 10 total articles. The figure shows the overlay visualization of the authors and the connections between the authors. The colors demonstrate the year of publication, and the size of the circle displays the weight of the author in terms of the number of published documents in this domain. The lines indicate the connectivity between the authors. For instance, Franceschi [29] was involved in 3 documents and had a total of 17 connections (Figure 5b). The same applies to Brandes (Figure 5c) [30]. Nevertheless, Angelini [31] for instance was involved in one document only (smaller circle) and had only a total link of eight (Figure 5d).

Figure 5.

The overlay visualization of noncanonical IDH-mutated article’s authors (Scopus indexed).

3.2 Age distribution in noncanonical IDH-mutated glioma

There were only three articles that reported the significance of the age distribution in the IDH-mutated gliomas [5, 29, 32]. Posetsch and Franceschi and their colleagues reported a younger age for patients harboring all types of IDH1 noncanonical mutations as compared to IDH1 canonical mutation (median age 35 vs. 43 years and 29 vs. 39 years) [29, 32]. Yet, Hartmann et al. reported a significantly younger age only for patients with IDH1 R132C noncanonical mutations with a median age of 34.9 vs. 42.9 years [5].

3.3 Patient outcome

A recently published systematic review and meta-analysis aimed to evaluate the clinical role of IDH noncanonical mutations documented a possible favorable prognostic role for IDH noncanonical mutations [33]. Another study reported a prolonged survival for patients with IDH1 noncanonical mutations as compared to IDH canonical mutation [29]. However, two other studies reported no association between the noncanonical mutations and the survival rate [23, 32]. Nevertheless, the later studies were lacking the reporting of the survival hazard ratio (HR) with the confidence interval.

3.4 Current therapy and future direction

One of the most remarkable phenomena noticed in IDH-mutated glioma is the production of 2HG. This oncometabolite was found to be involved in the activation of different cancer-associated signaling pathways in addition to tumorigenesis and tumor progression.

Targeting the mutant enzymes of the IDH1/2 has long been sought as a novel therapeutic strategy to prevent the progression of cancers harboring the IDH1/2 mutation [34]. The benefit of this targeted therapy in glioma using small-molecule inhibitors have been established by several continuing investigations [35, 36]. An example of IDH-R132H enzyme inhibitor is the compound AGI-5198, which is an allosteric, selective inhibitor inhibiting the synthesis of 2HG in mouse and human glioma cells [36, 37]. Researchers also found that mutant IDH1 promotes selective vulnerability by altering NAD+ supply [38]. The expression of Naprt1 (a rate-limiting enzyme within the NAD+ salvage system) can be reduced by the introduction of mutant IDH1 and results in more depressed basal NAD+ levels. Exposure to NAMPT inhibitors thus effectively hinders both NAD+ salvage pathways in IDH1-mutant cells, resulting in a metabolic crisis that activates the energy sensor AMPK and initiation of autophagy. They also highlighted that reduced NAD+ salvage plays a major role in the mechanism of NAMPT inhibitor hypersensitivity [38].

Ongoing phase I/II clinical trials are currently in progress to assess the safety of different IDH-mutant inhibitors in glioma patients. Early clinical results suggest that the IDH1-mutant inhibitor AG-120 (ivosidenib) is an example of an IDH1-mutant inhibitor that is satisfactorily accepted in patients with previously treated non-contrast-enhancing gliomas [39].

4. Conclusion

Noncanonical IDH mutations are observed in only a limited number of all gliomas and are exceedingly rare among glioblastomas. It is unclear if tumors with these mutations are associated with more favorable outcome compared to canonical IDH mutants. Further study of the natural history of noncanonical IDH-mutant cancerous gliomas and analysis of the treatment effect of IDH mutation-specific targeted therapy is needed in the future.

5. Recommended articles

The recommended articles are [1, 4, 5, 15, 24, 29, 31, 32, 34, 39].

Abbreviations

LGG	low-grade glioma
IDH	isocitrate dehydrogenase
WHO	World Health Organization
NADPH	nicotinamide adenine dinucleotide phosphate
aKG	alpha-ketoglutarate