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

Sophie Gardrat,Sergio Roman-Roman,Marc-Henri Stern,Manuel Rodrigues,Richard Marais,Stéphane Dayot,Alexandre Houy,Nathalie Cassoux,Kelly Brooks,Raymond Barnhill,Virginie Raynal,Sylvain Baulande,Ivan Bièche

doi:10.3390/cancers13153836

Abstract

Simple SummaryConjunctival 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.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.

Highlights

Melanomas are a heterogeneous group of tumors that may arise from diverse tissues including glabrous or non-glabrous skin, mucosae, uvea, or leptomeninges
Samples from 47 Conjunctival melanoma (ConjMel) patients treated between May 2004 and June 2016 at the Institut Curie were sequenced with a commercial panel of 400 genes (1.75 Mb) including genes implicated in melanoma oncogenesis
Our data support that ConjMel is a biologically distinct, heterogeneous group of melanomas presenting a mixed phenotype with features of mucosal melanomas associated with genetic scars of chronic UV exposure similar to iris melanomas, a subset of uveal melanomas displaying a UV-induced, high mutation burden [33,34]

Summary

Introduction

Melanomas are a heterogeneous group of tumors that may arise from diverse tissues including glabrous or non-glabrous skin, mucosae, uvea, or leptomeninges. Clinical and genetic features further vary between CM subtypes, with CM arising from chronically sun-damaged skin such as facial CM occurring in older patients, which is associated with a higher frequency of BRAFnonV600E , NRAS, NF1, and KIT mutations [5] The frequencies of these genetic aberrations differ depending on the tissue of origin of these melanomas, for instance, KIT mutations are more common in mucosal melanomas. These mutations are not observed in uveal and leptomeningeal melanomas, which are instead commonly mutated in the G-protein coupled receptor pathway including GNAQ, GNA11, CYSLTR2, and PLCB4 [6]. Immune checkpoint inhibitors have shown a high activity in CM because of their high clonal mutation burden, whereas their efficacy is reduced in mucosal melanoma, a subtype carrying a much lower mutation burden [8,9]

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