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| REVIEW |
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| Year : 2022 | Volume
: 5
| Issue : 1 | Page : 5-11 |
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The diverse landscape of histone-mutant pediatric high-grade gliomas: A narrative review
Evan Lubanszky1, Cynthia Hawkins2
1 The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
2 The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto; Division of Pathology, Hospital for Sick Children, Toronto, ON, Canada
| Date of Submission | 17-Jan-2022 |
| Date of Decision | 30-Jan-2022 |
| Date of Acceptance | 12-Feb-2022 |
| Date of Web Publication | 30-Mar-2022 |
Correspondence Address:
Dr. Cynthia Hawkins
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital For Sick Children, 555 University Avenue Toronto, ON, M5g 1x8
Canada
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/glioma.glioma_1_22
Pediatric high-grade gliomas (pHGGs) are the leading cause of tumor-related death in children, with diffuse midline gliomas representing the worst prognoses. Despite decades of clinical trials, no effective treatment has been found, and we are in desperate need of novel therapeutics. The discovery of highly recurrent histone H3 mutations in pHGGs represents a major breakthrough in our understanding of tumor initiation and development. In this review, we summarize our current knowledge of the molecular pathology of these tumors, including their genomic/epigenetic alterations, mechanism of action, and partner mutations contributing to tumor progression.
Keywords: Diffuse, epigenetic(s), glioma, H3.3G34R, H3K27M, histone(s), midline, review
How to cite this article:
Lubanszky E, Hawkins C. The diverse landscape of histone-mutant pediatric high-grade gliomas: A narrative review. Glioma 2022;5:5-11 |
How to cite this URL:
Lubanszky E, Hawkins C. The diverse landscape of histone-mutant pediatric high-grade gliomas: A narrative review. Glioma [serial online] 2022 [cited 2023 Oct 2];5:5-11. Available from: http://www.jglioma.com/text.asp?2022/5/1/5/341375 |
| Introduction | |  |
Pediatric high-grade gliomas (pHGGs) represent a highly aggressive, heterogeneous, and deadly group of central nervous system tumors.[1] In children, high-grade gliomas (World Health Organization [WHO] grades 3 and 4) represent approximately 10% of central nervous system tumors and are the leading cause of tumor-related death.[2] Despite decades of clinical trials and advancements in treatment strategies, including multi-faceted approaches centered around focal radiation, chemotherapy, and surgical resection (when possible), the outcome for patients with pHGGs has shown little improvement.[3],[4] However, our understanding of the molecular underpinnings of these tumors is rapidly expanding, which holds promise for future development of more targeted therapeutic strategies. In this review, we summarize our current knowledge of the molecular pathology of these tumors, including their genomic/epigenetic landscapes, mechanism of action, and the obligate partner mutations contributing to tumor progression.
| Search Strategy | | |
The literature search on the PubMed database was performed using the key terms “diffuse midline glioma,” “DMG-H3K27M mutant,” “H3G34R mutant glioma.” This review included original publications from 1990 to 2021 on pHGGs including, but not limited to, histone-mutant diffuse midline and hemispheric gliomas in children/youth. The literature search strategy utilized here was aimed at investigating oncohistone pHGGs within the larger spectrum of pHGGs. This included searching for both clinical and nonclinical histone-mutant pHGG studies investigating the age, location, and prognosis of pHGGs, as well as the primary and accessory mutations that have been shown to contribute to tumorigenesis, and their mechanisms of action.
