Abstract
To assess the relationship of E2 gene disruption with viral gene expression and clinical outcome in human papillomavirus (HPV) positive head and neck squamous cell carcinoma, we evaluated 31 oropharyngeal and 17 non-oropharyngeal HPV16 positive carcinomas using two PCR-based methods to test for disruption of E2, followed by Sanger sequencing. Expression of HPV16 E6, E7 and E2 transcripts, along with cellular ARF and INK4A, were also assessed by RT-qPCR. Associations between E2 disruption, E2/E6/E7 expression, and clinical outcome were evaluated by Kaplan-Meier analysis for loco-regional recurrence and disease-specific survival. The majority (n = 21, 68%) of HPV16 positive oropharyngeal carcinomas had an intact E2 gene, whereas the majority of HPV16 positive non-oropharyngeal carcinomas (n = 10, 59%) had a disrupted E2 gene. Three of the oropharyngeal tumors and two of the non-oropharyngeal tumors had deletions within E2. Detection of an intact E2 gene was associated with a higher DNA viral load and increased E2/E6/E7, ARF and INK4A expression in oropharyngeal tumors. Oropharyngeal carcinomas with an intact E2 had a lower risk of loco-regional recurrence (log-rank p = 0.04) and improved disease-specific survival (p = 0.03) compared to tumors with disrupted E2. In addition, high E7 expression was associated with lower risk of loco-regional recurrence (p = 0.004) as was high E6 expression (p = 0.006). In summary, an intact E2 gene is more common in HPV16 positive oropharyngeal than non-oropharyngeal carcinomas; the presence of an intact E2 gene is associated with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome compared to patients with a disrupted E2 gene in oropharyngeal cancer.
Highlights
Each year head and neck squamous cell carcinoma (HNSCC) accounts for 550,000 cancer cases worldwide, resulting in 300,000 deaths [1]
We evaluated the status of the E2 gene by directly testing for E2 disruption in HPV16 positive oropharyngeal squamous cell carcinomas (OPSCCs) and non-OP HNSCC tumors to assess the relationship between E2 disruption to viral oncogene expression, host gene expression and clinical outcome
Based on our data showing that the presence of an intact E2 gene was associated with high E6 and E7 expression in OPSCC, and that HPV16 positive OPSCC with disrupted E2 had poorer clinical outcomes compared to HPV16 positive OPSCC with intact E2, we evaluated if expression of the E6 and E7 oncogenes was associated with clinical outcome
Summary
Each year head and neck squamous cell carcinoma (HNSCC) accounts for 550,000 cancer cases worldwide, resulting in 300,000 deaths [1]. HPV16 is one such oncogenic, or high-risk type, found in over 90% of HPV positive oropharyngeal squamous cell carcinomas (OPSCCs) [4]. Inhibition of pRb activity by E7 is in turn associated with overexpression of the cell cycle regulator p16, and p16 immunohistochemistry has been used as a surrogate test for HPV infection in OPSCC [5,6,11,12,13]. The p16 transcript, p16INK4A, is transcribed from the CDKN2A locus, which encodes an alternative transcript p14ARF Both p16INK4A and p14ARF are tumor suppressors [14] and over expression of both transcripts has been associated with HPV status in OPSCC [15]
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