title: Investigation of p16(INK4a) as a prognostic biomarker in oral epithelial dysplasia.
abstract: BACKGROUND
  Human papilloma virus is a risk factor for oropharyngeal cancer. Evidence for a similar aetiological role in the development of oral dysplasia or its transformation to oral cancer is not as clear. Meta-analyses estimate the prevalence of high-risk human papilloma virus (HPV) serotypes to be three times higher in pre-malignant lesions and cancer than in normal oral mucosa. However, this does not imply a causal relationship. Conflicting results are reported from the few studies examining the prognostic significance of HPV positivity in the development of oral cancer. We aimed to examine the ability of p16(INK4a) protein expression, a surrogate marker of HPV infection, to predict malignant progression in a large cohort of oral dysplasia patients.
  
  
  METHODS
  One hundred forty eight oral dysplasia cases underwent immunohistochemical analysis using a monoclonal antibody against p16(INK4a) . Clinical factors were also collated on each case. Slides were double scored independently by two trained observers. Univariate analyses using both logistic and Cox regression models were performed.
  
  
  RESULTS
  Thirty nine of 148 cases progressed to cancer. Ten of 148 cases (7%) were p16(INK4a) positive. High grade of dysplasia (P = 0.0002) and lesion morphology (P = 0.03) were found to be prognostic of malignant progression. p16(INK4a) score was not prognostic in this cohort (P = 0.29). This did not change with a time to event analysis (P = 0.24).
  
  
  CONCLUSIONS
  Few studies have assessed the aetiological role of HPV in cancer development from dysplastic lesions. Our study, using one of the largest cohorts of oral dysplasia, demonstrated a low rate of p16(INK4a) positivity and was unable to confirm a prognostic ability for this biomarker.
authors.affiliation: Institute of Head and Neck Studies and Education (InHANSE), Birmingham, UK; University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; University Hospital Coventry and Warwickshire, Coventry, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Nankivell
authors.forename: Hazel
authors.initials: H
authors.lastname: Williams
authors.forename: Keith
authors.initials: K
authors.lastname: Webster
authors.forename: David
authors.initials: D
authors.lastname: Pearson
authors.forename: Alec
authors.initials: A
authors.lastname: High
authors.forename: Kenneth
authors.initials: K
authors.lastname: MacLennan
authors.forename: Burcu
authors.initials: B
authors.lastname: Senguven
authors.forename: Christopher
authors.initials: C
authors.lastname: McConkey
authors.forename: Pamela
authors.initials: P
authors.lastname: Rabbitts
authors.forename: Hisham
authors.initials: H
authors.lastname: Mehanna
mesh_terms: D052685:Alphapapillomavirus / Q000502:physiology; D000911:Antibodies, Monoclonal; D015415:Biomarkers / Q000032:analysis; D002278:Carcinoma in Situ / Q000737:chemistry / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000473:pathology; D009062:Mouth Neoplasms / Q000737:chemistry* / Q000473:pathology; D030361:Papillomavirus Infections / Q000175:diagnosis; D011230:Precancerous Conditions / Q000737:chemistry* / Q000473:pathology; D011379:Prognosis
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: biomarker; human papilloma virus; oral dysplasia; p16; prognostic; progression