Abstract
According to the 2016 World Health Organization (WHO) classification of central nervous system tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). IDH-mutant astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma often have wild-type p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing telomerase activation. This study analyzed IDH, ATRX, and TERT promoter mutations, and the correlation between them. Immortalized cells overcome the telomere-related crisis by activating telomerase or ALT. In glioma, telomerase is mainly activated by TERT promoter mutation, while ALT is usually associated with ATRX mutation. Although the mechanism of how ATRX mutation induces ALT remains unclear, ATRX loss alone is believed to be insufficient to induce ALT. Treatments targeting telomere maintenance are promising.
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Introduction
In the 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation. IDH1/2-mutant gliomas are further subdivided on the basis of the presence of a combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). Diffuse or anaplastic astrocytoma does not have 1p/19q co-deletion, while oligodendroglioma or anaplastic oligodendroglioma shows 1p/19q co-deletion [1]. Astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while oligodendroglioma often has wild-type (WT) p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing activation of telomerase [1] (Fig. 1). This study analyzed IDH, ATRX, and TERT promoter mutations and the correlation between them.
IDH mutation
IDHs are a group of enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG). The human body contains three types of IDHs: IDH1, IDH2, and IDH3 [2]. IDH1 is located in the cytosol/peroxisomes, while IDH2 and IDH3 are present in the mitochondria [3]. IDH1 and IDH2 are nicotinamide adenine dinucleotide phosphate (NADP) dependent, while IDH3 is nicotinamide adenine dinucleotide (NAD) dependent [4]. Only IDH3 is associated with the tricarboxylic acid cycle [5]. Mutant IDH1/2 converts α-KG into 2-hydroxyglutarate (2-HG) [6].
IDH1/2 mutation has been reported in not only gliomas [7] but also other tumors, such as acute myelogenous leukemia [8] and chondrosarcoma [9]. In addition, 2-HG accumulation reportedly contributes to tumorigenesis in these cases [7].
After Parsons [10], many studies have been conducted on IDH mutations in glioma [11,12,13,14]. Nearly all IDH mutations involve a single amino acid substitution. The mutation occurs at the arginine residue at codon 132 in IDH1 and codon 140 or 172 in IDH2, although R140 mutations are not found in glioma. The commonest is the R132H mutation (c.395G > A), which accounts for ~ 90% of all IDH mutations. IDH1 and IDH2 mutations usually occur exclusively [7]. IDH1/2 mutation is reportedly detected in 80–90% of grade II and III glioma and 5% of primary glioblastoma [3]. After publication of the 2016 WHO classification of CNS tumors, a glioma needs to have an IDH mutation to be classified as an oligodendroglioma [1]. Since the IDH1R132H alteration occupies ~ 90% of IDH mutations, immunohistochemistry (IHC) evaluation with the IDH1R132H antibody can cover ~ 90% of IDH1/2 mutation cases. In addition, direct DNA sequence analysis is performed to detect the IDH mutations, depending on the facilities.
IDH mutation has been detected as a common mutation between primary and recurrent tumors [15,16,17]. It has also been detected as a common mutation among samples from multiple regions in the same patients [16]. Therefore, IDH mutation is considered to occur at the early stage of tumorigenesis and as a driver mutation in IDH-mutant gliomas [7, 15]. The mechanism underlying gliomagenesis by mutant IDH1/2 has not been clearly elucidated. However, several possible hypotheses are reported (Fig. 2). The structures of 2-HG and α-KG are similar, and 2-HG competes with α-KG and inhibits α-KG-dependent enzymes, such as the ten-eleven translocation (TET) enzyme family of five methylcytosine hydroxylases and Jumonji C domain-containing histone demethylases [15, 18]. Mutant IDH-induced 2-HG in glioma inhibits the TET family, which might lead to global DNA methylation in the glioma CpG island methylation phenotype (G-CIMP) [19]. Gliomas with G-CIMP show gene expression of the proneural type classified by Verhaak et al. [20, 21]. These epigenetic changes are believed to affect gene expression, contributing to tumorigenesis. Histone demethylase inhibition by 2-HG increases histone methylation. This epigenetic status might also affect gene expression [18]. 2-HG reportedly stabilizes hypoxia-inducible factor 1-alpha (HIF-1α) expression and subsequently results in an increase in HIF-1α target gene expression by inhibition of prolyl-hydroxylase enzymes [22]. Consequently, IDH-mutant glioma cells escape from a hypoxic environment [4]. In addition, 2-HG increases reactive oxygen species through the NAPD/NAPDH balance, contributing to tumorigenesis [23].
