Pediatric high-grade glioma is not one tumor type but many
Stratifying tumors by their clinical characteristics and underlying biology will enable future targeting of specific therapies for glioma in children.
New data from a large meta-analysis show that pediatric high-grade glioma (HGG) is not one disease but rather represents multiple diseases marked by a diversity of clinical and genetic characteristics.1
Pooling data from more than 1000 cases of pediatric HGG and diffuse intrinsic pontine glioma (DIPG), researchers at the Institute of Cancer Research in London, United Kingdom, found that these aggressive childhood brain tumors represent at least 10 different diseases made up of a diverse set of clinical and biological subgroups. Importantly, the study found a number of genetic mutations and errors in key genes that drive the different tumor types.
“‘High-grade glioma’ is a term that captures an incredible diversity of different tumor subtypes,” says Chris Jones, PhD, leader, Glioma Team, Centre for Evolution and Cancer, Divisions of Molecular Pathology and Cancer Therapeutics, the Institute of Cancer Research, Surrey, United Kingdom, and one of the authors of the study recently published in Cancer Cell.1
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“Currently, these tumors are largely grouped together for clinical trials,” Jones says. “In fact, they have different clinical characteristics and underlying biology, and will need to be stratified for future targeted therapies.”
Molecular profiling of HGG
The researchers used integrated molecular profiling to analyze the pooled data, which was collected from 20 publicly available datasets and included 157 unpublished cases. As such, the information represents the largest dataset of pediatric HGG worldwide.
Although prior profiling studies have identified key genetic and epigenetic differences between HGG in children and adults-notably identification in pediatric HGG of recurrent mutations in genes encoding histones H3.3 and H3.1 with G34R/V and K27M variants that represent different clinical and biological subgroups- limitations of these studies (eg, modest size, use of different platforms and analytical techniques) have not allowed for a robust interpretation and conclusion about these subtypes in the context of the whole spectrum of disease.
With the largest dataset to date on pediatric HGG, the current study was able to accumulate a sufficiently sized dataset to uncover genes/processes from specific subgroups that, the researchers say, “may play a role as diagnostic, prognostic, or predictive markers of drug targets in these diseases.”1
Among the key findings of the study was that histone mutations cosegregate with distinct alterations and downstream pathways. The study found specific alterations in genes encoding histone H3 mutations, including the loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M.
The finding builds on and adds robustness to prior data showing the importance of histone-defined subgroups of pediatric HGG and their diverse characteristics based on age of incidence; clinical outcome; anatomic location; methylation and gene expression profiles; copy-number changes; cosegregating somatic mutations; and pathway dysregulation.
These more robust findings suggest that the mutations may be a good therapeutic target, and indicate a potential future approach to treatment.
Identifying mutations
Another key finding of the study is that specific mutations, namely H3/IDH1 wild-type (WT) tumors and those with a mutation in the BRAF gene, are less aggressive than other mutation types and therefore may resemble low-grade lesions. Treatment of these mutations may be possible with drugs already being used to treat these mutations in other cancers or with other treatments under development, Jones says.2
Jones emphasizes that these mutations can easily be detected by a single polymerase chain reaction (PCR) assay and immunohistochemistry. “These are already either established, or beginning to be, in the clinic,” he says. “Other groups may be distinguished by methylation array profiling, which is being validated for clinical practice but is not yet widely available.”
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Overall, Jones emphasizes the need for precise ways to diagnose these cancers to ensure optimal treatment. Treating cancer based only on traditional methods isn’t good enough anymore, he says, advising physicians to start thinking about these tumors as completely different cancers and to diagnose and treat them based on their genetic profiles.2
“An integrated diagnosis including traditional histopathology plus modern molecular analyses is necessary to truly understand what we are dealing with, and to be able to direct the patient toward the best treatment,” Jones says.
REFERENCES
1. Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. 2017;32(4):520.e5-537.e5.
2. Institute of Cancer Research. Study splits incurable childhood brain tumours into 10 new diseases [press release]. Available at: https://www.icr.ac.uk/news-archive/study-splits-incurable-childhood-braintumours-into-10-new-diseases. Published September 28, 2017. Accessed October 13, 2017.
