260 Mosaic BRAF fusions are a recurrent cause of multiple congenital melanocytic naevi

Congenital melanocytic naevi (CMN) are moles present at birth, and when multiple or very extensive can involve other organ systems as well predisposing to melanoma. Some CMN develop a highly proliferative phenotype whose progression is poorly understood. Genotypically, caused by mosaic NRAS missense mutations in 67% of cases BRAF 7% cases. Single gene fusions have been previously described. To investigate the remaining 25%, skin biopsies from 19 patients shown be double wildtype for NRAS/BRAF underwent transcriptome-wide paired-end RNA sequencing detect fusion transcripts. 11/19 were found fusions, which 7 had multinodular phenotype. In identified, was fused 11 different partner genes (GOLGA4, QKI, STRN3, AGAP3, MKRN2, PHIP, LCA5, EEA1, AKAP9, SEC31A, MIER3) resulting loss 5’ regulatory domain but preservation kinase domain. RNAseq findings validated PCR skin, patient-derived naevus cells available. 7/11 contained dimerisation domains gene, thought functionally relevant Patient cell lines harbouring BRAF-fusions, showed significant increase expression compared WT p.(V600E) lines, markedly increased activation MAPK pathway. We identify here recurrent cause allowing genetic diagnosis further 15% cases, linking this genotype pruritic Although MEK inhibition does not resolution lesions, pathway patient suggests it may therapeutic against clinical hyperactivity lesions.