Different cellular p16 INK4a localisation may signal different survival outcomes in head and neck cancer

N. Zhao, M. K. Ang, X. Y. Yin, M. R. Patel, K. Fritchie, L. Thorne, K. L. Muldrew, M. C. Hayward, W. Sun, M. D. Wilkerson, B. S. Chera, T. Hackman, A. M. Zanation, J. E. Grilley-Olson, M. E. Couch, W. W. Shockley, M. C. Weissler, C. G. Shores, W. K. Funkhouser, A. F. OlshanD. N. Hayes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Background: Recently, the management of head and neck squamous cell carcinoma (HNSCC) has focused considerable attention on biomarkers, which may influence outcomes. Tests for human papilloma infection, including direct assessment of the virus as well as an associated tumour suppressor gene p16, are considered reproducible. Tumours from familial melanoma syndromes have suggested that nuclear localisation of p16 might have a further role in risk stratification. We hypothesised p16 staining that considered nuclear localisation might be informative for predicting outcomes in a broader set of HNSCC tumours not limited to the oropharynx, human papilloma virus (HPV) status or by smoking status.Methods:Patients treated for HNSCC from 2002 to 2006 at UNC (University of North Carolina at Chapel Hill) hospitals that had banked tissue available were eligible for this study. Tissue microarrays (TMA) were generated in triplicate. Immunohistochemical (IHC) staining for p16 was performed and scored separately for nuclear and cytoplasmic staining. Human papilloma virus staining was also carried out using monoclonal antibody E6H4. p16 expression, HPV status and other clinical features were correlated with progression-free (PFS) and overall survival (OS).Results:A total of 135 patients had sufficient sample for this analysis. Median age at diagnosis was 57 years (range 20-82), with 68.9% males, 8.9% never smokers and 32.6% never drinkers. Three-year OS rate and PFS rate was 63.0% and 54.1%, respectively. Based on the p16 staining score, patients were divided into three groups: high nuclear, high cytoplasmic staining group (HN), low nuclear, low cytoplasmic staining group (LS) and high cytoplasmic, low nuclear staining group (HC). The HN and the LS groups had significantly better OS than the HC group with hazard ratios of 0.10 and 0.37, respectively, after controlling for other factors, including HPV status. These two groups also had significantly better PFS than the HC staining group. This finding was consistent for sites outside the oropharynx and did not require adjustment for smoking status.Conclusion:Different p16 protein localisation suggested different survival outcomes in a manner that does not require limiting the biomarker to the oropharynx and does not require assessment of smoking status.

Original languageEnglish
Pages (from-to)482-490
Number of pages9
JournalBritish Journal of Cancer
Issue number3
StatePublished - 24 Jul 2012
Externally publishedYes


  • HPV infection
  • p16 cellular localisation
  • tissue microarray


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