DNA-methylation patterns imply a common cellular origin of virus- and UV-associated Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a neuroendocrine tumor either induced by integration of the Merkel cell polyomavirus into the cell genome or by accumulation of UV-light-associated mutations (VP-MCC and UV-MCC). 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 (n = 9 and n = 4, 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 SOX2 and INSM1, or linked to binding sites of EZH2 and SUZ12 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.

Current In Vitro and In Vivo Models to Study MCPyV-Associated MCC

“…Supporting this hypothesis, recent research studying MCPyV+ MCC identified overlapping somatic mutations when performing genetic analysis of a tumor consisting of a benign trichoblastoma derived from the epithelial lineage and MCPyV+ MCC [ 100 ]. Additionally, an analysis of tissue-specific DNA methylation patterns revealed similarities between MCCs and epithelial cancers, including squamous cell carcinoma [ 101 ]. These shared molecular traits further support the hypothesis that MCCs, like Merkel cells, arise from epithelial progenitors in which the MCPyV viral genome had integrated prior to clonal expansion.…”

Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma

“…From a very recent study on DNA-methylation patterns in epithelial and non-epithelial neuroendocrine cancers and MCC-derived cell lines, a common epithelial origin of both MCPyV-positive and -negative MCC cell lines has been suggested. Therefore, the observed differences may be attributed to viral vs. mutation-driven carcinogenesis rather than to the distinct cells of origin [ 45 ].…”

Merkel Cell Polyomavirus (MCPyV) and Cancers: Emergency Bell or False Alarm?

“…Hence, Merkel cell carcinomas can be subdivided into two major groups: the virus-associated MCCs (VP-MCCs) and the virus-negative MCCs (VN-MCCs or UV-MCCs). Despite evidently different aetiologies, both groups share mutations in vital cell-cycle related genes (meaning they regulate similar molecular paths in different means) [ 29 , 54 , 55 , 56 ], as well as similar disease phenotype [ 57 ] and same emergence location (on sun-exposed regions of the body, such as the head, neck, and limbs [ 58 , 59 ]). On the contrary, VP-MCCs seem to have an insignificant mutational burden and a lower number of somatic mutations compared to VN-MCCs [ 60 , 61 , 62 , 63 ].…”