Merkel cell polyomavirus‒negative Merkel cell carcinoma originating from in situ squamous cell carcinoma: a keratinocytic tumor with neuroendocrine differentiation
Résumé
While virus-negative Merkel cell carcinoma (MCC) is characterized by high frequency of UV-induced mutations, expression of two viral oncoproteins is regarded as key mechanism driving Merkel cell polyomavirus (MCPyV)-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 MCPyV-negative MCC demonstrated in all cases many mutations shared between SCC and MCC 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 suggests that RB1 inactivation in SCC facilitates MCC development and that epigenetic changes may contribute to the SCC/MCC transition.
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