IDH1R132H is a main mutation among IDH mutations, so IHC evaluation using IDH1R132H antibody is widely used. To check other types of mutations, direct DNA sequence analysis is also performed. IHC is reportedly 100% sensitive and specific in detecting IDH1R132H mutations [24]. The consistency rate between IHC and DNA sequence analysis is reported to be 88% in diffuse glioma patients [25]. As noninvasive methods, mutant IDH1/2-induced 2-HG is reported to be detectable by magnetic resonance spectroscopy [26].
IDH1/2 mutation is considered a driver mutation in IDH-mutant glioma, and inhibition of mutant IDH1/2 is a promising treatment for such gliomas. Several clinical trials are ongoing [4, 27]. In experimental studies, the effects of IDH inhibitors are controversial. IDH inhibitors inhibit the proliferation of IDH1-mutant glioma cells [28], while inhibition of IDH mutation is ineffective [29] or works only in a narrow window of time [30].
Telomere length in gliomas
Telomeres are DNA–protein complexes that protect chromosome ends. These protein complexes are called Shelterin, which comprise TRF1, TRF2, POT1, TIN1, TPP1, and RAP1 [31]. Telomeres in vertebrates comprise a region of 3000–20,000 TTAGGG repeats at the ends of chromosomes [32]. The length of a telomere shortens after each cell division, and cells go to the arrest stage after limitation [33]. To overcome this issue, many types of tumor cells maintain the telomere length via telomerase activation, while some types of tumors elongate the telomere length by telomere-independent manner, which is known as ALT [32]. These oncogenic changes in glioma are generally exclusive [34]. Telomerase has two principle components, the 1132-amino acid telomerase reverse transcriptase (TERT) and an associated telomerase RNA molecule (TERC) [35]. TERT promoter mutation increases TERT expression and activates telomerase activity [36, 37]. Another mechanism is ALT, with which ATRX, death-associated protein 6 (DAXX), and histone H3.3 are reportedly associated [32, 38].
IDH-mutant diffuse or anaplastic astrocytoma shows the ALT phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma or IDH-WT glioblastoma shows TERT promoter mutation [36, 39, 40]. Although both tumor types have the same IDH mutation, why astrocytoma selects the ALT phenotype and oligodendroglioma selects TERT promoter mutation to resolve telomeric dysfunction and maintain telomere length remains unknown.
Telomerase
TERT promoter mutation occurs at positions 124 and 146 bp upstream of the TERT ATG start site, called C228T and C250T, respectively [34]. These mutations are exclusive. Messenger RNA (mRNA) expression of TERT increases in gliomas with TERT promoter mutation compared to gliomas without TERT promoter mutation [36, 37]. The telomere length is shorter in glioma with TERT promoter mutation compared to glioma without TERT promoter mutation [37]. TERT promoter mutations generate identical 11 bp sequences that form a de novo binding site. The E26 transformation-specific transcription factor GA-binding protein selectively binds to the site and activates TERT [41]. TERT promoter mutation is believed to be associated with tumorigenesis in two phases: by promoting immortalization and genomic instability. In the first phase, TERT promoter mutation extends the cellular life span by extending the shortest telomeres but does not prevent most telomere shortening. In the second phase, the critically short telomeres inducing genome instability and telomerase are upregulated. Consequently, cells maintain growth [42]. TERT promoter mutation is considered the main mechanism of TERT transcript upregulation; however, other mechanisms have also been reported [43, 44]. For example, mutant IDH activates the TERT promoter, increasing histone lysine methylation and c-Myc/Max binding at the TERT promoter [44].
