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).
Highlights
Sporadic vascular malformations (VMs) are congenital malformations of blood vessels with high associated morbidity and limited treatment options (Figure 1 and Figure 2)
Identified variants were in KRAS (n = 4) and BRAF (n = 1), encoding key proximal components of the RAS/MAPK signaling pathway, known to be pathogenic, but previously undescribed as causal in any type of VM
A cluster of variants was identified in exon 2 of MAP2K1 (n = 4), confirming a hot spot very recently reported in extracranial AVM, but not known prior to our study [9], and adding 1 small intragenic deletion (c.159_173del, p.[F53_Q58delinsL]) (Table 2 and Figure 3) to the allelic spectrum
Summary
Sporadic vascular malformations (VMs) are congenital malformations of blood vessels with high associated morbidity and limited treatment options (Figure 1 and Figure 2). Application of next-generation sequencing to a range of sporadic syndromes featuring VMs has rapidly established the paradigm that such disorders are commonly caused by postzygotic variants activating key cellular growth pathways [2,3,4,5,6,7,8,9,10,11]. Variants overlap with those documented in cancer, but the allelic spectra may differ. Therapeutic options are severely limited, and multidisciplinary management remains challenging, for high-flow arteriovenous malformations (AVM)
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