Subtypes of Pediatric High-Grade Gliomas ID'd

A new molecular analysis of glioblastomas and diffuse intrinsic pontine gliomas in children indicates that the tumors can be subdivided into 10 categories, a finding that could point to new treatment strategies for some subsets of patients (Cancer Cell 2017;32:520–37).

Therapies prescribed for adults with gliomas do not work well in children, likely because pediatric and adult diseases are molecularly distinct. For example, previous research has shown that pediatric patients often carry mutations in the genes encoding the H3.3 or H3.1 histones, but these mutations rarely occur in adults. Chris Jones, PhD, of The Institute of Cancer Research in London, UK, and colleagues hypothesized that comprehensively profiling a large number of pediatric high-grade gliomas would further define the molecular subtypes of the disease.

The researchers analyzed molecular data from 1,067 children and young adults with high-grade glioma or diffuse intrinsic pontine glioma. The data included whole-genome or whole-exome sequences, methylation measurements, and copy-number profiles. Data for 910 of the patients came from previous studies; the researchers generated data for the remaining 157 patients themselves.

Jones and colleagues found that the patients fell into 10 groups based on driver mutations, age, tumor location, methylation patterns, and other variables. Three groups, constituting 50.3% of patients, carried mutations in histone genes. One of these groups, characterized by the K27M mutation in the gene that encodes histone H3.3, included 63% of the patients with diffuse intrinsic pontine glioma. They were around 8 years old at diagnosis, had tumors in the midline or the pons—part of the brain stem—and had a median survival of 11 months. In contrast, children in a second group, who carried the K27M mutation in the genes that encode histones H3.1 or H3.2, almost always developed tumors in the pons, had a median age of 5 at diagnosis, and typically lived about 15 months.

The remaining seven groups had wild-type histone genes. One group included people with IDH1 mutations, who accounted for about 6.25% of the cases in the study. Another group of 11 patients had tumors that were hypermutators, carrying near-record numbers of mutations for human cancers. “The extraordinary diversity of high-grade glioma in kids suggests it's not one disease, it's multiple diseases,” says Jones.

Jones adds that the team's findings could indicate potential treatment targets for some groups. Patients with the K27M mutation in the histone H3.3 gene, for instance, often have translocations that increase copy number of TOP3A, which codes for the homologous recombination protein topoisomerase III alpha. No inhibitors of topoisomerase III alpha are available, but the study suggests that developing such drugs or identifying existing compounds that block the protein could benefit some patients.

Javad Nazarian, PhD, of Children's National Health System in Washington, DC, who wasn't involved in the research, praises the study for including a large number of patients and for using samples obtained prior to treatment, which is essential for determining whether specific mutations are involved in the development of the disease. “I think it's a fantastic start,” he says. “This study is going to be very impactful and helpful in the field, specifically for providing molecular clues that may have therapeutic implications.”

Oren Becher, MD, of the Northwestern Feinberg School of Medicine in Chicago, IL, who wasn't connected to the study, also lauds the work. Now, “functional studies will be needed to pinpoint therapeutic targets,” he says. “We have not had any success stories for pediatric high-grade glioma in 50 years. Hopefully, this study will spur people to develop specific treatments for these tumors.” –Mitch Leslie

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