Genomic Profiling of Mucosal Melanoma Identifies Novel Fusion Transcripts and Therapeutic Molecular Hubs
Background: Mucosal melanomas (MM) 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 comprehensive genomic analysis of unique sinonasal mucosal melanoma (SN-MM) cell lines.Methods: The genomic landscape of the SN-MM cell lines was explored using a multi-omic approach, including whole exome-, RNA-, and targeted sequencing. Bioinformatics analyses were performed for variant calling and structural prediction. Key findings, such as fusion transcripts and single-nucleotide variants, were validated on diagnostic biopsies. Functional in vitro assays assessed MAPK pathway activation and sensitivity to chemical inhibitors.Results: SN-MM cell lines showed a low tumor mutational burden and low genomic instability, suggesting 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. The MAPK pathway was found to have a significant functional role, sustained by variants like BRAF p.Asn581Ser, NRAS p.Gly12Asp, and the MKRN1-BRAF fusion. This pathway's activation is effectively inhibited by the MEK inhibitor, trametinib.Conclusions: This genomic and functional profiling unveils novel molecular hubs in MM. The findings propose that MEK inhibitors are a relevant therapeutic option also for non-BRAF V600-mutant tumors, offering a new strategy for this challenging disease. Further validation of novel variants may reveal additional clinically meaningful targets.