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

SIMPLE SUMMARY: Conjunctival melanoma (ConjMel) is a rare but potentially deadly eye tumor developing on the ocular mucosal surface, which is partially exposed to sunlight. The relationships between potential etiological factors such as ultraviolet exposure and ConjMel mutational landscape have not been precisely described in large cohorts. Here, we report the sequencing of 400 cancer genes in 47 primary ConjMel and show several associations between mutations and etiological factors. BRAF- and CDKN2A-mutated ConjMel affect younger patients while NF1-mutated tumors tend to develop in older ones. CTNNB1 mutations are more frequent in nevi-derived ConjMel, suggesting that the Wnt pathway is pivotal in their tumorigenesis. We further identified concomitant KIT/SF3B1 mutations in BRAF/RAS-wild type, sun-protected tumors, suggesting a similar profile as previously observed in genital and anorectal melanomas, thus unveiling a distinct, mucosal-specific, tumorigenic pathway. Finally, we report for the first time new targetable oncogenic mutations, opening new therapeutic options for these patients. ABSTRACT: 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 BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%; Fisher’s exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.