Hibbert Julia, Halec Gordana, Baaken Dan, Waterboer Tim, Brenner Nicole
Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany.
Cancers (Basel). 2021 Jun 16;13(12):3010. doi: 10.3390/cancers13123010.
Antibodies against HPV16 early proteins have been shown to be promising biomarkers for the identification of HPV-driven oropharyngeal cancer (HPV-OPC) among OPC cases in multiple studies. A systematic literature search was performed to identify original research articles comparing HPV early antigen serology with established reference methods to determine molecular HPV tumor status. Random-effects models were used to calculate summary estimates for sensitivity and specificity of HPV16 E2, E6 and E7 serology for HPV-OPC. Subgroup analyses were performed to explore heterogeneity across studies and describe variables associated with test performance. We identified = 23 studies meeting all eligibility criteria and included these in the meta-analysis. E6 serology showed the best performance with pooled sensitivity and specificity estimates of 83.1% (95% confidence interval (CI) 72.5-90.2%) and 94.6% (95% CI 89.0-97.4%), respectively, while E2 and E7 serological assays were highly specific (E2: 92.5% (95% CI 79.1-97.6%); E7: 88.5% (95% CI 77.9-94.4%)) but moderately sensitive (E2: 67.8% (95% CI 58.9-75.6%); E7: 67.0% (95% CI 63.2-70.6%)). Subgroup analyses revealed increased pooled sensitivity for bacterially (89.9% (95% CI 84.5-93.6%)) vs. in vitro expressed E6 antigen (55.3% (95% CI 41.0-68.7%)), while both showed high specificity (95.2% (95% CI 93.0-96.7%) and 91.1% (95% CI 46.6-99.2%), respectively). Pooled specificity estimates for HPV16 E2, E6 and E7 serology were significantly lower in studies utilizing HPV DNA PCR as the only molecular reference method compared to those using a combination of any two reference methods (HPV DNA, RNA, in situ hybridization (ISH), p16 immunohistochemistry (IHC)), or histopathological reference methods (ISH or p16 IHC) as stand-alone marker. In conclusion, HPV16 E6 seropositivity is a highly sensitive and specific biomarker for HPV-OPC. However, its performance differs between serological assays and depends on molecular reference methods.
多项研究表明，针对人乳头瘤病毒16型（HPV16）早期蛋白的抗体有望成为在口咽癌（OPC）病例中识别HPV驱动的口咽癌（HPV-OPC）的生物标志物。我们进行了一项系统的文献检索，以确定将HPV早期抗原血清学与既定参考方法进行比较以确定分子HPV肿瘤状态的原创性研究文章。采用随机效应模型计算HPV16 E2、E6和E7血清学对HPV-OPC的敏感性和特异性的汇总估计值。进行亚组分析以探讨各研究间的异质性，并描述与检测性能相关的变量。我们确定了23项符合所有纳入标准的研究，并将其纳入荟萃分析。E6血清学表现最佳，汇总敏感性和特异性估计值分别为83.1%（95%置信区间（CI）72.5-90.2%）和94.6%（95%CI 89.0-97.4%），而E2和E7血清学检测具有高度特异性（E2：92.5%（95%CI 79.1-97.6%）；E7：88.5%（95%CI 77.9-94.4%）），但敏感性中等（E2：67.8%（95%CI 58.9-75.6%）；E7：67.0%（95%CI 63.2-70.6%））。亚组分析显示，与体外表达的E6抗原（55.3%（95%CI 41.0-68.7%））相比，细菌表达的E6抗原的汇总敏感性增加（89.9%（95%CI 84.5-93.6%）），而两者均显示出高特异性（分别为95.2%（95%CI 93.0-96.7%）和91.1%（95%CI 46.6-99.2%））。与使用任何两种参考方法（HPV DNA、RNA、原位杂交（ISH）、p16免疫组织化学（IHC））组合或组织病理学参考方法（ISH或p16 IHC）作为独立标志物的研究相比，在仅使用HPV DNA PCR作为唯一分子参考方法的研究中，HPV16 E2、E6和E7血清学的汇总特异性估计值显著更低。总之，HPV16 E6血清阳性是HPV-OPC的一种高度敏感和特异的生物标志物。然而，其性能在血清学检测之间存在差异，并取决于分子参考方法。
