HGG-39. Integrative analyses of BRAFp.v600e mutated gliomas: from epigenetic to metabolic characteristics

Abstract

BRAF p.v600e mutation is encountered in brain tumors, mostly low grade pediatric diffuse gliomas (LGG) and epileptogenic glioneuronal tumors such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. We studied retrospectively a monocentric cohort of 17 LGGs (14 GG and 3 pilocytic astrocytomas) and 7 BRAF pv600e HGG. The patients were aged below 20 years. We focused on extended tumors’ biology assessment (MethylEpic 850K, Next-Generation sequencing, RNA sequencing and metabolomics), as well as tumor immune microenvironment by immunohistochemistry. Among the LGGs, only one had a CDKN2A deletion and one a gain on chromosome 5. All except two LGGs had a complete surgical resection. Four of them were treated by chemotherapies but underwent relapses. All HGGs had a surgical resection followed by a first line chemotherapy (mainly Stupp protocol) and radiotherapy. Five patients relapsed rapidly, benefiting from targeted therapy with vemurafenib and/or biotherapy associating dabrafenib plus trametinib. Among those HGGs, we had both subgroups: “de novo” tumors and patients with a history of LGG tumors. Both were responding well to targeted treatments. The biology uncovers in all HGGs a loss of CDKN2A gene and/or protein. Additionally to this gene abnormality, specific transcriptomic expressions were associated to therapeutic response and immune microenvironment. Epigenetic modulation was linked to specific metabolic switches when BRAF p.v600e gliomas were getting higher grade features (e.g., glutaminolysis, serinolysis and phospholipidic metabolism). Those characteristics seem to be able to predict in LGG p.v600e potential evolution.