Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma.
Pilocytic astrocytomas (PAs), WHO malignancy grade I, are the most frequently occurring central nervous system tumour in 5- to 19-year-olds. Recent reports have highlighted the importance of MAPK pathway activation in PAs, particularly through a tandem duplication leading to an oncogenic BRAF fusion gene. Here, we report two alternative mechanisms resulting in MAPK activation in PAs. Firstly, in striking similarity to the common BRAF fusion, tandem duplication at 3p25 was observed, which produces an in-frame oncogenic fusion between SRGAP3 and RAF1. This fusion includes the Raf1 kinase domain, and shows elevated kinase activity when compared with wild-type Raf1. Secondly, a novel 3 bp insertion at codon 598 in BRAF mimics the hotspot V600E mutation to produce a transforming, constitutively active BRaf kinase. Although these two alterations are not common, they bring the number of cases with an identified 'hit' on the Ras/Raf-signalling pathway to 36 from our series of 44 (82%), confirming its central importance to the development of pilocytic astrocytomas.
Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, Cambridgeshire, UK. davidjones@cantab.net
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Jones
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Kocialkowski
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Liu
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Pearson
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Ichimura
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Collins
D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055028:Comparative Genomic Hybridization; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D015321:Gene Rearrangement; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics* / Q000378:metabolism
D020690:GTPase-Activating Proteins; D015514:Oncogene Proteins, Fusion; C465659:SRGAP3 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf