The Genetic Signatures of Pediatric High-Grade Glioma: No Longer a One-Act Play☆,☆☆

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Advances in understanding pediatric high-grade glioma (pHGG) genetics have revealed key differences between pHGG and adult HGG and have uncovered unique molecular drivers among subgroups within pHGG. The 3 core adult HGG pathways, the receptor tyrosine kinase-Ras-phosphatidylinositide 3-kinase, p53, and retinoblastoma networks, are also disrupted in pHGG, but they exhibit a different spectrum of effectors targeted by mutation. There are also similarities and differences in the genomic landscape of diffuse intrinsic pontine glioma (DIPG) and pediatric nonbrainstem (pNBS)-HGG. In 2012, histone H3 mutations were identified in nearly 80% of DIPGs and ~35% of pNBS-HGG. These were the first reports of histone mutations in human cancer, implicating novel biology in pediatric gliomagenesis. Additionally, DIPG and midline pNBS-HGG vary in the frequency and specific histone H3 amino acid substitution compared with pNBS-HGGs arising in the cerebral hemispheres, demonstrating a molecular difference among pHGG subgroups. The gene expression signatures as well as DNA methylation signatures of these tumors are also distinctive, reflecting a combination of the driving mutations and the developmental context from which they arise. These data collectively highlight unique selective pressures within the developing brainstem and solidify DIPG as a specific molecular and biological entity among pHGGs. Emerging studies continue to identify novel mutations that distinguish subgroups of pHGG. The molecular heterogeneity among pHGGs will undoubtedly have clinical implications moving forward. The discovery of unique oncogenic drivers is a critical first step in providing patients with appropriate, targeted therapies. Despite these insights, our vantage point has been largely limited to an in-depth analysis of protein coding sequences. Given the clear importance of histone mutations in pHGG, it will be interesting to see how aberrant epigenetic regulation contributes to tumorigenesis in the pediatric context. New mechanistic insights may allow for the identification of distinct vulnerabilities in this devastating spectrum of childhood tumors.

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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    ☆

    S.J.B. is supported by NIH grant P01 CA096832 and ALSAC of St. Jude Children׳s Research Hospital.

    ☆☆

    The authors declare no conflicts of interest.

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