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Whether VP- and UV-MCC have the same or different cellular origins is unclear; with mesenchymal or epidermal origins discussed. DNA-methylation patterns have a proven utility in determining cellular origins of cancers. Therefore, we used this approach to uncover evidence regarding the cell of origin of classical VP- and UV-MCC cell lines, i.e., cell lines with a neuroendocrine growth pattern (<jats:italic>n<\/jats:italic>\u2009=\u20099 and <jats:italic>n<\/jats:italic>\u2009=\u20094, respectively). Surprisingly, we observed high global similarities in the DNA-methylation of UV- and VP-MCC cell lines. CpGs of lower methylation in VP-MCC cell lines were associated with neuroendocrine marker genes such as <jats:italic>SOX2<\/jats:italic> and <jats:italic>INSM1<\/jats:italic>, or linked to binding sites of <jats:italic>EZH2<\/jats:italic> and <jats:italic>SUZ12<\/jats:italic> of the polycomb repressive complex 2, i.e., genes with an impact on carcinogenesis and differentiation of neuroendocrine cancers. Thus, the observed differences appear to be rooted in viral compared to mutation-driven carcinogenesis rather than distinct cells of origin. To test this hypothesis, we used principal component analysis, to compare DNA-methylation data from different epithelial and non-epithelial neuroendocrine cancers and established a scoring model for epithelial and neuroendocrine characteristics. Subsequently, we applied this scoring model to the DNA-methylation data of the VP- and UV-MCC cell lines, revealing that both clearly scored as epithelial cancers. In summary, our comprehensive analysis of DNA-methylation suggests a common epithelial origin of UV- and VP-MCC cell lines.<\/jats:p>","DOI":"10.1038\/s41388-021-02064-1","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T05:15:31Z","timestamp":1634620531000},"page":"37-45","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["DNA-methylation patterns imply a common cellular origin of virus- and UV-associated Merkel cell carcinoma"],"prefix":"10.1038","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4181-7685","authenticated-orcid":false,"given":"Jan","family":"Gravemeyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4663-7966","authenticated-orcid":false,"given":"Ivelina","family":"Spassova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0229-5917","authenticated-orcid":false,"given":"Monique E.","family":"Verhaegen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9791-3257","authenticated-orcid":false,"given":"Andrzej A.","family":"Dlugosz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2973-7869","authenticated-orcid":false,"given":"Daniel","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6529-0606","authenticated-orcid":false,"given":"Anja","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-653X","authenticated-orcid":false,"given":"J\u00fcrgen C.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"key":"2064_CR1","doi-asserted-by":"publisher","first-page":"3720","DOI":"10.1158\/0008-5472.CAN-15-0702","volume":"75","author":"PW Harms","year":"2015","unstructured":"Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM, Dhanasekaran SM, et al. 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