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

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 <i>BRAF</i>, <i>NRAS</i>, <i>HRAS</i>, and <i>KIT</i> were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with <i>BRAF</i> and <i>CDKN2A</i>-mutated ConjMel tended to be younger while the <i>NF1</i>-mutated one tended to be older. The eight tumors arising from nevi were enriched in <i>CTNNB1</i> mutations (63% vs. 8%; Fisher's exact <i>p</i>-test = 0.001) compared to non-nevi ConjMel and five were devoid of <i>BRAF</i>, <i>RAS</i>, <i>NF1</i>, or <i>KIT</i> mutations, suggesting a specific oncogenic process in these tumors. The two <i>KIT</i>-mutated cases carried <i>SF3B1</i> mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in <i>ERBB2</i>, <i>IDH1</i>, <i>MET</i>, and <i>MAP2K1</i> (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. <i>CTNNB1</i> mutations were associated with nevus-derived ConjMel. Concomitant <i>KIT</i>/<i>SF3B1</i> mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.