title: Variable expression of the forgotten oncogene E5 in HPV-positive oropharyngeal cancer.
abstract: BACKGROUND
  The role of the HPV E6/E7 oncogenes in head and neck squamous cell cancer (HNSCC) has been studied extensively, but the role of the viral E5 protein remains poorly understood. Studies in cervical cancer indicate that E5 increases epidermal growth factor receptor (EGFR) recycling to the cell surface and enhances growth factor signal transduction.
  
  
  OBJECTIVE
  This study was designed to examine the relationship between HPV E5, EGFR, and survival in HPV-positive HNSCC.
  
  
  METHODS
  A retrospective search of the London Health Sciences Centre pathology database was performed to identify oropharyngeal cancer samples. HPV E5 and EGFR expression was measured by reverse transcriptase real-time PCR.
  
  
  RESULTS
  The majority of oropharyngeal tumor samples (59/82, 72%) were HPV-16 positive. Among the HPV-positive tumors, highly variable E5 expression was detected from early polycistronic transcripts. Tumors with high E5 expression levels had significantly higher EGFR levels (p=0.03). High E5 levels were correlated with improved recurrence-free survival, but not overall survival (p=0.02 and 0.71, respectively), whereas high EGFR was strongly associated with decreased recurrence-free and overall survival (p<0.001 and 0.006 respectively). Multivariate analysis revealed E5 and EGFR to be the strongest predictors of recurrence-free survival (p<0.01).
  
  
  CONCLUSIONS
  HPV E5-encoded transcripts are variably expressed in HPV-positive HNSCC and this is correlated with EGFR expression in HPV-positive OPC. However, E5 and EGFR independently predict recurrence-free survival in opposing manners. These findings require further validation to determine if E5 and EGFR are useful biomarkers to stratify treatment intensity for patients with HPV-positive HNSCC.
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Um
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Neil
authors.initials: N
authors.lastname: Mundi
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada; Department of Oncology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Yoo
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Department of Oncology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Palma
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada; Department of Oncology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fung
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada; Department of Oncology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: MacNeil
authors.affiliation: Department of Pathology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Bret
authors.initials: B
authors.lastname: Wehrli
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Department of Oncology, The University of Western Ontario, London, Ontario, Canada; Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Department of Oncology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Barrett
authors.affiliation: Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada; London Regional Cancer Program, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Department of Oncology, The University of Western Ontario, London, Ontario, Canada; Department of Pathology, The University of Western Ontario, London, Ontario, Canada. Electronic address: Anthony.Nichols@lhsc.on.ca.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Nichols
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008131:London; D008297:Male; D008875:Middle Aged; D015513:Oncogene Proteins / Q000096:biosynthesis*; D009959:Oropharyngeal Neoplasms / Q000401:mortality / Q000473:pathology / Q000821:virology*; D027383:Papillomaviridae / Q000235:genetics*; D030361:Papillomavirus Infections / Q000150:complications* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D012189:Retrospective Studies; D016019:Survival Analysis; D014764:Viral Proteins / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D015513:Oncogene Proteins; D014764:Viral Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: E5; EGFR; Human papillomavirus; Oropharyngeal cancer; Viral oncogene