Genomic and Transcriptomic Analysis of Sinonasal Mucosal Melanoma and Conjunctival Melanoma

This study compared 25 sinonasal mucosal melanomas (SNMM) and 9 conjunctival melanomas (CM) using whole-exome and RNA sequencing. Median patient age was 64 years for SNMM and 54 years for CM. SNMM predominantly occurred in the nasal cavity (14/25, 56%) or both nasal cavity and paranasal sinuses (9/25, 36%). All CM cases were unilateral. NRAS mutations were found in 20% (5/25) of SNMM and 22% (2/9) of CM cases. RAS mutations were significantly associated with shorter progression-free survival in SNMM. BRAF mutations were detected in 22% (2/9) of CM cases (all V600E) and 8% (2/25) of SNMM cases (non-V600E). NF1 mutations occurred in 16% (4/25) of SNMM and 11% (1/9) of CM cases. Only one KIT mutation was found, in an SNMM case. Nearly all SNMM and CM cases exhibited alterations in the RTK-RAS signaling pathway. CM showed a higher frequency of UV-associated mutations than SNMM. RNA sequencing identified two novel gene fusions (PTPRK::PAX3 and GNA13::NF1) in SNMM. The most common tumor microenvironment subtype in both was D-type. SNMM had higher cancer-associated fibroblast infiltration but lower CD4+ T cell infiltration than CM. Among tumor suppressor genes, CDKN2B exhibited the highest frequency of biallelic inactivation in SNMM (5/25, 20%) and CM (1/6, 17%). Reactome pathway enrichment analysis revealed enrichment of cell cycle-related pathways in both tumor types. In conclusion, these findings delineate distinct genomic profiles of SNMM and CM, revealing significant pathogenic similarities, particularly the involvement of the RTK-RAS pathway and cell cycle-related pathways, despite potential differences in etiological factors.