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The mutational load within most non\u2010cutaneous melanomas reflects their lower ultraviolet light (UV) exposure. The genetic drivers within non\u2010cutaneous 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\u2010shielded 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\u2010cutaneous melanomas, identification of additional drivers in specific subtypes, integrative multi\u2010omics 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\u2010cutaneous melanoma patients.<\/jats:p>","DOI":"10.1111\/exd.14287","type":"journal-article","created":{"date-parts":[[2021,1,17]],"date-time":"2021-01-17T16:55:01Z","timestamp":1610902501000},"page":"13-30","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Genetic drivers of non\u2010cutaneous melanomas: Challenges and opportunities in a heterogeneous landscape"],"prefix":"10.1111","volume":"31","author":[{"given":"Ismael A.","family":"Vergara","sequence":"first","affiliation":[{"name":"Melanoma Institute Australia The University of Sydney Sydney NSW Australia"},{"name":"Faculty of Medicine and Health The University of Sydney Sydney NSW Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James 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