Mosaic BRAF fusions are a recurrent cause of congenital melanocytic naevi targetable by MEK inhibition

Twenty-five percent of children with multiple congenital melanocytic naevi (CMN) have no established genetic cause, of which a high proportion develop a hyperproliferative, inflammatory and severely pruritic phenotype resistant to treatment. Fusion genes have been reported in individual cases. Nineteen patients from a cohort of 117 were WT for known causative mutations and underwent RNAseq of affected tissue. We find here mosaic BRAF gene fusions in 11/19, and mosaic RAF1 fusions in 1/19. Most fusions resulted in loss of the 5 regulatory domain with preservation of the kinase domain. Sanger sequencing and break-apart probes validated fusions in multiple skin samples from the same individuals, but not in blood samples, confirming clonality and mosaicism. Primary culture of BRAF-fusion naevus cells demonstrated highly increased MAPK activation in some patients despite only mildly increased BRAF expression, suggesting additional mechanisms of kinase activation. MAPK hyperactivation was quenched by trametinib in vitro. Treatment of a patient with trametinib caused rapid improvement in tissue bulk impairing bodily movement, inflammation, and severe pruritus. Mosaic BRAF fusions are a recurrent cause of multiple CMN in 21% of this cohort. MAPK hyperactivation may be cause of the frequent hyperproliferative phenotype and is responsive to trametinib.