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Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma

Oncogene volume 28, pages 2119–2123 (2009)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr MG McCabe, Dr M Dimitriadi, Miss S Rigby, Miss F McDuff, Dr S Turner and Professor Y Yuasa for their help and for reagents. We also thank the Mapping and Microarray Facility groups of the Wellcome Trust Sanger Institute, UK and the Centre for Microarray resources in the Department of Pathology, University of Cambridge for technical assistance. This work was supported by grants from Cancer Research UK, the Samantha Dickson Brain Tumour Trust and CAMPOD.

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Authors and Affiliations

  1. Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, Cambridgeshire, UK

    D T W Jones, S Kocialkowski, L Liu, D M Pearson, K Ichimura & V P Collins

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  1. D T W Jones
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  2. S Kocialkowski
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  3. L Liu
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  4. D M Pearson
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  5. K Ichimura
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  6. V P Collins
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Correspondence to D T W Jones.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Jones, D., Kocialkowski, S., Liu, L. et al. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28, 2119–2123 (2009). https://doi.org/10.1038/onc.2009.73

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