Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma Defined by BRAF Mutation and CDKN2A Deletion


Key Points

  • BRAF V600E and CDKN2A deletion were common in pediatric secondary high-grade glioma.
  • BRAF V600E was associated with a prolonged time to transformation.

In a study reported in the Journal of Clinical Oncology, Mistry et al found that presence of BRAF V600E mutation and CDKN2A deletion defined a clinically distinct subtype of pediatric secondary high-grade glioma. BRAF V600E mutation was associated with a prolonged time to transformation.

Study Details

The study involved 886 patients treated at The Toronto Hospital for Sick Children for pediatric low-grade glioma from 1986 to 2013. Exome sequencing and array comparative genomic hybridization were performed on available samples, and detailed genetic analysis was performed in the secondary high-grade glioma cohort.

BRAF and CDKN2A Alterations

Overall, 26 patients (2.9%) fulfilled the criteria for malignant transformation to secondary high-grade glioma. Patients with secondary high-grade glioma had a high frequency of nonsilent somatic mutations (median 25 mutations per exome) compared with patients with primary pediatric high-grade glioma (P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were common in secondary high-grade glioma; no secondary high-grade glioma patients had BRAF-KIAA1549 fusion.

The most recurrent alterations in secondary high-grade glioma were BRAF V600E and CDKN2A deletion, observed in 39% and 57% of cases. All of the BRAF V600E mutations and 80% of CDKN2A alterations could be traced back to pediatric low-grade glioma counterparts. The presence of BRAF V600E distinguished secondary high-grade glioma from primary high-grade glioma (P = .0023), and BRAF and CDKN2A alterations were significantly less common in low-grade glioma that did not transform (P < .001 for both).

Prolonged Latency to Transformation

Pediatric low-grade gliomas with BRAF V600E mutation had a longer latency to transformation vs wild-type gliomas, with a median time to transformation of 6.65 years (range = 3.5­–20.3 years) vs 1.59 years (range = 0.32­–15.9 years; P = .0389). Respective 5-year overall survival was 75% vs 29% (P = .024).

The investigators concluded: “BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of [secondary high-grade glioma]. The prolonged course to transformation for BRAF V600E [pediatric low-grade gliomas] provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of [secondary high-grade glioma].”

Uri Tabori, MD, of The Hospital for Sick Children, The University of Toronto, is the corresponding author of the Journal of Clinical Oncology article.

The study was supported by b.r.a.i.n.child Canada, JPA Foundation, and Canadian Institute of Health. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.