MAPK pathway activation through BRAF gene fusion in pilocytic astrocytomas; a novel oncogenic fusion gene with diagnostic, prognostic, and therapeutic potential

• Published in: The Journal of pathology 2010-12, Vol.222 (4), p.324-328
• Main Authors: Jeuken, Judith WM, Wesseling, Pieter
• Format: Article
• Language: English
• Subjects: Astrocytoma; Astrocytoma - diagnosis; Astrocytoma - genetics; Astrocytoma - therapy; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; BRAF gene fusion; Brain Neoplasms - diagnosis; Brain Neoplasms - genetics; Brain Neoplasms - therapy; Child; Children; Fusion protein; Gene fusion; Humans; Investigative techniques, diagnostic techniques (general aspects); KIAA1549; MAP kinase; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; MAPK activation; Medical sciences; Neurology; Oncogene Fusion - physiology; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - physiology; paediatric pilocytic astrocytoma; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Signal transduction; Survival; Tumors of the nervous system. Phacomatoses
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2780

Recently, a new mechanism for activation of B‐RAF was identified resulting from a tandem duplication, generating a fusion protein with constitutive BRAF activity and thereby activating the MAPK pathway. Different fusion variants involving BRAF and KIAA1549 were demonstrated, present in 80% of pilocytic astrocytomas in children. As the KIAA1549–BRAF fusion gene is detected at a much lower frequency in diffuse low‐grade astrocytomas and survival was much longer than expected in the patients with a ‘non‐pilocytic’ astrocytoma carrying the fusion gene, identification of this fusion gene can be of diagnostic and prognostic value. In the near future, interference with the (fusion gene causing) activation of the MAPK signalling cascade may open new therapeutic avenues for children with pilocytic astrocytomas, as a first line of defence against tumour growth or in situations where the tumour has become refractory to other therapeutic modalities. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Invited Commentary for Forshew et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas, J Pathol 2009; 218: 172–181.