title: Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation.
abstract: Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that may arise anywhere in the body. AVMs typically progress, causing destruction of surrounding tissue and, sometimes, cardiac overload. AVMs are difficult to control; they often re-expand after embolization or resection, and pharmacologic therapy is unavailable. We studied extracranial AVMs in order to identify their biological basis. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) on AVM tissue from affected individuals. Endothelial cells were separated from non-endothelial cells by immune-affinity purification. We used droplet digital PCR (ddPCR) to confirm mutations found by WES and WGS, to determine whether mutant alleles were enriched in endothelial or non-endothelial cells, and to screen additional AVM specimens. In seven of ten specimens, WES and WGS detected and ddPCR confirmed somatic mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1). Mutant alleles were enriched in endothelial cells and were not present in blood or saliva. 9 of 15 additional AVM specimens contained mutant MAP2K1 alleles. Mutations were missense or small in-frame deletions that affect amino acid residues within or adjacent to the protein's negative regulatory domain. Several of these mutations have been found in cancers and shown to increase MEK1 activity. In summary, somatic mutations in MAP2K1 are a common cause of extracranial AVM. The likely mechanism is endothelial cell dysfunction due to increased MEK1 activity. MEK1 inhibitors, which are approved to treat several forms of cancer, are potential therapeutic agents for individuals with extracranial AVM.
authors.affiliation: Department of Plastic & Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Couto
authors.affiliation: Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: August Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Department of Plastic & Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Konczyk
authors.affiliation: Department of Plastic & Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goss
authors.affiliation: Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fishman
authors.affiliation: Department of Plastic & Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Mulliken
authors.affiliation: Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.affiliation: Department of Plastic & Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: arin.greene@childrens.harvard.edu.
authors.forename: Arin K
authors.initials: AK
authors.lastname: Greene
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001165:Arteriovenous Malformations / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human
keywords: MAP2K1; MEK1; arteriovenous malformation; vascular anomaly