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Merkel Cell Polyomavirus‒Negative Merkel Cell Carcinoma Originating from In Situ Squamous Cell Carcinoma: A Keratinocytic Tumor with Neuroendocrine Differentiation

Published:August 31, 2021DOI:https://doi.org/10.1016/j.jid.2021.07.175
      Although virus-negative Merkel cell carcinoma (MCC) is characterized by a high frequency of UV-induced mutations, the expression of two viral oncoproteins is regarded as a key mechanism driving Merkel cell polyomavirus‒positive MCC. The cells in which these molecular events initiate MCC oncogenesis have yet not been identified for both MCC subsets. A considerable proportion of virus-negative MCC is found in association with squamous cell carcinoma (SCC), suggesting (i) coincidental collision, (ii) one providing a niche for the other, or (iii) one evolving from the other. Whole-exome sequencing of four combined tumors consisting of SCC in situ and Merkel cell polyomavirus‒negative MCC showed many mutations shared between SCC and MCC in all cases, indicating a common ancestry and thereby a keratinocytic origin of these MCCs. Moreover, analyses of the combined cases as well as of pure SCC and MCC suggest that RB1 inactivation in SCC facilitates MCC development and that epigenetic changes may contribute to the SCC/MCC transition.

      Abbreviations:

      COSMIC (Catalogue Of Somatic Mutation In Cancer), CNV (copy number variation), MCC (Merkel cell carcinoma), MCPyV (Merkel cell polyomavirus), SCC (squamous cell carcinoma), SCCis (squamous cell carcinoma in situ)
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      • The Origins of Merkel Cell Carcinoma: Defining Paths to the Neuroendocrine Phenotype
        Journal of Investigative DermatologyVol. 142Issue 3
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          Two recent reports leverage careful genomic analysis to show that human Merkel cell carcinomas (MCCs) arising from squamous cell carcinoma in situ bear hallmarks of genetic relatedness, suggesting that a subset of MCCs can arise from pre-existing intraepithelial keratinocytic proliferations in human skin. This has important implications for our understanding of cells of origin and the diverse drivers of MCC formation.
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