| Oncohistones | | |
Our understanding of pHGG biology was revolutionized by the discovery of novel mutations in histone coding genes in pediatric tumors, referred to as “oncohistones.”[5],[6] More specifically, mutations in histone H3 coding genes have not only enhanced our understanding of pHGG tumorigenesis, but they have also allowed us to classify these tumors based on their specific H3 histone mutation.[5],[7],[8] Histones are nuclear proteins that are essential for the condensing of DNA into nucleosomes via the formation of histone octamers around which DNA wraps itself, and play key roles in the regulation of chromatin.[9] The histone H3 family of proteins consists of canonical histone H3.1 and its variant H3.3, encoded by the H3C2 (HIST1H3B) and H3-3A (H3F3A) genes, respectively.[10] H3.1 and H3.3 can also be distinguished by their pattern of deposition, with H3.1 expressed during S-phase and therefore deposited in a DNA replication-dependent manner throughout the genome.[11] H3.3, in contrast, is expressed throughout the cell cycle and is deposited in actively transcribed regions, pericentric heterochromatin, and telomeres in a DNA replication-independent manner.[11]
Each histone protein consists of the main protein structure, and a highly conserved, protruding amino-acid tail, which is subject to various post-translational modifications (PTMs). These PTMs, such as methylation or acetylation, are known to have a wide range of effects on chromatin structure and transcription, with key sites including Lysine 27 on histone H3.[12] It is on these histones H3 tails that the hallmark mutations of pHGGs occur, consisting of either a lysine-to-methionine substitution at position 27 of histone H3.1 or H3.3 tails (hereafter referred to as K27M mutations) or a glycine-to-arginine mutation at position 34 of the histone H3.3 tail (hereafter referred to as G34R mutations).[5],[7] Characterization of tumors bearing one of these mutations has revealed that these oncohistones define subgroups of pHGGs with distinct anatomical locations, age of onset, co-occurring mutations, and prognoses.[13] Although exceptionally rare, other histone mutations seen clinically include H3.2K27M seen in histone H3.2, and a glycine-to-valine substitution leading to the H3.3G34V mutant.[14],[15],[16]
| H3K27M Tumors | | |
The H3K27M mutation was initially reported in pHGGs nearly one decade ago, serving as the first description of histone mutations in cancer.[5],[7],[8] H3K27M mutations are present in the majority of midline pHGGs, representing a defining characteristic of these tumors such that in 2016 the WHO recognized a new, molecularly defined diagnostic subgroup of diffuse midline gliomas (DMGs) known as DMG H3K27M-mutant.[17] H3K27M-mutant DMGs dominate diffuse pontine tumors (occurring in ~80%), however, this mutation is also present in gliomas arising from other midline structures such as the spinal cord and the thalamus.[18],[19],[20] Due to this midline location, surgical resection of these aggressively infiltrating tumors is not feasible, and thus patients with H3K27M-mutant DMGs face a dismal prognosis, with nearly 100% fatality and a median overall survival of <1 year.[20],[21] Within the H3K27M-mutant classification, both H3.1 and H3.3K27M mutant DMGs are represented, with H3.1K27M mutations occurring less commonly than H3.3K27M (~15% vs. ~65%, respectively), having a slightly earlier age of diagnosis (~4 years vs. ~6.5 years), and longer survival (~15 months vs. ~10.8 months).[3],[22],[23]
| Molecular Mechanisms of H3K27M | | |
The H3K27M mutation is a highly recurrent, somatic mutation that is suggested to have a dominant-negative mechanism of action.[24] Despite DMG-H3K27M mutant tumors carrying the mutation on only ~5%–17% of H3 histone proteins, this mutation results in widespread loss of both H3K27 trimethylation (H3K27 me3) and DNA methylation.[8],[25] With the epigenetic H3K27 me3 marks maintaining a repressive effect on translation and contributing to the preservation of cellular identity, H3K27M prevents the deposition of this PTM, ultimately leading to aberrant gene expression.[8],[25] Trimethylation of H3K27 is catalyzed by the Polycomb Repressive Complex (PRC2), specifically through the catalytic enhancer of zeste homolog (EZH1 or 2) subunit of PRC2.[26] Although the effects of H3K27M-mediated inhibition of PRC2 have been characterized, the mechanism by which H3K27M confers these effects has not been fully elucidated, with competing hypotheses emerging in recent years.[27]
Quickly emerging ideas included H3K27M serving as a gain of function mutation enabling both the sequestration and inhibition of PRC2 at this mutated residue, preventing the complex from methylating cognate residues on a global level.[8] This sequestration was proposed to function through methionine's increased binding affinity for EZH2 over lysine, sequestering PRC2 at the H3K27M site, and preventing the hydrolysis of methyl-donor group S-adenosylmethionine for the deposition of trimethyl marks.[8],[28] This has been supported by studies demonstrating H3K27 me3 marks proximal to the H3K27M residue work cooperatively with H3K27M to sequester PRC2.[29] In contrast, some in vivo studies, such as by Piunti et al.,[30] have demonstrated that the localization of the PRC2 complex is inversely correlated with the localization of H3K27M, and the formation of locus-specific H3K27M/H3K27ac heterotypic nucleosomes promote the exclusion of PRC2 from chromatin binding, resulting in a loss of H3K27 me3.[30],[31]
Bridging the gap between these two hypotheses, Stafford et al.[32] proposed a third hypothesis, suggesting that allosterically active PRC2 can bind more strongly to H3K27M residues, however, following this binding the EZH2 subunit undergoes a conformational change, rendering it catalytically inactive. PRC2 is subsequently released, with a lasting inhibition preventing the deposition of additional H3K27 me3 marks.[32] Beyond PRC2 inhibition, H3K27M has been shown to have additional effects including DNA hypomethylation and a global increase of other histone PTMs associated with active transcription, including increased di-and trimethylation of H3K36. Together, these effects demonstrate the multiple consequences of H3K27M on the global chromatin landscape and transcription, beyond H3K27M itself.[32],[33]
| Wild-Type Diffuse Midline Gliomas | | |
Approximately 15% of DMGs do not possess a histone H3 mutation, despite an overall survival similar to that of H3.1K27M tumors (~15 months) and harboring the characteristic decrease in global H3K27 me3.[34],[35],[36] Instead, these DMGs are characterized by overexpression of CXorf67, a gene encoding the Enhancer of Zeste Homologs Inhibitory Protein (EZHIP). Interestingly, the mechanism by which EZHIP confers a global reduction in H3K27 me3 is similar to H3K27M in its reliance on the PRC2 complex, and its sequestration at specific chromatin sites as proposed by Lewis et al.[8],[37] EZHIP has been shown to interact preferentially with allosterically activated PRC2 at CpG islands, with the C-terminus of EZHIP possessing a peptide mimic of K27M that binds with the active site of EZH2. Together, EZHIP can stabilize the PRC2-EZHIP-H3K27 me3 complex with high affinity, preventing the complex from spreading to cognate residues, leading to the widespread loss of H3K27 me3. However, H3K27 me3 is retained at these CpG islands, which has been proposed to be necessary for maintaining cell proliferation and silencing tumor suppressor genes.[37] Interestingly, this broad loss of H3K27 me3 is seen prominently in posterior-fossa type-A (PFA) ependymomas, which have been shown to overexpress EZHIP, and like WT-DMGs, they retain H3K27 me3 marks at CpG islands.[37] Despite this shared phenotype and dependency on the PRC2 complex to mediate the H3K27 me3 loss, PFA-ependymomas differ from DMGs in many ways, most importantly they are much less invasive and are less aggressive with a 10-year overall survival of ~56% (10-year progression-free survival ~37%).[38],[39],[40] Although both tumor types utilize the PRC2 complex as a mechanism for its effects on chromatin, the differences between these tumors potentially highlight the roles of the cell of origin and additional alterations contributing to the progression and overall prognoses of these diseases.
| Co-Alterations in Diffuse Midline Gliomas | | |
The complexity of H3K27M-DMGs is amplified by the presence of specific co-occurring mutational “hits” contributing to both the initiating stages of tumorigenesis and its maintenance.[18],[41] Clonal evolution analyses have shown H3K27M to be the primary truncal mutation in these tumors, with their respective co-mutations occurring as either secondary clonal “hits,” such as TP53, or sub-clonal alterations such as PDGFRA.[6],[42] To date, DMG modeling attempts have relied on the presence of these additional mutations to generate tumors in the brain, supporting their role as obligate partners to their respective oncohistone mutations.[43],[44] Further genetic analyses have established the unique association of these secondary and sub-clonal co-mutations with H3.3K27M, H3.1K27M, or EZHIP-mutant tumors, respectively. In recent years, efforts dedicated to single-cell RNA-sequencing of H3K27M tumors have suggested that these tumors arise in an oligodendrocyte progenitor-like population during development.[45] This has been supported by modeling efforts demonstrating that the introduction of H3K27M in radial glial precursors early in embryonic development led to a significant increase in oligodendrogenic gene expression, accompanied by a decrease in neurogenic markers.[44] As our characterization of DMGs expands, so has our understanding of the complexity of DMGs in terms of the spatial specificity of the co-occurring mutations in each of these tumors [Figure 1].[46] | Figure 1: Histone mutation, location, and commonly associated mutations in pediatric high-grade gliomas. (A) Most frequent locations of histone-mutant pHGGs, including pons (green), thalamus (blue), cerebral hemispheres (purple), and spine (orange). (B) Most commonly associated somatic alterations in each histone-mutant subgroups (H3.3K27M, H3.1K27M, H3.3-WT (EZHIP), and H3.3G34R-mutants). Colors correspond with the location of primary histone mutation. Created with BioRender. com. EZHIP: Enhancer of zeste homolog inhibitory protein, pHGG: Pediatric high-grade glioma, WT: Wild-type
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H3.3K27M
H3.3K27M-mutant DMGs most commonly possess mutations or deletions in tumor suppressor 53 (TP53), a cell cycle regulator and well-established oncogene, occurring in approximately 60%–80% of cases, making it the most common mutation after those in histone H3.[47] These mutations occur as secondary “hits” in the evolution of DMGs, not restricted to a sub-clonal population.[6],[42] Specific mutations in TP53 vary in DMG, however, they are most commonly within the DNA-binding or tetramer-forming domains, altering protein conformation or leading to truncation.[48],[49] The conferred loss of function has been shown to drive tumorigenesis in a variety of cancers.[41],[50] TP53 mutations are not restricted locally to the pons but are also present in the surrounding areas often infiltrated by DMGs, including the thalamus [Figure 1].[41],[42] These mutations are often accompanied by a third “hit,” the sub-clonal amplification of platelet-derived growth factor-alpha (PDGFRα) in approximately 30% of H3.3K27M DMGs.[3] Amplifications in PDGFRα are focal, arising predominantly in the pons and driving aberrant receptor tyrosine kinase signaling, resulting in increased phosphoinositide 3-kinase (PI3K)/Akt/mTOR and RAS/MAPK signaling, and subsequent cell proliferation and survival.[18],[41],[42],[51] Additional sub-clonal alterations reported in H3.3K27M include mutations in FGFR1 (~20% of tumors) and amplifications in MYC/PVT1 (~14% of tumors).