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Arteriovenous Malformation MAP2K1 Mutation Causes Cartilage Overgrowth By A Cell Non-autonomous Mechanism
Dennis J. Konczyk, Jeremy A. Goss, Patrick J. Smits, Christopher L. Sudduth, Alyaa Al-Ibraheemi, Joyce Bischoff, Arin K. Greene.
Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

PURPOSE: Arteriovenous malformation (AVM) is a 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 the MAP2K1 mutation (i.e., cell-autonomous or cell-non autonomous). Because cartilage does not contain blood vessels, we tested patients with auricular AVMs to determine if overgrown cartilage contained somatic AVM-causing mutations.
METHODS: AVM tissue was obtained during a clinically-indicated procedure to reduce the size of an overgrown ear in 3 patients. Cartilage was separated from its surrounding tissue and was isolated by laser capture microdissection (LCM). Cartilage, adjacent tissue, endothelial cells (ECs), and non-ECs were tested with droplet digital PCR (ddPCR) for MAP2K1 mutations. AVM cartilage also was compared to normal control ear cartilage histologically.
RESULTS: MAP2K1 (p.K57N) mutations were found in the tissue adjacent to the cartilage in all 3 patients; MAF was 6-8%. The mutation was enriched in ECs (MAF 51%) compared to non-ECs (MAF 0%). A MAP2K1 mutation was not identified in the overgrown cartilage specimens. AVM ear cartilage appeared similar to normal control ear cartilage histologically with the same chondrocyte and extracellular matrix density and relationship.
CONCLUSION: 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). The mutation may cause cartilage overgrowth by stimulating chondrocytes to increase extracellular matrix production. MAP2K1 inhibitors might inhibit secondary overgrowth of tissues in AVM adjacent to blood vessels containing MAP2K1 mutations.


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