Mosaic BRAF fusions are a recurrent cause of congenital melanocytic naevi targetable by MEK inhibitionMore about Open Access at the Crick
Authors listSara Barberan Martin Satyamaanasa Polubothu Alicia Bruzos Gavin Kelly Stuart Horswell Aimie Sauvadet Dale Bryant Davide Zecchin Melissa Riachi Fanis Michailidis Amir Sadri Noreen Muwanga-Nanyonjo Pablo Lopez-Balboa Nicole Knöpfel Neil Bulstrode Alan Pittman Iwei Yeh Veronica Kinsler
Among children with multiple congenital melanocytic naevi (CMN), 25% have no established genetic cause, of which many develop a hyperproliferative and severely pruritic phenotype resistant to treatment. Gene fusions have been reported in individual cases of CMN. Here, we study 169 CMN patients, 38 of whom were double wild-type for NRAS/BRAF mutations. Nineteen of these 38 patients had sufficient tissue to undergo RNAseq, which revealed mosaic BRAF fusions in 11/19 patients and mosaic RAF1 fusions in 1/19. Recurrently, fusions involved the loss of the 5' regulatory domain of BRAF or RAF1 but preserved the kinase domain. We validated all cases and detected the fusions in two separate naevi in 5/12 patients, confirming clonality. The absence of the fusion in blood in 8/12 patients indicated mosaicism. Primary culture of BRAF-fusion naevus cells from 3/12 patients demonstrated highly increased MAPK activation, despite only mildly increased BRAF expression, suggesting additional mechanisms of kinase activation. Trametinib quenched MAPK hyperactivation in vitro and treatment of two patients caused rapid improvement in bulk tissue, improving bodily movement, and reducing inflammation and severe pruritus. These findings offer a genetic diagnosis to an additional group of patients and trametinib as a treatment option for the severe associated phenotypes.
Pages Epub ahead of print