[18],[41] With the majority of these clonal/subclonal mutations converging on the RAS/MAPK pathway, it suggests this pathway may be required for tumor progression. This has been supported by H3.3K27M animal models, which have relied on the presence of RAS pathway activation to generate tumors.[52],[53] Further modeling has demonstrated both in vitro and in vivo that H3K27M-driven epigenetic changes induce activation of the RAS/MAPK pathway, suggesting its role as an initiating event in these tumors.[44]
H3.1K27M
In contrast, H3.1K27M-mutant tumors are largely restricted to the pons and have established co-occurring mutations in activin-receptor type-1 (ACVR1) and PI3K, encoded by PIK3CA and PIK3R1.[3],[18],[41] ACVR1 is mutated in approximately 32% of DMGs and is present in ~85% of H3.1K27M tumors.[41],[54] ACVR1 encodes the serine/threonine-protein kinase ALK2 (activin receptor-like kinase-2), which regulates various processes including proliferation, differentiation, and apoptosis through the bone morphogenetic protein signaling pathway.[34],[55] Once mutated, ALK2-mediated bone morphogenetic protein signaling can activate independent of receptor-ligand binding, driving the expression of the DNA-binding protein inhibitors ID1/2, and helps accelerate tumorigenesis while repressing cellular differentiation.[55],[56],[57] PIK3CA by contrast encodes the catalytic subunit of PI3K, and PIK3CA mutations are present in ~15%–25% of H3.1K27M tumors, leading to increased lipid kinase activity driving cellular growth, angiogenesis, and cellular transformation.[18],[41],[55],[58],[59] Mutations in PIK3CA have been shown in sub-clonal populations, suggesting a role as an accessory tumor driver, and ~85–90 of PI3KCA mutations occur in the presence of ACVR1 mutations in H3.1K27M tumors.[6],[41],[54] Mouse modeling of H3.1K27M tumors demonstrated the cooperation of H3.1K27M, ACVR1, and PIK3CA mutations, when expressed in an oligodendrocyte progenitor population, were required for the development of diffuse gliomas.[60] As with H3.3K27M, these tumors also possess TP53 mutations, although at a lower frequency (~30%).[41] Taken together, the differences between the deposition of histone H3.1 and H3.3, as well as their respective co-alterations, differences in patient age and prognosis, suggest that, although these oncohistones harbor the same K27M mutation, the mechanism by which these tumors form may be distinct.
Enhancer of zeste homologs inhibitory protein
EZHIP-expressing DMGs constitute a set of tumors that share commonalities with their H3K27M counterparts, specifically in their co-mutations. As the investigation of EZHIP-DMGs genomic landscape rapidly expands, the most commonly harbored mutations are already becoming established with ACVR1 and members of the PI3K pathway serving as the main targets, at high frequencies (~72% and ~33%, respectively), similar to their H3.1K27M counterparts.[61] Their third most common mutation is in TP53, although in ~11% of cases, far less than what is seen in H3.3K27M tumors. As with H3K27M DMGs, these mutations predominate in the pons, however, each has been found in other sites including the thalamus and spine [Figure 1]. Histone WT gliomas localized in the thalamus have shown high levels of EZHIP expression, accompanied by EGFR alterations in ~27% of tumors.[62] Together, these demonstrate a rapidly expanding classification of DMGs that, like their histone-mutant cousins, are quickly being established as complex heterogeneous entities of their own.
