Martin, SB;
Polubothu, S;
Bruzos, AL;
Kelly, G;
Horswell, S;
Sauvadet, A;
Bryant, D;
Zecchin, D;
Riachi, M;
Michailidis, F;
et al.
Martin, SB; Polubothu, S; Bruzos, AL; Kelly, G; Horswell, S; Sauvadet, A; Bryant, D; Zecchin, D; Riachi, M; Michailidis, F; Sadri, A; Muwanga-Nanyonjo, N; Lopez-Balboa, P; Knöpfel, N; Bulstrode, N; Pittman, A; Yeh, I; Kinsler, VA
(2024)
Mosaic BRAF Fusions Are a Recurrent Cause of Congenital Melanocytic Nevi Targetable by MAPK Pathway Inhibition.
J Invest Dermatol, 144 (3).
593-600.e7.
ISSN 1523-1747
https://doi.org/10.1016/j.jid.2023.06.213
SGUL Authors: Pittman, Alan Michael
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Abstract
Among children with multiple congenital melanocytic nevi, 25% have no established genetic cause, of whom many develop a hyperproliferative and severely pruritic phenotype resistant to treatment. Gene fusions have been reported in individual cases of congenital melanocytic nevi. We studied 169 patients with congenital melanocytic nevi in this study, 38 of whom were double wild type for pathogenic NRAS/BRAF variants. Nineteen of these 38 patients had sufficient tissue to undergo RNA sequencing, which revealed mosaic BRAF fusions in 11 of 19 patients and mosaic RAF1 fusions in 1 of 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 nevi in 5 of 12 patients, confirming clonality. The absence of the fusion in blood in 8 of 12 patients indicated mosaicism. Primary culture of BRAF-fusion nevus cells from 3 of 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.
Item Type: | Article | ||||||||
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Additional Information: | ª 2023 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). | ||||||||
Keywords: | 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Dermatology & Venereal Diseases | ||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | ||||||||
Journal or Publication Title: | J Invest Dermatol | ||||||||
ISSN: | 1523-1747 | ||||||||
Language: | eng | ||||||||
Dates: |
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Publisher License: | Creative Commons: Attribution 4.0 | ||||||||
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PubMed ID: | 37716647 | ||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/115732 | ||||||||
Publisher's version: | https://doi.org/10.1016/j.jid.2023.06.213 |
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