Somatic Arteriovenous Malformation MAP2K1 Mutation Causes Cartilage Overgrowth by a Cell Non-Autonomous Mechanism
Dennis J. Konczyk, BS, Jeremy A. Goss, MD, Patrick J. Smits, PhD, Christopher L. Sudduth, MD, Arin K. Greene, MD MMSc.
Boston Children's Hospital, Boston, MA, USA.
BACKGROUND: Arteriovenous malformation (AVM) is congenital vascular anomaly most commonly caused by somatic MAP2K1 mutations in the endothelial cell. The purpose of this study was to determine if tissue overgrowth associated with AVM is caused by direct or indirect effects of a MAP2K1 mutation (i.e., cell-autonomous or cell-non autonomous).
METHODS: AVM tissue was obtained during a clinically-indicated procedure to reduce the size of an overgrown ear. Cartilage was separated from the overlying skin/subcutis grossly as well as by laser capture microdissection (LCM). Tissues were tested with droplet digital PCR (ddPCR) for MAP2K1 mutation (p.K57N) and measured for the abundance of mutant alleles.
RESULTS: Skin/subcutaneous AVM tissue contained a mutation in MAP2K1 (p.K57N); the whole tissue mutant allele frequency was 3.1%. Staining with hematoxylin, eosin, and alcian blue delineated cartilage from the surrounding vessel-rich connective tissue. MAP2K1 (p.K57N) mutations were found in microscopic connective tissue adjacent to the cartilage (mutant allele frequency: 7.5%). MAP2K1 mutations were not identified in the cartilage.
CONCLUSIONS: MAP2K1 mutations in AVMs are not found in cartilage and thus, the likely mechanism of cartilage overgrowth is paracrine signaling from adjacent mutant blood vessels (i.e., cell-non autonomous). MAP2K1 inhibitors might inhibit secondary overgrowth of tissues in AVM adjacent to blood vessels containing MAP2K1 mutations.
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