BI-21BRAF MUTATION AND CDKN2A DELETIONS DEFINE A CLINICALLY DISTINCT SUBGROUP OF CHILDHOOD SECONDARY HIGH GRADE GLIOMA

PURPOSE: Pediatric secondary high grade glioma (sHGG), which result from malignant transformation of low grade glioma (PLGG), are a poorly understood group of tumors with devastating outcomes. PATIENTS AND METHODS: We performed a population-based study combined with long-term follow-up of PLGG that transformed to sHGG. Exonic-sequencing and copy number alterations were investigated on a discovery cohort, followed by detailed genetic analysis of all tumors. Clinical and outcome data analysis of a genetically distinct subgroup was performed. RESULTS: sHGG were observed in 28/888 (3.2%) patients treated in Southern Ontario for PLGG with a median latency of 2.74 years (range, 0.18-20.3 years). sHGG were characterized by a high somatic mutation load (23 per genome). Alterations in chromatin modifying genes and major telomere maintenance pathways were observed in 57% and 54% of sHGG respectively. However, specific mutations in IDH1, H3F3A G34 and ATRX were extremely rare. The most recurrent somatic alterations were the oncogenic BRAF V600E mutation and deletion of the tumor suppressor gene CDKN2A, observed in 39% and 57% of sHGG respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced to the patient-matched PLGG counterparts. These early alterations were rarely observed in non-transformed PLGG (p < 0.0001) and primary childhood high grade glioma (p = 0.0023). The BRAF mutant sHGG subgroup was characterized by longer latency periods to transformation than non-BRAF mutant sHGG (median 6.59 versus 1.62 years; p < 0.0001). Furthermore, 5-year overall survival of children with BRAF mutant and wild-type PLGG that transformed were 75% ± 15% and 29% ± 12% respectively (p = 0.024). CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation provides a window of opportunity for aggressive surgical interventions, targeted therapy against oncogenic BRAF, and extended surveillance to potentially mitigate the devastating transformation event.