Several studies have reported the correlation between TERT promoter mutation and prognosis in glioma [39, 45,46,47], but few studies have compared prognoses within the same diagnosis based on the 2016 WHO classification [46]. Pekmezci et al. showed that of 291 grade II or III oligodendroglioma, IDH-mutant and 1p/19q-codeleted patients, 94% had only TERT promoter mutation, 0.69% had only ATRX mutation, 1.7% had both TERT promoter and ATRX mutation, and 4% had neither TERT promoter nor ATRX mutation [46]. The group with TERT promoter mutation had significant better overall survival (OS) compared to the group with TERT promoter WT group [46]. Of 154 IDH-WT astrocytoma patients, 60% showed only TERT promoter mutation, and 2% had both TERT promoter and ATRX mutation. The group with TERT promoter mutation had significantly worse OS compared to the TERT promoter WT group [46]. Akyerli et al. classified hemispheric diffuse glioma using the IDH and TERT promoter mutation status: both IDH and TERT promoter mutation, only IDH mutation, only TERT promoter mutation, and neither IDH nor TERT promoter mutation. Every group had a distinct demographic, anatomical, clinical, and prognostic correlation [39], and the TERT promoter mutation status of tumors was unchanged over time or recurred [39]. Similarly, in a meta-analysis, Vuong et al. classified WHO grade II or III glioma patients into four groups on the basis of the IDH and TERT promoter mutation status and showed the difference in OS between the groups (both IDH and TERT promoter mutation > only IDH mutation > neither IDH nor TERT promoter mutation > only TERT promoter mutation) [47].
Telomere maintenance is expected to be a new therapeutic target. Several approaches have been followed, such as vaccines, antisense oligonucleotides, and small-molecule inhibitors, to inhibit TERT, TRRC, or TERT promoter mutation [48,49,50,51,52,53]. However, these reagents might be ineffective in tumors with the ALT phenotype.
ALT
Although telomerase activity is the most frequent mechanism for maintaining telomere length, 10%–15% of cancers also show a telomerase-independent mechanism for elongating telomeres (ALT) [54]. Although the ALT phenotype is uncommon in tumors, it is common in certain cancer subtypes, including glioma and sarcoma [32, 54]. Among gliomas, ALT is often detected in WHO grade II or III IDH-mutant astrocytoma, and IDH-mutant glioblastoma [46]. Tumor cells with the ALT phenotype depend on the activation of a homologous recombination DNA repair mechanism to maintain telomere length [55]. ALT often begins with the loss of chromatin-remodeling proteins in telomeres, resulting in DNA damage response, recombination, and abnormal protein behavior, which reportedly initiates ALT [32, 55].
Addition of ATRX suppresses the ALT phenotype, so ATRX loss is associated with the ALT phenotype [56]. However, studies have reported that ATRX loss alone is insufficient to induce the ALT phenotype [56, 57]. In contrast, IDH1R132H overexpression in glioma cell lines downregulates ATRX and induces telomere lengthening consistent with ALT [58]. The authors suggested that IDH1R132H alone is sufficient to diminish ATRX expression and induces ALT. Inconsistent with their findings, neither overexpressed IDH1R132H alone nor ATRX knockout alone induces the ALT phenotype [44, 57]. Exogenous IDH1R132H expression combined with ATRX mutation induces the ALT phenotype [57]. Mutant IDH1 downregulates a Shelterin protein, RAP1, which leads to telomere dysfunction. Mutant IDH1 also downregulates XRCC, which leads to nonhomologous end-joining (NHEJ) inhibition. This downregulation of RAP1 and XRCC reportedly contributes to ALT in glioma cells with ATRX loss [57].
