Molecular Biology Laboratory, Department of Otolaryngology, Head and Neck Surgery, Heidelberg University, Heidelberg, Germany.
Cancer Res. 2012 Oct 1;72(19):4993-5003. doi: 10.1158/0008-5472.CAN-11-3934. Epub 2012 Sep 18.
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 p16(INK4a) 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 p16(INK4a), 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 p16(INK4a) 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 p16(INK4a) expression to identify HPV16-driven tumors in OPSCC patient populations.
口咽鳞状细胞癌（OPSCC）与人类乳头瘤病毒（HPV）感染相关，其预后优于 HPV 阴性的 OPSCC。然而，目前仍不清楚哪种生物标志物可以可靠地确定哪些 OPSCC 标本确实受到 HPV 感染的驱动。在这项研究中，我们分析了 199 例新鲜冷冻的 OPSCC 标本的 HPV DNA、病毒载量、典型的宫颈癌 RNA 表达模式（CxCaRNA(+)）以及 HPV 靶向肿瘤抑制蛋白 p16(INK4a)，作为 HPV 感染的标志物。在这一组标本中，有 49%的癌症相关 HPV 型 16（HPV(+)）存在 DNA。然而，高病毒载量的发生率只有 16%，CxCaRNA(+)的发生率只有 20%，CxCaRNA(+)是 HPV16 致癌活性的标志物。在 CxCaRNA(+)肿瘤中，78%的标本表现出 p16(INK4a)的过表达，这也发生在 14%的 HPV 阴性肿瘤中。使用 HPV 阴性作为参考组的多变量生存分析，作为单一标志物的 CxCaRNA(+)可将因口咽癌而死亡的风险降低至最低[HR=0.28，95%置信区间（CI），0.13-0.61]，紧随其后的是高病毒载量（HR=0.32，95%CI，0.14-0.73）。相比之下，HPV(+)和 p16(INK4a)高的 OPSCC 呈较弱的负相关（HR=0.55，95%CI，0.29-1.08）。综上所述，我们的研究结果表明，病毒载量或 RNA 模式分析比 p16(INK4a)表达更适合于识别 OPSCC 患者人群中 HPV16 驱动的肿瘤。
