Variable expression of the forgotten oncogene E5 in HPV-positive oropharyngeal cancer

Sung Ho Um; Neil Mundi; John Yoo; David A Palma; Kevin Fung; Danielle MacNeil; Bret Wehrli; Joe S Mymryk; John W Barrett; Anthony C Nichols

doi:10.1016/j.jcv.2014.06.019

Variable expression of the forgotten oncogene E5 in HPV-positive oropharyngeal cancer

J Clin Virol. 2014 Sep;61(1):94-100. doi: 10.1016/j.jcv.2014.06.019. Epub 2014 Jun 30.

Authors

Affiliations

¹ Department of Otolaryngology Head & Neck Surgery, The University of Western Ontario, London, Ontario, Canada.
² 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.
³ 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.
⁴ Department of Pathology, The University of Western Ontario, London, Ontario, Canada.
⁵ 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.
⁶ 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.
⁷ 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.

PMID: 25027574
DOI: 10.1016/j.jcv.2014.06.019

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.

Study design: 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.

Keywords: E5; EGFR; Human papillomavirus; Oropharyngeal cancer; Viral oncogene.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Biomarkers / analysis
ErbB Receptors / biosynthesis*
Female
Gene Expression Profiling*
Humans
London
Male
Middle Aged
Oncogene Proteins / biosynthesis*
Oropharyngeal Neoplasms / mortality
Oropharyngeal Neoplasms / pathology
Oropharyngeal Neoplasms / virology*
Papillomaviridae / genetics*
Papillomavirus Infections / complications*
Papillomavirus Infections / mortality
Papillomavirus Infections / pathology
Papillomavirus Infections / virology*
Retrospective Studies
Survival Analysis
Viral Proteins / biosynthesis

Substances

Biomarkers
Oncogene Proteins
Viral Proteins
EGFR protein, human
ErbB Receptors