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Updated: Apr 6, 2026
Merkel Cell Polyomavirus Infection and Detection
Published on: February 7, 2019
The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma
Paul William Harms1,2,3, Pankaj Vats1,4, Monique Elise Verhaegen3
1Michigan Center for Translational Pathology, University of Michigan Medical School.
Abstract:
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study, we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n = 16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 ± 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 ± 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways.
Insights
Merkel cell carcinoma (MCC) has two distinct molecular pathways. MCPyV-negative MCC shows high mutation burden and UV damage, while MCPyV-positive MCC has low mutation burden.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer.
- Merkel cell polyomavirus (MCPyV) is implicated in some MCC cases.
- The molecular drivers of MCPyV-negative MCC remain largely unknown.
Purpose of the Study:
- To investigate the molecular pathogenesis of MCPyV-negative MCC.
- To compare the genomic landscape of MCPyV-negative and MCPyV-positive MCC.
Main Methods:
- Integrative sequencing of 16 MCC cases (2 MCPyV-negative, 14 validation).
- Analysis of mutations, mutation burden, and mutational signatures.
Main Results:
- Identified activating oncogene mutations (HRAS) and loss-of-function mutations (PRUNE2, NOTCH) in MCPyV-negative MCC.
- MCPyV-negative MCC exhibited high mutation burden with a UV signature (85% C>T transitions).
- MCPyV-positive MCC had low mutation burden and lacked a UV signature.
Conclusions:
- Suggests a dichotomy in MCC tumorigenesis: viral-dependent (MCPyV-positive) versus UV-dependent (MCPyV-negative).
- Reveals novel genetic alterations in MCPyV-negative MCC, including HRAS, PRUNE2, and NOTCH mutations.
