title: Presence of human polyomavirus 6 in mutation-specific BRAF inhibitor-induced epithelial proliferations.
abstract: OBJECTIVE
  A frequent adverse effect of mutation-specific BRAF inhibitor therapy is the induction of epithelial proliferations including cutaneous squamous cell carcinomas. To date, the only factor identified contributing to their development is the activation of the mitogen-activated signal transduction cascade by mutations in the RAS genes. However, these mutations explain only 60% of the tumors; hence, it is important to identify what is causing the remaining tumors.
  
  
  OBJECTIVE
  To test for the presence of human papillomaviruses (HPVs) and the recently identified human polyomaviruses (HPyVs), Merkel cell polyomavirus (MCPyV), and trichodysplasia spinulosa-associated polyomavirus (TSPyV), as well as HPyV-6, HPyV-7, HPyV-9, and HPyV-10, in epithelial proliferations occurring after BRAF inhibitor therapy to determine whether these oncogenic viruses may contribute to BRAF inhibitor-induced skin tumors.
  
  
  METHODS
  Retrospective study at a university hospital in Austria of epithelial proliferations that developed in patients with melanoma after initiation of treatment with the BRAF inhibitor vemurafenib. Samples were analyzed for (1) presence of the most frequently observed RAS mutations by SNaPshot technology, (2) detection of the viruses by real-time polymerase chain reaction, and (3) presence of capsid proteins of the most abundantly detected virus by immunohistochemical analysis.
  
  
  METHODS
  RAS mutational status, as well as HPV and HPyV presence, in BRAF inhibitor-induced epithelial proliferations.
  
  
  RESULTS
  Eighteen biopsy samples from 6 patients were retrieved from our hospital's archive. We identified RAS mutations in 10 (62%) of the 16 samples with clear results. DNA of HPyV-9, HPyV-10, and TSPyV were virtually absent in the samples. MCPyV DNA was present in 13 of 18 samples, and HPV, HPyV-6, and HPyV-7 DNA were present in all samples. In general, the amount of DNA encoding the latter viruses was rather low, with the exception of HPyV-6 in several samples of 1 individual patient. Notably, the relevance of the presence of HPyV-6 in the epithelial proliferation was underlined by immunohistochemical detection of the core protein VP1 of HPyV-6.
  
  
  CONCLUSIONS
  The presence of both high HPyV-6 DNA load and VP1 protein suggests that polyomaviruses may contribute to the epithelial proliferations observed in patients receiving BRAF inhibitor therapy, albeit the relative impact as compared with that of RAS mutations appears circumstantial.
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria2Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Schrama
authors.affiliation: Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Leopold
authors.initials: L
authors.lastname: Groesser
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Selma
authors.initials: S
authors.lastname: Ugurel
authors.affiliation: Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hafner
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland.
authors.forename: Diana V
authors.initials: DV
authors.lastname: Pastrana
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Buck
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cerroni
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Theiler
authors.affiliation: Department of Dermatology, Medical University of Graz, Graz, Austria.
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000821:virology; D004279:DNA, Viral / Q000302:isolation & purification; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D027383:Papillomaviridae / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000473:pathology / Q000821:virology; D011120:Polyomavirus / Q000302:isolation & purification; D027601:Polyomavirus Infections / Q000453:epidemiology* / Q000473:pathology / Q000821:virology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000821:virology*; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D014412:Tumor Virus Infections / Q000453:epidemiology* / Q000473:pathology / Q000821:virology; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D004279:DNA, Viral; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf