BRAF Mutation and CDKN2A Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma

Abstract

Purpose To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). Patients and Methods We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. Results sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). Conclusion BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.

Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

“…Interestingly, 12 % of patients diagnosed with low grade thalamic tumours also tested positive for H3K27M despite previous reports suggesting it to be exclusive to high grade cases when not located in the brainstem [31, 33]. Of note, two of five low grade cases positive for H3K27M later transformed to high grade malignancies at the time of second surgery, a rare occurrence in paediatric low grade glioma and consistent with the diagnosis of secondary HGG [25]. While it is possible that these H3K27M positive thalamic gliomas were under-graded histologically based on sampling bias, the significant survival difference observed between low grade and high grade H3K27M tumours supports the idea that these tumours were indeed distinct from their high grade counterparts.…”

Molecular Testing of Brain Tumor

“…2) [96]. The BRAF V600E mutant PLGG has longer transformation latency periods than the BRAF wild type PLGG (median latency period, 6.65 years vs 1.59 years, respectively) [96].…”

Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

“…The RAF/MEK/ERK pathway is important in central nervous system tumors (Gierke et al, 2016; Mistry et al, 2015), and with BRAF V600E mutations in more than 50% of select tumors (Penman et al, 2015) there is great potential for the use of BRAF V600E inhibitors. Indeed, the first pediatric patient successfully treated with vemurafenib (Rush et al, 2013) was followed by similar case reports in brain tumor patients of all ages (Bautista et al, 2014; Skrypek et al, 2014), and clinical trials in children and adolescents are ongoing using both vemurafenib (NCT01748149) and dabrafenib (NCT01677741).…”