title: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas.
abstract: Brain tumors are the most common solid tumors of childhood, and pilocytic astrocytomas (PA) are the most common central nervous system tumor in 5 to 19 year olds. Little is known about the genetic alterations underlying their development. Here, we describe a tandem duplication of approximately 2 Mb at 7q34 occurring in 66% of PAs. This rearrangement, which was not observed in a series of 244 higher-grade astrocytomas, results in an in-frame fusion gene incorporating the kinase domain of the BRAF oncogene. We further show that the resulting fusion protein has constitutive BRAF kinase activity and is able to transform NIH3T3 cells. This is the first report of BRAF activation through rearrangement as a frequent feature in a sporadic tumor. The frequency and specificity of this change underline its potential both as a therapeutic target and as a diagnostic tool.
authors.affiliation: Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, United Kingdom. davidjones@cantab.net
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kocialkowski
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.forename: Danita M
authors.initials: DM
authors.lastname: Pearson
authors.forename: L Magnus
authors.initials: LM
authors.lastname: Bäcklund
authors.forename: Koichi
authors.initials: K
authors.lastname: Ichimura
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D019556:COS Cells; D002522:Chlorocebus aethiops; D002897:Chromosomes, Human, Pair 7; D020440:Gene Duplication; D050939:Gene Fusion; D011905:Genes, ras; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016019:Survival Analysis
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf