PDF file - 100K, Area under the time-dependent receiver operating characteristic (ROC) curves for overall and progression-free survival over 5 years follow-up. Curves are based on the clinical model (black) together with the viral markers (HPV16 DNA (red), viral load (green), HPV16 E6* RNA (blue), HPV16 CxCa-like RNA patterns (turquois) and HPV marker combination (purple)), with the cellular marker p16INK4a (yellow) or with the combination of p16INK4a and HPV16 DNA (gray). The horizontal line at 0.5 is included for reference corresponding to random guessing.
ARTICLE ABSTRACT
Oropharyngeal squamous cell carcinomas (OPSCC) that are associated with human papilloma virus (HPV) infection carry a more favorable prognosis than those that are HPV-negative. However, it remains unclear which biomarker(s) can reliably determine which OPSCC specimens are truly driven by HPV infection. In this study, we analyzed 199 fresh-frozen OPSCC specimens for HPV DNA, viral load, RNA expression patterns typical for cervical carcinomas (CxCaRNA+), and the HPV-targeted tumor suppressor protein p16INK4a as markers for HPV infection. In this set of specimens, there was a 49% prevalence of DNA for the cancer-associated HPV type 16 (HPV+). However, there was only a 16% prevalence of high viral load and only a 20% prevalence of CxCaRNA+, a marker of HPV16 carcinogenic activity. Among the CxCaRNA+ tumors, 78% of the specimens exhibited overexpression of p16INK4a, which also occurred in 14% of the HPV-negative tumors. Using a multivariate survival analysis with HPV negativity as the reference group, CxCaRNA+ as a single marker conferred the lowest risk of death [HR = 0.28, 95% confidence interval (CI), 0.13–0.61] from oropharyngeal cancer, closely followed by high viral load (HR = 0.32, 95% CI, 0.14–0.73). In contrast, a weaker inverse association was found for OPSCC that were HPV+ and p16INK4a high (HR = 0.55, 95% CI, 0.29–1.08). In summary, our findings argued that viral load or RNA pattern analysis is better suited than p16INK4a expression to identify HPV16-driven tumors in OPSCC patient populations. Cancer Res; 72(19); 4993–5003. ©2012 AACR.
