title: Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma.
abstract: OBJECTIVE
  Merkel cell carcinoma (MCC) is rare skin cancer that is often associated with Merkel cell polyomavirus (MCPyV) infection. Polyomaviruses repress tumor suppressor proteins, thus influencing cell-cycle progression, but the effect of MCPyV on the key cell-cycle regulating proteins is poorly understood.
  
  
  METHODS
  We evaluated expression of the MCPyV large T-antigen (LTA), Ki-67, and the key putative tumor suppressor proteins, the retinoblastoma protein (RB and phospho-RB) and p53, and their regulatory proteins (cyclin D1, cyclin E, p16, p21, p27, and MDM2) by using immunohistochemistry from tumors of 91 MCC patients identified from a population-based nationwide cohort. Tumor MCPyV DNA was measured by using quantitative PCR, and TP53 mutations were identified with sequencing.
  
  
  RESULTS
  MCPyV LTA expression was strongly associated with presence of MCPyV DNA in tumor, and it was almost invariably associated with tumor RB expression (P < 0.0001 for both comparisons). Both MCC LTA and RB expression were strongly associated with favorable MCC-specific and overall survival in univariable analyses (P ≤ 0.01 for all four analyses). Presence of MCPyV LTA was also associated with the female gender, the intermediate type of tumor histology, location of the tumor in a limb, cell proliferation rate, and absence of p53 expression. TP53 mutations were detected only in MCPyV DNA-negative tumors.
  
  
  CONCLUSIONS
  MCPyV DNA-positive MCC has several clinical and molecular features that differ from MCPyV DNA-negative cancers. MCPyV-associated MCCs express RB, but may not harbor TP53 mutations. These findings provide further support that MCPyV causes the majority of MCCs.
authors.affiliation: Laboratory of Molecular Oncology, Biomedicum Helsinki, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Sihto
authors.forename: Heli
authors.initials: H
authors.lastname: Kukko
authors.forename: Virve
authors.initials: V
authors.lastname: Koljonen
authors.forename: Risto
authors.initials: R
authors.lastname: Sankila
authors.forename: Tom
authors.initials: T
authors.lastname: Böhling
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000821:virology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D008297:Male; D059965:Merkel cell polyomavirus; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D027601:Polyomavirus Infections / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000821:virology*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000821:virology*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014412:Tumor Virus Infections / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000821:virology*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D018797:Cell Cycle Proteins; D004279:DNA, Viral; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53