Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

Mod Pathol. 2014 Aug;27(8):1073-87. doi: 10.1038/modpathol.2013.235. Epub 2014 Jan 10.


Merkel cell carcinoma is a highly aggressive cutaneous neuroendocrine tumor that has been associated with Merkel cell polyomavirus in up to 80% of cases. Merkel cell polyomavirus is believed to influence pathogenesis, at least in part, through expression of the large T antigen, which includes a retinoblastoma protein-binding domain. However, there appears to be significant clinical and morphological overlap between polyomavirus-positive and polyomavirus-negative Merkel cell carcinoma cases. Although much of the recent focus of Merkel cell carcinoma pathogenesis has been on polyomavirus, the pathogenesis of polyomavirus-negative cases is still poorly understood. We hypothesized that there are underlying human somatic mutations that unify Merkel cell carcinoma pathogenesis across polyomavirus status, and to investigate we performed whole exome sequencing on five polyomavirus-positive cases and three polyomavirus-negative cases. We found that there were no significant differences in the overall number of single-nucleotide variations, copy number variations, insertion/deletions, and chromosomal rearrangements when comparing polyomavirus-positive to polyomavirus-negative cases. However, we did find that the retinoblastoma pathway genes harbored a high number of mutations in Merkel cell carcinoma. Furthermore, the retinoblastoma gene (RB1) was found to have nonsense truncating protein mutations in all three polyomavirus-negative cases; no such mutations were found in the polyomavirus-positive cases. In all eight cases, the retinoblastoma pathway dysregulation was confirmed by immunohistochemistry. Although polyomavirus-positive Merkel cell carcinoma is believed to undergo retinoblastoma dysregulation through viral large T antigen expression, our findings demonstrate that somatic mutations in polyomavirus-negative Merkel cell carcinoma lead to retinoblastoma dysregulation through an alternative pathway. This novel finding suggests that the retinoblastoma pathway dysregulation leads to an overlapping Merkel cell carcinoma phenotype and that oncogenesis occurs through either a polyomavirus-dependent (viral large T antigen expression) or polyomavirus-independent (host somatic mutation) mechanism.

Publication types

  • Comparative Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Merkel Cell / chemistry
  • Carcinoma, Merkel Cell / genetics*
  • Carcinoma, Merkel Cell / virology
  • DNA Mutational Analysis / methods*
  • Exome*
  • Female
  • Genes, Retinoblastoma*
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • Male
  • Merkel cell polyomavirus / isolation & purification
  • Middle Aged
  • Mutation*
  • Phenotype
  • Polyomavirus Infections / genetics*
  • Polyomavirus Infections / metabolism
  • Polyomavirus Infections / virology
  • Retinoblastoma Protein / analysis
  • Retinoblastoma Protein / genetics*
  • Skin Neoplasms / chemistry
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / virology
  • Tumor Virus Infections / genetics*
  • Tumor Virus Infections / metabolism
  • Tumor Virus Infections / virology


  • Biomarkers, Tumor
  • Retinoblastoma Protein