Harnessing liquid biopsy to unveil RAS-MEK pathway somatic pathogenic variants in extracranial arterio-venous malformations.

BACKGROUND: Arterio-venous malformations (AVMs) have been associated with somatic genetic variants in the RAS-MEK pathway, generating interest in the role of MEK inhibitors. However, open biopsy for molecular characterisation carries a potentially life-threatening bleeding risk. METHODS: We utilized liquid biopsy from the AVM efferent draining vein in 10 children and young adults (female 7, age range 7.3-22.2 years) with extracranial AVMs to identify the underlying somatic variants. RESULTS: Here we show identification of somatic mosaic variants in 8 of 10 patients. There were no procedural complications. Two patients with spinal arteriovenous metameric syndrome (Cobb syndrome) demonstrated somatic activating KRAS variants. Two additional patients had somatic in-frame deletion-insertion variants of HRAS. Three patients had other variants involving the RAS-MEK pathway and one within PIK3CA. Five patients have commenced molecularly directed pharmacotherapy leading to reduced disability. Variant allele frequency was inversely correlated with sampling distance from the nidus. One patient who underwent sampling at two separate embolization sessions demonstrated a higher variant allele frequency in the sample obtained after embolization was completed. CONCLUSIONS: Our study further supports the role of the RAS-MEK pathway in AVM pathophysiology. In addition, we demonstrate the effective use of liquid biopsy to genotype extracranial AVMs in children. Finally, we provide insights into how the localized high-pressure high-flow conditions within the AVM distinctly shape cell free DNA fragmentation patterns.