Abstract
Purpose Immunohistochemical staining of p16 is routinely used as a surrogate for human papilloma virus infection in oropharyngeal squamous cell carcinoma; however, its relevance and association with oral squamous cell carcinoma (OSCC) outcomes require further investigation. We used fluorescence immunohistochemistry (F-IHC) and automated quantitative analysis (AQUA) to evaluate p16 expression in OSCC samples. We compared the transcriptomes of patients with high p16 expression (p16+) and patients with low p16 expression (p16−). Materials and methods 56 OSCC patients were included in the study. Clinical data were obtained from the Alberta Cancer Registry and chart review. p16 protein expression was quantified using F-IHC and AQUA on tissue microarrays containing triplicate cores of formalin-fixed paraffin-embedded (FFPE) tissue. Kaplan–Meier curves were used to analyze the association between p16 expression and 5-year disease-specific survival (DSS). The Illumina Whole Genome cDNA-mediated annealing, selection, extension and ligation (WG-DASL) assay was employed to assess gene expression. Results High p16 expression was associated with significantly improved DSS ( p = 0.01). 68 genes were differentially regulated in p16+ versus p16− samples. Pathway enrichment analysis revealed that the p16+ group overexpressed genes involved in the immune response, cell adhesion, mesoderm and ectoderm development and blood vessel morphogenesis. The improved prognosis observed in p16+ patients may be explained by the increased expression of genes encoding tumor suppressors such as SPINT2 and NEFH, T cell glycoprotein CD2, transcription factor ELF3, ERAP1/2 aminopeptidases and downregulation of oncogenes such as a Ras homolog, NRIP3 and a gene implicated in metastasis (FABP4). Conclusions We identified distinct gene expression patterns in OSCC patients based on their p16 expression status that may explain the improved prognosis of p16+ patients. The differential expression of several candidate genes is being confirmed by real-time PCR. The genes identified using this high-throughput technique provide mechanistic insights and potential therapeutic targets in OSCC.
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