Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy
Lara Al-Olabi, … , E. Elizabeth Patton, Veronica A. Kinsler
Lara Al-Olabi, … , E. Elizabeth Patton, Veronica A. Kinsler
Published February 20, 2018
Citation Information: J Clin Invest. 2018;128(4):1496-1508. https://doi.org/10.1172/JCI98589.
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Clinical Research and Public Health Vascular biology

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

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).

Authors

Lara Al-Olabi, Satyamaanasa Polubothu, Katherine Dowsett, Katrina A. Andrews, Paulina Stadnik, Agnel P. Joseph, Rachel Knox, Alan Pittman, Graeme Clark, William Baird, Neil Bulstrode, Mary Glover, Kristiana Gordon, Darren Hargrave, Susan M. Huson, Thomas S. Jacques, Gregory James, Hannah Kondolf, Loshan Kangesu, Kim M. Keppler-Noreuil, Amjad Khan, Marjorie J. Lindhurst, Mark Lipson, Sahar Mansour, Justine O’Hara, Caroline Mahon, Anda Mosica, Celia Moss, Aditi Murthy, Juling Ong, Victoria E. Parker, Jean-Baptiste Rivière, Julie C. Sapp, Neil J. Sebire, Rahul Shah, Branavan Sivakumar, Anna Thomas, Alex Virasami, Regula Waelchli, Zhiqiang Zeng, Leslie G. Biesecker, Alex Barnacle, Maya Topf, Robert K. Semple, E. Elizabeth Patton, Veronica A. Kinsler

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Figure 2

Imaging of sporadic VMs secondary to mutations in MAPK pathway genes demonstrating involvement of all blood vessel sizes.

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Imaging of sporadic VMs secondary to mutations in MAPK pathway genes dem...
(A) Lateral image from a digitally subtracted angiogram showing a leash of small, abnormal vessels shunting through a dense capillary bed to early filling veins. (B) Axial contrast-enhanced fat-saturated T1 weighted MRI image showing a grossly enlarged right pinna and thickened posterior auricular soft tissues. The abnormal tissue is filled with multiple signal voids, representing enlarged abnormal vessels. The pinna enhances avidly. (C) Lateral image from a digitally subtracted angiogram, with the catheter tip in the grossly enlarged left internal maxillary artery, which supplies a leash of abnormal high-flow vessels in the face. (D) Thermography of low-flow VMs with overgrowth of the left chest wall and arm demonstrates increased temperature (shown in magenta) compared with the right-sided structures (E), and in the right forearm and thumb compared with the left (F). 3D reconstruction of an abdominal CT angiogram demonstrating multifocal vascular disease, with severe stenoses of the descending aorta, coeliac axis, superior mesenteric artery origin, and right renal artery (E).