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

Martin, Sara Barberan; Polubothu, Satyamaanasa; Bruzos, Alicia Lopez; Kelly, Gavin; Horswell, Stuart; Sauvadet, Aimie; Bryant, Dale; ... Kinsler, Veronica; + view all (2023) Mosaic BRAF fusions are a recurrent cause of congenital melanocytic naevi targetable by MEK inhibition. Journal of Investigative Dermatology 10.1016/j.jid.2023.06.213. (In press). Green open access

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Abstract

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.

Type: Article
Title: Mosaic BRAF fusions are a recurrent cause of congenital melanocytic naevi targetable by MEK inhibition
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jid.2023.06.213
Publisher version: https://doi.org/10.1016/j.jid.2023.06.213
Language: English
Additional information: Copyright © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10177636
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