Evidence map›Paper›PMID 29298116›Full record

ArticleThe New England journal of medicine2018

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.

Sergey I Nikolaev, Sandra Vetiska, Ximena Bonilla, Emilie Boudreau, Suvi Jauhiainen, Behnam Rezai Jahromi, Nadiya Khyzha, Peter V DiStefano, Santeri Suutarinen, Tim-Rasmus Kiehl and 15 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The New England journal of medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 232 papers, 7 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
232citing papers in PubMed, 7 pooled it
33.1field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

232 citing papers in PubMed, 7 syntheses or guidelines pooled it, 455 citations in OpenAlex.

  1. Translational relevance of animal models available on brain arteriovenous malformations, a systematic review.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
    Pooled it
  2. Guideline
  3. Pooled it
  4. Cancer in Multilineage Mosaic RASopathies due to Pathogenic Variants in HRAS or KRAS: A Systematic Review and Meta-analysis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024
    Pooled it
  5. Pooled it
  6. KRAS/BRAF mutations in brain arteriovenous malformations: A systematic review and meta-analysis.Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences · 2021
    Pooled it
  7. Pooled it
  8. Trial
  9. c-KIT expands the tool kit for treating arteriovenous malformation.The Journal of clinical investigation · 2026
    Article
  10. Article
  11. Review
  12. Review
  13. iScience · 2026
    Article
  14. RAS Inhibitor RMC-7977 Blocks Vascular Overgrowth of NRASJournal of cellular and molecular medicine · 2026
    Article
  15. Article
  16. Review
  17. Mutant KRAS in brain endothelial cells promotes vascular inflammation and impairs vascular integrity in brain arteriovenous malformation.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
    Article
  18. Towards precision medicine for brain arteriovenous malformations.The Journal of clinical investigation · 2026
    Review
  19. Review
  20. Review

172 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

25 authors at 5 institutions in 5 countries.

Sergey I NikolaevFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Sandra VetiskaFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Ximena BonillaFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Emilie BoudreauFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Suvi JauhiainenFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Behnam Rezai JahromiFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Nadiya KhyzhaFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Peter V DiStefanoFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Santeri SuutarinenFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Tim-Rasmus KiehlFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Vitor Mendes PereiraFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Alexander M HermanFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Timo KringsFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Hugo Andrade-BarazarteFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Takyee TungFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Taufik ValianteFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Gelareh ZadehFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Mike TymianskiFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Tuomas RauramaaFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Seppo Ylä-HerttualaFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Joshua D WytheFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Stylianos E AntonarakisFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Juhana FrösenFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Jason E FishFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Ivan RadovanovicFrom the Department of Genetic Medicine and Development, University of Geneva Medical School (S.I.N., X.B., S.E.A.), Service of Genetic Medicine, University Hospitals of Geneva (S.I.N., S.E.A.), and iGE3, Institute of Genetics and Genomics of Geneva (S.E.A.) - all in Geneva; the Department of Fundamental Neurobiology, Krembil Research Institute (S.V., M.T., I.R.), Toronto General Hospital Research Institute (E.B., N.K., P.V.D., J.E.F.), the Department of Pathology (T.-R.K.), the Division of Neurosurgery, Department of Surgery (V.M.P., T.K., H.A.-B., T.T., T.V., G.Z., M.T., I.R.), and the Joint Division of Medical Imaging, Department of Medical Imaging (V.M.P., T.K.), Toronto Western Hospital, University Health Network, the Department of Laboratory Medicine and Pathobiology, University of Toronto (E.B., N.K., P.V.D., T.-R.K., J.E.F.), and the Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research (E.B., N.K., P.V.D., J.E.F.) - all in Toronto; the Department of Molecular Medicine, AIV Institute, University of Eastern Finland (S.J., B.R.J., S.S., S.Y.-H., J.F.), and the Hemorrhagic Brain Pathology Research Group, Department of Neurosurgery and NeuroCenter (S.J., B.R.J., S.S., T.R., J.F.), and the Department of Pathology (T.R.), Kuopio University Hospital - all in Kuopio, Finland; and the Cardiovascular Research Institute and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston (A.M.H., J.D.W.).
Krembil Research InstituteUniversity Health Network · CAUniversity of Eastern Finland · FIUniversity of Geneva · CHBaylor College of Medicine · US

Funding

Molecular Physiology of the Cardiovascular SystemT32HL007676 · NHLBI · BAYLOR COLLEGE OF MEDICINE · PI HAMILTON, SUSAN L · 1989 to 2020
$7.9M
NHLBI NIH HHS T32 HL007676
6 · The paper itself

Abstract

backgroundSporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown.

methodsWe analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples.

resultsWe detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRAS

conclusionsWe identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

Indexed as

MutationAdultCells, CulturedDNA Mutational AnalysisExomeGene ExpressionHumansHuman Umbilical Vein Endothelial CellsIntracranial Arteriovenous MalformationsMAP Kinase Kinase KinasesMAP Kinase Signaling SystemPhosphorylationProto-Oncogene Proteins p21(ras)KRAS protein, humanMAP Kinase Kinase KinasesProto-Oncogene Proteins p21(ras)

Identifiers

PMID29298116
PMCPMC8161530
OpenAlexW2781825595

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