Comprehensive genomic profiling of mucosal melanoma reveals novel fusion transcripts and dysregulation of cell-cycle, MAPK, and PI3K pathways.

Mucosal melanomas (MMs) are rare, aggressive cancers with poor outcomes and limited response to standard therapies. A significant knowledge gap exists regarding their genomic landscape and corresponding druggable targets. This study explores this issue through a multi-omic analysis, including whole exome-, RNA-, and targeted sequencing, of unique sinonasal mucosal melanoma (SN-MM) cell lines. SN-MM cell lines showed a low tumour mutational burden and low genomic instability, suggesting that their DNA repair mechanisms are largely intact. However, they exhibited a high prevalence of structural variants, likely from catastrophic genomic events. We also found novel, clinically actionable variants, including oncogenic fusion transcripts. Key findings, such as fusion transcripts and single-nucleotide variants, were validated on diagnostic biopsies. Moreover, using a break-apart FISH assay, we identified BRAF rearrangements as recurrent events in MM, supporting their biological relevance. The MAPK pathway was found to have a significant functional role, sustained by variants such as BRAF p.Asn581Ser, NRAS p.Gly12Asp, and the MKRN1::BRAF fusion. This pathway activation was effectively inhibited by the MEK inhibitor trametinib. This genomic and functional profiling unveiled novel molecular hubs in MM. The findings propose that MEK inhibitors may represent a relevant therapeutic option for BRAF fusions and non-V600 BRAF mutant tumours, providing a novel strategy for this challenging disease. Further molecular and functional validation of novel variants, and particularly of BRAF rearrangements, may reveal additional clinically relevant therapeutic targets. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.