Genomic and Transcriptomic Analysis of Sinonasal Mucosal Melanoma and Conjunctival Melanoma

ABSTRACT

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.