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A significant knowledge gap exists regarding their genomic landscape and corresponding druggable targets. This study explores this issue through a multi\u2010omic analysis, including whole exome\u2010, RNA\u2010, and targeted sequencing, of unique sinonasal mucosal melanoma (SN\u2010MM) cell lines. SN\u2010MM 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\u2010nucleotide variants, were validated on diagnostic biopsies. Moreover, using a break\u2010apart FISH assay, we identified\n                    <jats:italic>BRAF<\/jats:italic>\n                    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\n                    <jats:italic>BRAF<\/jats:italic>\n                    p.Asn581Ser,\n                    <jats:italic>NRAS<\/jats:italic>\n                    p.Gly12Asp, and the\n                    <jats:italic>MKRN1<\/jats:italic>\n                    ::\n                    <jats:italic>BRAF<\/jats:italic>\n                    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\n                    <jats:italic>BRAF<\/jats:italic>\n                    fusions and non\u2010V600\n                    <jats:italic>BRAF<\/jats:italic>\n                    mutant tumours, providing a novel strategy for this challenging disease. Further molecular and functional validation of novel variants, and particularly of\n                    <jats:italic>BRAF<\/jats:italic>\n                    rearrangements, may reveal additional clinically relevant therapeutic targets. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70108","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:38:36Z","timestamp":1788241116000},"page":"380-395","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive genomic profiling of mucosal melanoma reveals novel fusion transcripts and dysregulation of cell\u2010cycle,\n                    <scp>MAPK<\/scp>\n                    , and\n                    <scp>PI3K<\/scp>\n                    pathways"],"prefix":"10.1002","volume":"270","author":[{"given":"Matilde","family":"Monti","sequence":"first","affiliation":[{"name":"Department of Molecular and Translational Medicine University of Brescia  Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina Brigida","family":"Romanello","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine University of Brescia  Brescia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Agnelli","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Innovation, Pathology Unit 2 Fondazione IRCCS Istituto Nazionale Dei Tumori  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology University of Verona  Verona 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