Recurrent somatic BRAF insertion (p.V504_R506dup): a tumor marker and a potential therapeutic target in pilocytic astrocytoma

• DOI: 10.1038/s41388-018-0623-3
• Publication Date: 2018-12-21T09:30:16Z
• Authors: Fida Khater; Sylvie Langlois; Pauline Cassart; Anne-Marie Roy; Mathieu Lajoie; Jasmine Healy; Chantal Richer; Pascal St-Onge; Nelson Piché; Sebastien Perreault; Sonia Cellot; Monia Marzouki; Nada Jabado; Daniel Sinnett
• Keywords: Male; Proto-Oncogene Proteins B-raf; 0301 basic medicine; Adolescent; Astrocytoma; Article; Cell Line; 3. Good health; 03 medical and health sciences; HEK293 Cells; Genes, Duplicate; Mutation; Biomarkers, Tumor; Humans; Neoplasm Recurrence, Local

Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated RAS/RAF/MEK/ERK signaling. In this study, we report the identification of a novel recurrent BRAF insertion (p.V504_R506dup) in five PA cases harboring exclusively this somatic tandem duplication. This recurrent alteration leads to an addition of three amino acids in the kinase domain of BRAF and has functional impact on activating MAPK phosphorylation. Importantly, we show that this mutation confers resistance to RAF inhibitors without changing effectiveness while downstream MEK inhibitors remain effective. Our results further emphasize the importance of BRAF alterations in PA and the need to characterize them in a given tumor as this can affect therapeutic strategies and their potential use as tumor marker in molecular diagnostics.