The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma

Cancer Res. 2015 Sep 15;75(18):3720-3727. doi: 10.1158/0008-5472.CAN-15-0702. Epub 2015 Aug 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Merkel Cell / genetics*
  • Carcinoma, Merkel Cell / secondary
  • Carrier Proteins / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / radiation effects
  • DNA Mutational Analysis / methods
  • DNA, Neoplasm / genetics
  • Exome / genetics
  • Gene Expression Profiling
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Merkel cell polyomavirus
  • Middle Aged
  • Mutation*
  • Neoplasm Proteins / genetics*
  • Neoplasms, Radiation-Induced / genetics
  • Nerve Tissue Proteins / genetics
  • Oncogene Proteins, Fusion / genetics
  • Oncogenes*
  • Parotid Neoplasms / genetics
  • Parotid Neoplasms / secondary
  • Point Mutation
  • Receptors, Notch / genetics
  • Skin Neoplasms / genetics*
  • Ultraviolet Rays / adverse effects


  • Carrier Proteins
  • DNA, Neoplasm
  • GPRIN2 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Oncogene Proteins, Fusion
  • PRUNE2 protein, human
  • Receptors, Notch