| H3.3G34R Tumors | | |
Approximately 15% of hemispheric pHGGs possess a G34R or V mutation in H3-3A and are mutually exclusive to those possessing H3K27M mutations.[7],[63] Unlike H3K27M-mutant DMGs, H3.3G34R tumors are localized to the cerebral hemispheres and occur more commonly in teenagers and young adults.[41] Although the current standard of care for these tumors is similar to H3K27M-DMGs, consisting of a multi-modal approach including chemotherapy and focal radiation, the prognosis for patients possessing H3G4R-hemispheric tumors is better than H3K27M-DMGs.[4] An important factor contributing to patient survival is that the location of hemispheric tumors allows for at least partial surgical resection prior to chemotherapy/radiation.[64]
| Molecular Mechanisms of H3.3G34R | | |
The molecular mechanisms driving H3.3G34R tumors are less defined relative to those suggested for H3K27M. Unlike H3K27, H3.3G34 itself is not subject to posttranslational modifications, rather the effects of H3.3G34R have been shown to impact neighboring H3K36 by decreasing both tri-and di-methylation, leading to transcriptional dysregulation.[8] H3K36 me3 is a PTM associated with active transcription and known to serve as an antagonist to H3K27 me3.[65] H3K36 me3 is catalyzed by the SETD2 methyltransferase, and it has been suggested that H3.3G34R-mediated effects on H3K36 methylation are a result of inhibiting SETD2 from depositing these PTMs.[8],[66] Subsequent structural modeling has suggested that the large side chains of arginine relative to glycine may introduce steric hindrance of SETD2 as a possible mechanism for its inhibition.[67] Interestingly, unlike H3K27M mutations, the effects of H3.3G34R are only seen in cis in mutant nucleosomes, and the impact of this mutation is not dominant on global H3K36 me3.[8]
Beyond the direct impact of H3.3G34R on H3K36 me3, the implications of this mutation have been increasingly investigated with respect to DNA damage repair. There are multiple DNA damage repair pathways that ensure genomic integrity is maintained, especially in the presence of both endogenous and exogenous DNA damaging agents.[68] Without such pathways, persistent DNA damage results in the activation of apoptotic pathways and cellular transformation.[68],[69] The use of major DNA repair pathways nonhomologous end-joining and homologous repair is determined by the state of H3K36 methylation, with H3K36 me2 associated with nonhomologous end joining, and SETD2-dependent H3K36 me3 leading to homologous repair.[70],[71] With H3.3G34R impeding the trimethylation of H3K36, there is growing evidence of H3.3G34R mutations indirectly promoting genome instability and suggests a DNA repair-focused pathway by which this mutation contributes to tumorigenesis.
[TAG:2]Co-alterations in H3.3G34R [/TAG:2]
Like H3K27M-DMGs, the complexity of H3.3G34R tumors is increased by the presence of co-mutations that may act as secondary “hits.” H3.3G34R tumors have a high association with TP53 and ATRX mutations, occurring in over 90% of tumors.[5],[7],[41] ATRX is a member of the ATRX-DAXX chaperone complex which serves as a chromatin remodeler to incorporate the H3.3 histone in pericentric heterochromatin, telomeres, and at several transcription factor binding sites.[7],[11],[72] Mutations leading to loss of ATRX function result in telomere instability and are correlated to a telomerase-independent mechanism of telomere lengthening called “alternate lengthening of telomeres (ALT),” serving as a mechanism to maintain telomere length in mutated cells.[7],[41] Recent studies have shown that in ALT-dependent osteosarcoma lines with ATRX deficiency, the deposition of H3.3 in telomeres is compensated for by HIRA (Histone Regulator A), a chaperone complex responsible for the canonical deposition of H3.3.[73],[74] With HIRA serving as the sole, indispensable chaperone for telomeric maintenance, this could suggest that a similar compensation is aiding in the survival of ALT-dependent H3.3G34R cells. Interestingly, ~44% of H3.3G34R tumors have been shown to carry mutations/amplifications of PDGFRA, with this frequency nearly doubling in recurrence (~81%).[75] Like H3K27M-DMGs, the combination of primary H3.3G34R mutations and secondary mutational “hits” adds to the complex heterogeneity of these tumors, although the exact role of these additional mutations in tumorigenesis is not yet fully elucidated.[75]
| Limitations | | |
This review is limited by potential gaps in the literature search and aggregation process as this field is rapidly expanding, and author bias, which may inadvertently lead to the omission of potentially relevant work.
| Conclusion | | |
pHGGs are the leading cause of brain tumor-related death in children. The presence of histone H3 mutations inevitably correlates with poor prognoses and high fatality. The addition of key oncogenic partner mutations, such as TP53, contributes to both intra- and inter-tumor heterogeneities, making the treatment of these tumors difficult. However, as our understanding of the pHGG genetic landscape and the associated epigenetic alterations rapidly expands, there is hope for the improvement of patient outcomes shortly.
Acknowledgments
Nil.
Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.
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