Conjunctival melanoma is a molecular distinct mucosal melanoma with high expression of PD‐L1

Abstract

AbstractPurposeConjunctival melanoma is a unique mucosal melanoma due to its location in the sunexposed conjunctiva. The purpose of this study was to contextualize conjunctival melanoma as a mucosal melanoma based on molecular profiling. This is the first study of its kind.Material and Methods12 primary conjunctival melanomas and 28 primary mucosal melanomas from non‐sunexposed sites (nasal cavity, vagina, and rectum) were subjected to molecular profiling using targeted next‐generation sequencing (Oncomine Comprehensive Cancer Panel) and NanoString gene expression profiling (PanCancer Pathways Panel, 770 cancer genes). Normal conjunctiva and mucosa were used as internal controls.ResultsGenetically, conjunctival melanomas harboured BRAF‐V600E mutations and NF1 mutations, whereas other mucosal melanomas harboured more unspecific mutations, such as atypical BRAF mutations and mutations in KIT. Non‐sunexposed mucosal melanomas frequently presented amplification of MYC. When comparing the gene expression profile of conjunctival melanoma and non‐sunexposed mucosal melanoma, 41 genes were found to be significantly deregulated. 24 genes were upregulated, whereas 17 were downregulated in conjunctival melanoma. Many of the deregulated genes were involved in immunological pathways when performing an in silico pathway analysis. Most intriguingly, programmed death‐ligand 1 (PD‐L1) presented a significant 6‐fold upregulation in conjunctival melanoma. This finding could be validated with immunohistochemistry (p = 0.041, Fisher’s exact test). A network analysis revealed that PD‐L1 was co‐expressed with 8 other genes.ConclusionsComprehensive molecular profiling on the DNA and mRNA level revealed that conjunctival melanoma is a distinct molecular mucosal melanoma characterized by a higher frequency of BRAF‐V600E mutations, low expression of MYC and a high expression of PD‐L1 and other genes involved in immune response. This finding is important, as this suggests a higher response to checkpoint inhibition in conjunctival melanoma metastases when compared to other mucosal melanomas.