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

Al-Olabi, L; Polubothu, S; Dowsett, K; Andrews, KA; Stadnik, P; Joseph, AP; Knox, R; Pittman, A; Clark, G; Baird, W; et al. Al-Olabi, L; Polubothu, S; Dowsett, K; Andrews, KA; Stadnik, P; Joseph, AP; Knox, R; Pittman, A; Clark, G; Baird, W; Bulstrode, N; Glover, M; Gordon, K; Hargrave, D; Huson, SM; Jacques, TS; James, G; Kondolf, H; Kangesu, L; Keppler-Noreuil, KM; Khan, A; Lindhurst, MJ; Lipson, M; Mansour, S; O'Hara, J; Mahon, C; Mosica, A; Moss, C; Murthy, A; Ong, J; Parker, VE; Rivière, J-B; Sapp, JC; Sebire, NJ; Shah, R; Sivakumar, B; Thomas, A; Virasami, A; Waelchli, R; Zeng, Z; Biesecker, LG; Barnacle, A; Topf, M; Semple, RK; Patton, EE; Kinsler, VA (2018) Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest, 128 (4). pp. 1496-1508. ISSN 1558-8238 https://doi.org/10.1172/JCI98589
SGUL Authors: Mansour, Sahar

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Abstract

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. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Item Type: Article
Additional Information: This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Erratum available at J Clin Invest. 2018;128(11):5185. https://doi.org/10.1172/JCI124649
Keywords: Drug therapy, Molecular genetics, Signal transduction, Therapeutics, Vascular Biology, Immunology, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: J Clin Invest
ISSN: 1558-8238
Language: eng
Dates:
DateEvent
2 April 2018Published
12 March 2018Published Online
30 January 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
WT104076MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT098498Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MRC_MC_UU_12012/5Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_PC_U127585840Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
ZF-MEL-CHEMBIO-648489European Research Councilhttp://dx.doi.org/10.13039/501100000781
HG200328 11National Human Genome Research Institutehttp://dx.doi.org/10.13039/100000051
HG200388 03National Human Genome Research Institutehttp://dx.doi.org/10.13039/100000051
PubMed ID: 29461977
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109679
Publisher's version: https://doi.org/10.1172/JCI98589

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