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With current methods, identification of the site of origin of a melanoma metastasis is challenging. DNA methylation profiling has shown promise for the identification of the site of tumor origin in various settings. Here we explore the DNA methylation landscape of melanomas from different sites and analyze if different melanoma origins can be distinguished by their epigenetic profile. We performed DNA methylation analysis, next generation DNA panel sequencing, and copy number analysis of 82 non\u2010cutaneous and 25 cutaneous melanoma samples. We further analyzed eight normal melanocyte cell culture preparations. DNA methylation analysis separated uveal melanomas from melanomas of other primary sites. Mucosal, conjunctival, and cutaneous melanomas shared a common global DNA methylation profile. Still, we observed location\u2010dependent DNA methylation differences in cancer\u2010related genes, such as low frequencies of <jats:italic>RARB<\/jats:italic> (7\/63) and <jats:italic>CDKN2A<\/jats:italic> promoter methylation (6\/63) in mucosal melanomas, or a high frequency of <jats:italic>APC<\/jats:italic> promoter methylation in conjunctival melanomas (6\/9). Furthermore, all investigated melanomas of the paranasal sinus showed loss of PTEN expression (9\/9), mainly caused by promoter methylation. This was less frequently seen in melanomas of other sites (24\/98). Copy number analysis revealed recurrent amplifications in mucosal melanomas, including chromosomes 4q, 5p, 11q and 12q. Most melanomas of the oral cavity showed gains of chromosome 5p with <jats:italic>TERT<\/jats:italic> amplification (8\/10), while 11q amplifications were enriched in melanomas of the nasal cavity (7\/16). In summary, mucosal, conjunctival, and cutaneous melanomas show a surprisingly similar global DNA methylation profile and identification of the site of origin by DNA methylation testing is likely not feasible. Still, our study demonstrates tumor location\u2010dependent differences of promoter methylation frequencies in specific cancer\u2010related genes together with tumor site\u2010specific enrichment for specific chromosomal changes and genetic mutations. \u00a9 2021 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5808","type":"journal-article","created":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T10:11:14Z","timestamp":1632651074000},"page":"61-70","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Mucosal melanomas of different anatomic sites share a common global <scp>DNA<\/scp> methylation profile with cutaneous melanoma but show location\u2010dependent patterns of genetic and epigenetic 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