DNA Methylation Array Analysis Identifies Biological Subgroups of Cutaneous Melanoma and Reveals Extensive Differences with Benign Melanocytic Nevi

<b>Background/Objectives</b>: Genetics and epigenetics play an important role in the pathogenesis of cutaneous melanoma. The majority of cases harbor mutations in genes associated with the MAPK signaling pathway, i.e., <i>BRAF</i>, <i>NRAS</i>, or <i>NF1</i>. The remaining neoplasms, often located on acral sites, are condensed as the triple-wildtype subtype and are characterized by other molecular drivers. This study aimed to elucidate genetic and epigenetic differences within cutaneous melanoma and to compare it with melanocytic nevi. <b>Methods</b>: DNA was extracted from archived tissue samples of cutaneous melanoma (<i>n</i> = 19), melanocytic nevi (<i>n</i> = 11), and skin controls (<i>n</i> = 11) and subsequently analyzed by massive parallel (next generation) gene panel sequencing and genome-wide DNA methylation array analysis. The sample size was increased by including repository data from an external study. <b>Results</b>: There were major differences in the genomic landscape of MAPK-altered and triple-wildtype cutaneous melanoma, the latter presenting with a lower number of mutations, a different pattern of copy number variants, and a low frequency of <i>TERT</i> promoter mutations. Dimensional reduction of DNA methylation array analysis clearly separated cutaneous melanoma from melanocytic nevi but revealed no major differences between classical cutaneous melanoma and the triple-wildtype cases. However, it identified a possible biological subgroup characterized by intermediately methylated CpGs. <b>Conclusions</b>: Dimensional reduction of methylation array data is a useful tool for the analysis of melanocytic tumors to differentiate between malignant and benign lesions and may be able to identify biologically distinct subtypes of cutaneous melanoma.