The cIMPACT Update 2 report showed that diffuse astrocytic-appearing WHO grade II or III glioma with IDH mutation and ATRX nuclear expression loss and/or strong, diffuse p53 immunopositivity can be diagnosed as diffuse astrocytoma, IDH-mutant or anaplastic astrocytoma, IDH-mutant without checking the 1p/19q co-deletion status [59]. IHC analysis for ATRX, not sequence analysis for ATRX, was described in this report. Since ATRX is relatively large, it is difficult to perform the assay to detect the mutation as a routine test. Therefore, IHC analysis is usually performed as an alternative method for evaluating ATRX mutation. Ikemura et al. (2016) examined 193 patients and divided them into three groups: ATRX loss with staining loss in > 90% of tumor cells (n = 43), ATRX indeterminate with staining loss in 10%–90% of tumor cells (n = 0), and ATRX retained with staining loss in < 10% of tumor cells (n = 150) [60]. Other studies divided patients into two groups, with nuclear ATRX loss and with nuclear ATRX retention, using a cutoff value of 10% [61, 62].
ATRX mutation is associated with prognosis in glioma [63, 64]. However, in most cases, tumor diagnosis is performed on the basis of pre-2016 WHO classification. Since most IDH-mutant astrocytomas and IDH-mutant glioblastomas show ATRX loss and most IDH-mutant and 1p/19q-co-deleted oligodendrogliomas and IDH-WT glioblastomas show ATRX expression, the comparison between low-grade gliomas or between glioblastomas might be a comparison between astrocytoma and oligodendroglioma or between IDH-WT glioblastoma and IDH-mutant glioblastoma. In a comparison within the same diagnosis of 220 cases of IDH-mutant diffuse astrocytoma and 181 cases of IDH-mutant anaplastic astrocytoma, 78% had only ATRX mutation, 2% had both TERT and ATRX mutation, 5% had only TERT mutation, and 16% had neither TERT nor ATRX mutation. Neither TERT nor ATRX status was associated with survival [46]. In IDH-mutant glioblastoma patients, the rate of each mutation is similar to that in IDH-mutant WHO grade II and III astrocytoma patients. Sixty-three percentage had only ATRX mutation, 6% had both TERT and ATRX mutation, 12% had only TERT mutation, and 20% had neither TERT nor ATRX mutation. Neither TERT nor ATRX status was associated with survival [46].
Several new treatments have been recommended for targeting tumor cells with the ALT phenotype [35, 54]. CRISPR-Cas9 screening detected Wee1 as a target in ATRX-null tumor cells [65]. The ATR inhibitor reportedly disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells [66]. Histone deacetylase inhibitors might suppress ALT through NuRD inhibition [67]. Although these treatments are expected to be effective in tumor cells with the ALT phenotype, treatments that are effective independent of activated telomerase or ALT are promising. G-quadruplexes are tetra-stranded DNA structures formed by guanine-rich sequences. Studies have reported a G-quadruplex stabilizer that activated the pathways of response to DNA damage and induce senescence in both telomerase-positive and ALT phenotype cells [68].
Conclusion
In this review, we discussed the three mutations of IDH, ATRX, and TERT promoter in glioma. It remains unclear why astrocytoma, IDH-mutant has ALT phenotype, whereas oligodendroglioma, IDH-mutant and 1p/19q-codeleted showed activated telomerase. Further studies may clarify it and new treatments targeting maintenance of telomere are promising.
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Ohba, S., Kuwahara, K., Yamada, S. et al. Correlation between IDH, ATRX, and TERT promoter mutations in glioma. Brain Tumor Pathol 37, 33–40 (2020). https://doi.org/10.1007/s10014-020-00360-4
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DOI: https://doi.org/10.1007/s10014-020-00360-4