Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location‐dependent patterns of genetic and epigenetic alterations

Abstract

Cutaneous, ocular, and mucosal melanomas are histologically indistinguishable tumors that are driven by a different spectrum of genetic alterations. 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-cutaneous 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-dependent DNA methylation differences in cancer-related genes, such as low frequencies of RARB (7/63) and CDKN2A promoter methylation (6/63) in mucosal melanomas, or a high frequency of APC 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 TERT 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-dependent differences of promoter methylation frequencies in specific cancer-related genes together with tumor site-specific enrichment for specific chromosomal changes and genetic mutations.

Canine Oral Melanoma Genomic and Transcriptomic Study Defines Two Molecular Subgroups with Different Therapeutical Targets

“…In human melanomas, recurrent focal amplifications are frequent (over 50%) and significantly less common in cutaneous melanomas. The focal amplification of 5p15 ( TERT gene locus) is mainly observed in oral MM [ 92 ]; recurrent interchromosomal translocations between HSA 5 ( TERT ) and HSA 12 ( CDK4 ) were observed in 39.6% of cases [ 15 ]. Similarly, over 50% of canine oral MM cases harbored recurrent focal amplification of CDK4/MDM2 oncogenes.…”

Methylation classifiers: Brain tumors, sarcomas, and what's next

“…DNA methylation profiling shows a clear separation of pleomorphic sarcomas from nonmesenchymal neoplasms such as mesothelioma and melanoma, with the latter exhibiting distinct methylation signatures. 54,86,87 On the other hand, several tumor types, including undifferentiated pleomorphic sarcomas, myxofibrosarcomas, and many pleomorphic liposarcomas, are almost indistinguishable by their DNA methylation patterns. 45 Furthermore, sarcomas may exhibit a methylation profile differing from that of the respective reference set resulting in a failed prediction.…”

Genetic Basis and Molecular Mechanisms of Uveal Melanoma Metastasis: A Focus on Prognosis

“…They found out that only uveal melanomas are characterized by a different global DNA methylation profile, with distinct epigenetic signatures. Thus DNA methylation analysis differentiate uveal melanomas from melanomas of other primary sites ( 119 ).…”