Definition of Biologically Distinct Groups of Conjunctival Melanomas According to Etiological Factors and Implications for Precision Medicine.

Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in , , , and were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with and -mutated ConjMel tended to be younger while the -mutated one tended to be older. The eight tumors arising from nevi were enriched in mutations (63% vs. 8%; Fisher's exact -test = 0.001) compared to non-nevi ConjMel and five were devoid of , , , or mutations, suggesting a specific oncogenic process in these tumors. The two -mutated cases carried mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in , , , and (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. mutations were associated with nevus-derived ConjMel. Concomitant / mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.