The Genetic Signatures of Pediatric High-Grade Glioma: No Longer a One-Act Play☆,☆☆
Section snippets
Opening Remarks
The past several years mark a period of tremendous growth in our understanding of pediatric high-grade glioma (pHGG). Advances in genome-wide array-based and sequencing technologies, their precipitous drop in cost, and evaluation of increasingly larger cohorts have all contributed to novel insights into the genetics of these devastating cancers, greatly extending earlier studies that evaluated candidate genes based on their involvement in adult HGG (aHGG). Our aim is to provide context to these
The 3 Core aHGG Pathways Show a Different Spectrum of Alteration in pHGG
As the genomic landscape of aHGG came into view, it shaped initial work into the pediatric disease. The first pHGG studies focused primarily on investigating the involvement of high-frequency recurrent events found in adult tumors. For example, epidermal growth factor receptor (EGFR) is the most commonly altered receptor tyrosine kinase (RTK) in aHGG; with the corresponding gene locus undergoing amplification or intragenic deletion or both in ~50% of cases.7, 8, 9 First identified in adult
Copy Number Imbalances and Gene Expression Profiling
Despite some common copy number imbalances such as 13q and 14q loss in approximately one-third of patients with HGG regardless of age or location, aHGG and pHGG also exhibit a unique constellation of gains and losses that distinguish one from the other, and the same can be said for DIPGs and pNBS-HGGs.15, 16, 17, 18, 19, 23, 24, 25, 26 This suggests that unique combinations of genetic drivers underlie adult and pediatric tumorigenesis, and among childhood HGG, DIPG and pNBS-HGG tumorigenesis.
Histones Make Their Mark
The aforementioned work established the concept that oncogenic events driving pediatric HGG were different from those arising in adults. This appreciation, however, was not fully cemented until early 2012, with the discovery of recurrent histone mutations in pHGG (Fig. 2). As the first reports of histone mutations in human cancer, these mutations implicated novel mechanisms in pHGG tumor biology that are not found to play a significant role in the adult disease.
Whole-genome sequencing of 7
Understanding Mutant Histone Gain-of-Function
All histone H3 mutations in pHGG were heterozygous, and in any individual tumor, only 1 of 16 genes encoding histone H3 was mutated. This pattern clearly indicates a dominant gain-of-function effect.
Lysine 27 on histone H3 (H3K27) is a residue that can be acetylated or monomethylated, dimethylated, or trimethylated (H3K27me3). Although mutant histone H3.1/3.3 make up a minority of the total cellular histone H3 pool,64 p.K27M mutations led to loss of total H3K27me2/3 of the entire cellular H3
Additional Genetic Associations With pHGG Subgroups
Genome-wide sequencing approaches revealed that 20%-32% of DIPGs harbored somatic missense mutations in ACVR1, also known as ALK2,35, 39, 40, 41 which encodes a receptor serine-threonine kinase mediating bone morphogenetic protein–induced signal transduction.69 These mutations frequently co-occur with histone H3.1 p.K27M substitutions. Both alterations tend to occur in younger patients with DIPG and were not found in pHGG arising outside the brainstem.35, 39, 40, 41 Thus, these mutations
Closing Remarks
Advances in microarrays and next-generation sequencing technologies have provided unprecedented insight into pHGG biology. However, this insight is only a starting point. Researchers and clinicians must now endeavor to not only understand how this unique mutation spectrum contributes to tumorigenesis but also, more importantly, seek to exploit these genetic defects therapeutically. Recent discoveries should inform the generation of improved preclinical models that more faithfully resemble the
Acknowledgments
We thank Dr Zoltan Patay for the MRI used in Figure 3.
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Cited by (37)
Oncohistones
2023, Epigenetic Cancer Therapy, Second EditionDual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG
2021, Cell ReportsCitation Excerpt :Hypophosphorylated Rb interacts with E2F1, resulting in repression of the cell cycle and proliferation arrest. Dysregulation of the Rb pathway is common in pediatric brain cancers (Diaz and Baker, 2014). Similarly, 30% of DIPGs are known to have amplification of genes that regulate G1 to S cell cycle progression, particularly the cyclin D family members CDK4 and CDK6 (Mohammad et al., 2017; Paugh et al., 2011).
Pediatric Gliomas: Molecular Landscape and Emerging Targets
2021, Neurosurgery Clinics of North AmericaCitation Excerpt :The mutation is found only in a minority of DMGs and likely is not an independent oncogenic driver.10,12,64,65 The ACVR1 mutation is associated with younger age, increased survival, and HIST1H3B, PIK3CA, and PIK3R1 mutations (see Fig. 1).12,13,64 The latter 2, along with mutations in growth factor receptor genes (ie, Platelet Derived Growth Factor Receptor Alpha (PDGFRA), EGFR, FGFR, and ACVR1), altered PTEN promoter methylation, and overexpression of YB1, all are known to act through amplification of cell proliferation via the RTK/Ras/PI3K pathway (see Fig. 2).2,4,6,10,64
Clinical and Molecular Characteristics of Thalamic Gliomas: Retrospective Report of 26 Cases
2019, World NeurosurgeryCitation Excerpt :Approximately 50% of TP53 gene mutations occur in astrocytic gliomas and will be present in ∼30% of primary glioblastoma and more frequent in secondary glioblastomas (65%) than in primary glioblastomas.19-21 Some previous whole genome analysis studies have shown that H3K27M mutations have significant overlap with TP53 mutations.22,23 A total of 11 thalamic glioma cases had TP53 gene mutations, with greater TP53 mutation rates in the H3K27M mutation group (7 of 12; 58.33%) than the wild-type group (4 of 14; 28.57%).
Mechanism of cancer: Oncohistones in action
2018, Journal of Genetics and GenomicsCitation Excerpt :Interestingly, these point mutations are able to “drive” tumorigenesis even if they only occur in one copy of one allele of the genes that encode a particular histone, regardless of many other “good” copies of their genes (Morgan and Shilatifard, 2013). For example, histone H3 mutations in pediatric high-grade glioma (pHGG) were all heterozygous, with only one out of the sixteen H3 genes mutated in any individual tumor, suggesting a dominant gain-of-function effect (Diaz and Baker, 2014). The mutant histones are therefore named as “oncohistones”.
Chemotherapy of Pediatric High-Grade Gliomas
2018, Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy: Second Edition
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S.J.B. is supported by NIH grant P01 CA096832 and ALSAC of St. Jude Children׳s Research Hospital.
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The authors declare no conflicts of interest.