Genetic drivers of non‐cutaneous melanomas: Challenges and opportunities in a heterogeneous landscape

Non-cutaneous melanomas most frequently involve the uveal tract and mucosal membranes, including the conjunctiva. In contrast to cutaneous melanoma, they often present at an advanced clinical stage, are associated with worse clinical outcomes and show poorer responses to immunotherapy. The mutational load within most non-cutaneous melanomas reflects their lower ultraviolet light (UV) exposure. The genetic drivers within non-cutaneous melanomas are heterogeneous. Within ocular melanomas, posterior uveal tract melanomas typically harbour one of two distinct, sets of driver mutations and alterations of clinical and biological significance. In contrast to posterior uveal tract melanomas, anterior uveal tract melanomas of the iris and conjunctival melanomas frequently carry both a higher mutational burden and specific mutations linked with UV exposure. The genetic drivers in iris melanomas more closely resemble those of the posterior uveal tract, whereas conjunctival melanomas harbour similar genetic driver mutations to cutaneous melanomas. Mucosal melanomas occur in sun-shielded sites including sinonasal and oral cavities, nasopharynx, oesophagus, genitalia, anus and rectum, and their mutational landscape is frequently associated with a dominant process of spontaneous deamination and infrequent presence of UV mutation signatures. Genetic drivers of mucosal melanomas are diverse and vary with anatomic location. Further understanding of the causes of already identified recurrent molecular events in non-cutaneous melanomas, identification of additional drivers in specific subtypes, integrative multi-omics analyses and analysis of the tumor immune microenvironment will expand knowledge in this field. Furthermore, such data will likely uncover new therapeutic strategies which will lead to improved clinical outcomes in non-cutaneous melanoma patients.