Merkel cell carcinoma (MCC) is a rare but lethal cancer with the highest case-by-case fatality rate among all skin cancers. Eighty percent of cancers are associated with the Merkel cell polyomavirus (MCPyV). Twenty percent of MCCs are virus negative. Recent epidemiological data suggest that there are important, clinically relevant differences between these two subtypes of MCC. Recent studies in cancer genomics, mouse genetics, and virology experiments have transformed our understanding of MCC pathophysiology. Importantly, dramatic differences in the genetics of these two MCC subtypes suggest fundamental differences in their pathophysiology. We review these recent works and find that they provocatively suggest that MCPyV-positive and MCPyV-negative MCCs arise from two different cells of origin: the MCPyV-negative MCC from epidermal keratinocytes and the MCPyV-positive MCC from dermal fibroblasts. If true, this would represent the first cancer that we are aware of that evolves from cells of origin from two distinct germ layers: MCPyV-negative MCCs from ectodermal keratinocytes and MCPyV-positive MCCs from mesodermal fibroblasts. Future epigenetic experiments may prove valuable in confirming these distinct lineages for these MCC subtypes, especially for the clinical importance the cell of origin has on MCC treatment and prevention.
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S.J.C. is the Ruth K. Freinkel Assistant Professor of Dermatology. S.J.C. is supported by the NCI (K08 CA 191019). S.J.S. is the Harriet and Mary Zelencik Scientist in Children’s Cancer and Blood Diseases. The mouse work was supported by the NCI (R21 CA167104-01). The mice were maintained according to practices prescribed by the NIH at Stanford’s Research Animal Facility accredited by the AAPLAC (protocol 13565). We thank Dr. David MacPherson for the Pten mutant mice and Dr. Anton Berns for the Trp53 mutant mice. We would like to thank everyone in the Sage laboratory who helped in the generation and characterization of all the mutant mouse cohorts, specifically Margaret Zhu, Kim Tran, Garrett Seitz, and Anuradha Tathireddy, as well as Dr. Jinah Kim for help with the histopathology.
Conflict of interest
The authors declare that they have no competing interests.
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Sunshine, J.C., Jahchan, N.S., Sage, J. et al. Are there multiple cells of origin of Merkel cell carcinoma?. Oncogene 37, 1409–1416 (2018). https://doi.org/10.1038/s41388-017-0073-3
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