Merkel cell carcinoma update: the case for two tumours

Nirenberg, Alexander; Steinman, Howard K.; Dixon, John; Dixon, Anita

doi:10.1111/jdv.16158

Cited by 20 publications

(49 citation statements)

References 42 publications

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“…The possible role of HPyV6 in at least some cases adds to the number of cutaneous tumors, which are associated with viruses, which also include conventional squamous carcinoma (human papilloma virus) and some cases of Merkel cell carcinoma (Merkel cell polyomavirus). 25 Regarding the treatment of solitary KAs, particularly in view the findings of Carr and Houghton, 14 complete removal of the lesion is recommended. Surgical treatment with fullthickness excision is often recommended.…”

Section: Discussionmentioning

confidence: 99%

Keratoacanthoma: Update on the Debate

Nirenberg

Steinman

Dixon

2020

The American Journal of Dermatopathology

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Section: Discussionmentioning

confidence: 99%

Keratoacanthoma: Update on the Debate

Nirenberg

Steinman

Dixon

2020

The American Journal of Dermatopathology

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“…The cell of origin of MCC is unknown. In fact, VP- and UV-MCCs may originate from different cells or even different tissue types [ 6 , 7 ]. Recent observations indicate that cancer epigenomes, particularly DNA-methylation marks, result from both, transformation-specific changes and epigenetic patterns already present in the cell of origin that was transformed into a neoplastic cell [ 18 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…The cellular origin of MCC is unknown. Besides B cells and Merkel cells, the most prominent hypothesis discusses a mesenchymal origin of VP-MCCs and an epithelial origin of UV-MCCs [ 6 , 7 ]. UV-light exposure of keratinocytes explaining the accumulated UV-light mutations and reports of mixed squamous cell carcinoma (SCC)/UV-MCC tumors argue toward an epithelial origin of UV-MCC [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Expanding on our finding that dermal fibroblasts support the full infectious cycle within the human skin, additional models have been proposed to link MCPyV infection to MCC tumorigenesis [ 77 , 97 , 117 ]. One of the hypotheses is that dermal fibroblasts act as the origin cell for MCC: under yet-to-be-discovered conditions, MCPyV oncogenes expressed in infected HDFs may induce gene expression patterns as observed in MCC to trigger tumor development.…”

Section: Cell Of Origin For MCCmentioning

confidence: 99%

Merkel cell polyomavirus and associated Merkel cell carcinoma

Yang

You

2022

Tumour Virus Research

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Merkel cell polyomavirus (MCPyV) is a ubiquitous skin infection that can cause Merkel cell carcinoma (MCC), a highly lethal form of skin cancer with a nearly 50% mortality rate. Since the discovery of MCPyV in 2008, great advances have been made to improve our understanding of how the viral encoded oncoproteins contribute to MCC oncogenesis. However, our knowledge of the MCPyV infectious life cycle and its oncogenic mechanisms are still incomplete. The incidence of MCC has tripled over the past two decades, but effective treatments are lacking. Only recently have there been major victories in combatting metastatic MCC with the application of PD-1 immune checkpoint blockade. Still, these immune-based therapies are not ideal for patients with a medical need to maintain systemic immune suppression. As such, a better understanding of MCPyV's oncogenic mechanisms is needed in order to develop more effective and targeted therapies against virus-associated MCC. In this review, we discuss current areas of interest for MCPyV and MCC research and the progress made in elucidating both the natural host of MCPyV infection and the cell of origin for MCC. We also highlight the remaining gaps in our knowledge on the transcriptional regulation of MCPyV, which may be key to understanding and targeting viral oncogenesis for developing future therapies.

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Merkel cell carcinoma update: the case for two tumours

Cited by 20 publications

References 42 publications

Keratoacanthoma: Update on the Debate

Keratoacanthoma: Update on the Debate

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

Merkel cell polyomavirus and associated Merkel cell carcinoma

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