ArticleThe Journal of clinical investigation2018
Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT05983159 (A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations), which is not on this map. Cited by 143 papers, 3 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (TARGET-VM)
Who cites it
143 citing papers in PubMed, 3 syntheses or guidelines pooled it, 280 citations in OpenAlex.
- Diagnosis and management of superficial arteriovenous malformations: French healthcare network's recommendations.Orphanet journal of rare diseases · 2025Guideline
- Characteristics, Natural Course and Treatment of Intramuscular Capillary-type Haemangioma: A Systematic Literature Review.Acta dermato-venereologica · 2023Pooled it
- KRAS/BRAF mutations in brain arteriovenous malformations: A systematic review and meta-analysis.Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences · 2021Pooled it
- Selumetinib for pediatric arteriovenous malformation with aJAAD case reports · 2026Article
- From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity.International journal of molecular sciences · 2026Review
- Parents' experiences of diagnosis and specialist care of children's rare birthmarks.British journal of health psychology · 2026Article
- Drug therapy for extracranial superficial arteriovenous malformation: A systematic review.Journal of the European Academy of Dermatology and Venereology : JEADV · 2026Article
- Review
- SHOC2 Is a Novel Cause of Central Conducting Lymphatic Anomaly.American journal of medical genetics. Part A · 2026Article
- M2 Macrophage Polarization Characterizes an Immunosuppressive Microenvironment in Extracranial Arteriovenous Malformations.Biomedicines · 2026Article
- COMMD9-regulated endothelial cell abnormality-induced hypercoagulability is associated with Budd-Chiari syndrome.International journal of surgery (London, England) · 2026Article
- Zoledronic Acid in the Management of Melorheostosis of Radius and Ulna - A Rare Case Report with Literature Review.Journal of orthopaedic case reports · 2026Article
- Review
- Towards precision medicine for brain arteriovenous malformations.The Journal of clinical investigation · 2026Review
- Pathogenic mechanism of extracranial arteriovenous malformations: insights from clinical, pathological, and genetic analyses.Virchows Archiv : an international journal of pathology · 2026Article
- Advances in the Genetics and Molecular Biology of Brain Arteriovenous Malformations.Translational stroke research · 2026Review
- Detection rate and mutational landscape in extracranial arteriovenous malformations: a cohort study.BMC medicine · 2026Article
- De novo twig-like middle cerebral artery after suspected M1 dissection in early childhood with coexisting KRAS-mutated brain arteriovenous malformation: illustrative case.Journal of neurosurgery. Case lessons · 2026Article
- KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.EMBO molecular medicine · 2026Article
- Trametinib Decreased Intracerebral Hemorrhages and Endothelial-to-Mesenchymal Transition in KRASStroke · 2026Article
83 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
46 authors at 12 institutions in 3 countries.
Funding
Abstract
backgroundSporadic 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).
methodsTo 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.
resultsWe 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.
conclusionOur 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.
fundingThis 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).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.