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    Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy

    Al-Olabi, L. and Polubothu, S. and Dowsett, K. and Andrews, K.A. and Stadnik, P. and Joseph, A.P. and Knox, R. and Pittman, A. and Clark, G. and Baird, W. and Bulstrode, N. and Glover, M. and Gordon, K. and Hargrave, D. and Huson, S.M. and Jacques, T.S. and James, G. and Kondolf, H. and Kangesu, L. and Keppler-Noreuil, K.M. and Khan, A. and Lindhurst, M.J. and Lipson, M. and Mansour, S. and O’Hara, J. and Mahon, C. and Mosica, A. and Moss, C. and Murthy, A. and Ong, J. and Parker, V.E. and Rivière, J.-B. and Sapp, J.C. and Sebire, N.J. and Shah, R. and Sivakumar, B. and Thomas, A. and Virasami, A. and Waelchli, R. and Zeng, Z. and Biesecker, L.G. and Barnacle, A. and Topf, Maya and Semple, R.K. and Patton, E.E. and Kinsler, V.A. (2018) Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. Journal of Clinical Investigation 128 (4), pp. 1496-1508. ISSN 0021-9738.

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    BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.


    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Depositing User: Administrator
    Date Deposited: 09 May 2018 17:49
    Last Modified: 02 Aug 2023 17:41


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