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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).

SUBMITTER: Al-Olabi L

PROVIDER: S-EPMC5873857 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Al-Olabi Lara L Polubothu Satyamaanasa S Dowsett Katherine K Andrews Katrina A KA Stadnik Paulina P Joseph Agnel P AP Knox Rachel R Pittman Alan A Clark Graeme G Baird William W Bulstrode Neil N Glover Mary M Gordon Kristiana K Hargrave Darren D Huson Susan M SM Jacques Thomas S TS James Gregory G Kondolf Hannah H Kangesu Loshan L Keppler-Noreuil Kim M KM Khan Amjad A Lindhurst Marjorie J MJ Lipson Mark M Mansour Sahar S O'Hara Justine J Mahon Caroline C Mosica Anda A Moss Celia C Murthy Aditi A Ong Juling J Parker Victoria E VE Rivière Jean-Baptiste JB Sapp Julie C JC Sebire Neil J NJ Shah Rahul R Sivakumar Branavan B Thomas Anna A Virasami Alex A Waelchli Regula R Zeng Zhiqiang Z Biesecker Leslie G LG Barnacle Alex A Topf Maya M Semple Robert K RK Patton E Elizabeth EE Kinsler Veronica A VA

The Journal of clinical investigation 20180312 4

<h4>Background</h4>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).<h4>Methods</h4>To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been e ...[more]

PMID: 29461977

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Project description:BackgroundWe aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification.Methods and resultsThis retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty-five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V-Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen-activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3-4: RAS, 9/13 versus non-RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non-RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19).ConclusionsThis comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.

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

Publications

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

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