Abstract
BRAF alterations are recognized as a significant driver of disease in pediatric low-grade glioma (pLGG) but the implications of BRAF alterations on the natural history and response to treatment are unclear in adult glioma. We characterized the molecular and clinical features of a multi-institutional cohort of adults with BRAF-mutated gliomas. We identified patients with glioma containing BRAF alterations on sequencing in multi-institutional cohorts (Dana-Farber/Brigham Cancer Center, Johns Hopkins Hospital, GENIE, TCGA). BRAF alterations were grouped into previously defined classes: I (V600E; RAS-independent/dimerization-independent), II (RAS-independent/dimerization-dependent), III (RAS-dependent/dimerization-dependent) in addition to BRAF copy number gains, fusions, and other. We interrogated 289 BRAF-altered gliomas (199 patients >=18yrs, 90 patients <18yrs; range 0-85yrs), and observed histopathologic and molecular differences between BRAF-altered gliomas in adults versus pediatric patients. Amongst adults, the most common BRAF alterations were Class I followed by copy number gains, with glioblastoma (GBM) the most prevalent histology. In comparison, pediatric gliomas in our cohort frequently harbored Class I mutations followed by BRAF fusions, with primarily pilocytic astrocytoma and pLGG histologies. Principal component analysis and correlation analysis revealed molecular features associated with gliomas of different BRAF alterations and histologies, including mutation of NF1, a negative regulator of RAS, which was significantly associated with class II/III BRAF alterations (64.3%) and not observed in BRAFV600E-mutated gliomas (0%, n=62) (p<0.0001). Demographic and molecular features were evaluated for correlates for adult glioma risk stratification. Comparative survival analysis showed no significant difference between adult GBM harboring Class I compared to other BRAF alterations, whereas young adult age (18-35yrs) was associated with improved outcomes (p<0.05). Among 86 GBM patients with detailed clinicopathologic data, 7 received RAF-targeted therapy, with variable clinical response. This cohort of BRAF-altered adult gliomas demonstrates a broad range of molecular alterations with implications for treatment sensitivity and patient risk stratification.
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