Abstract: Somatic MAP2K1 Mutations Are Enriched in Blood Vessels in Patients with Arteriovenous Malformations

Abstract

BACKGROUND: Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that is locally destructive and characterized by abnormal connections between arteries and veins. We previously reported that whole tissue specimens from patients with AVM lesions contain somatic mutations in MAP2K1 (K57N and Q56P). The purpose of this study was to determine which tissue types in AVM contain MAP2K1 mutations. METHODS: We obtained AVM specimens from 2 patients (ear, lip) during a clinically-indicated procedure. We performed laser capture microdissection on formalin-fixed paraffin-embedded histologic sections to collect specific cell types: blood vessels, skin, and subcutaneous adipose. Genomic DNA was extracted from each tissue type and measured for the abundance of mutant MAP2K1 alleles compared to whole tissue using droplet digital PCR (ddPCR). RESULTS: Both specimens contained MAP2K1 mutations. The K57N whole tissue mutant allele frequency was 8% in AVM of the ear; tissue mutant allele frequencies were: blood vessels 7.8%, skin 0.2%, and subcutaneous adipose 0.1 %. The Q56P whole tissue mutant allele frequency was 10% in the lip AVM; specific tissue mutant allele frequencies were: blood vessels 9.3%, skin 0.3%, and subcutaneous adipose 0.1 %. CONCLUSION:MAP2K1 mutations in AVMs are enriched in blood vessels and not in other tissue types. Mutated blood vessels likely drive the progression and overgrowth of tissues associated with AVMs.