Circulating HPV DNA as a Prediagnostic Marker of Oropharyngeal Cancer

项目总结 人乳头瘤病毒感染的口咽癌(HPV-OPC)是头颈部癌症的一种，其发病率在#年迅速上升。 美国(US)。HPV-OPC最近超过宫颈癌，成为最常见的HPV相关恶性肿瘤。 与宫颈癌不同，目前还没有HPV-OPC的早期检测方法。人乳头瘤病毒16型E6抗体阳性 被认为是一种有希望的HPV-OPC早期生物标志物。我们小组以前的工作表明，HPV16E6抗体 在高达90%的HPV-OPC患者中存在，并在确诊前10年以上出现。然而，鉴于 在HPV16E6血清转换和癌症诊断之间存在较长的滞后时间，HPV16E6血清阳性的个体可能需要 在癌症临床可诊断之前，进行了十年或更长时间的跟踪调查。因此，早期发现的生物标记物表明 在考虑将HPV16E6抗体检测用于临床之前，需要考虑是否存在肿瘤。流通中 肿瘤(CT)HPV DNA检测是检测HPV-OPC的一种有前景的标志物。我们小组的工作证明了 诊断时，ctHPVDNA对HPV-OPC的敏感性为98.4%，特异性为98.6%。CtHPVDNA的研究进展 重点介绍了ctHPVDNA在诊断HPV-OPC和监测治疗后复发方面的应用。至 迄今为止，ctHPVDNA用于早期检测HPV-OPC的潜力尚未被探索。评估的主要障碍 在诊断前环境中的ctHPVDNA是迄今为止开发的分析需要大量的血液(&gt；1ml)，这具有 排除了前瞻性队列中的嵌套研究，因为在HPV-OPC诊断之前收集的血液样本是 有限而珍贵。利用我们在ctdna方面的经验，我们重新优化了基于液滴数字聚合酶链式反应(DdPCR)的 小量档案标本中ctHPVDNA的检测方法。这项研究的目的是进行第一次 诊断前评估ctHPVDNA动力学并将其与HPV16 E6进行比较的大型研究 血清阳性。将在前列腺癌、肺腺癌、结直肠癌和卵巢(PLCO)内进行嵌套病例对照研究 癌症筛查试验，这是一项前瞻性队列研究，涵盖了美国各地的154,935名中年男性和女性。Pre- 81例OPC患者和162名配对对照(1：2)的诊断血液样本将进行ctHPVDNA检测。全部为序列号 来自ctHPVDNA阳性病例的样本也将进行测试，以评估该标志物在诊断前的动力学。我们 假设ctHPVDNA将在癌症诊断之前被检测到，并且ctHPVDNA将比 HPV16E6血清阳性。这一建议是创新的，因为使用了一种专门针对 少量存档标本，这将使我们能够进行第一次研究，以评估ctHPVDNA在前 诊断设置。这项研究可能会带来更好的早期检测HPV-OPC的方法，并直接回应 国家癌症研究所(NCI)和国家牙科和牙科研究所联合发布的特殊利益通知 颅面研究(NIDCR)：推进头颈部癌症早期检测研究(AHEAD)；NOT-CA-20-031。

PROJECT SUMMARY The incidence of HPV-driven oropharyngeal cancer (HPV-OPC), a type of head and neck cancer, is rapidly increasing in the United States (US). HPV-OPC recently surpassed cervical cancer as the most common HPV-associated malignancy. Unlike cervical cancer, there are no methods of early detection for HPV-OPC. HPV16 E6 antibody positivity has been identified as a promising early biomarker of HPV-OPC. Previous work from our group showed that HPV16 E6 antibodies are present in up to 90% of HPV-OPC patients and appear more than 10 years prior to diagnosis. However, given the long lag time between HPV16 E6 seroconversion and cancer diagnosis, HPV16 E6 seropositive individuals may need to be followed for a decade or more before the cancer is clinically diagnosable. Thus, early detection biomarkers that indicate the presence or absence of tumor are needed before considering HPV16 E6 antibody testing for clinical use. Circulating tumor (ct)HPV DNA detection is a promising marker for detection of HPV-OPC. Work from our group has demonstrated that ctHPVDNA is 98.4% sensitive and 98.6% specific for HPV-OPC at the time of diagnosis. Prior studies of ctHPVDNA have focused on the utility of ctHPVDNA for diagnosing HPV-OPC and monitoring for recurrence post-treatment. To date, the potential of ctHPVDNA for early detection of HPV-OPC has not been explored. A major barrier to evaluating ctHPVDNA in a pre-diagnostic setting is that assays developed to date require a high volume of blood (>1ml), which has precluded nested studies in prospective cohorts given that blood samples collected prior to HPV-OPC diagnosis are limited and precious. Leveraging our experience in ctDNA, we have re-optimized our droplet digital PCR (ddPCR) based assay for detecting ctHPVDNA in small volumes of archived specimen. The objective of this study is to conduct the first large study to evaluate the kinetics of ctHPVDNA prior to diagnosis and to compare this biomarker to HPV16 E6 seropositivity. A nested case-control study will be conducted within the Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial, a prospective cohort study of 154,935 middle aged men and women from across the US. Pre- diagnostic blood samples from 81 OPC cases and 162 matched controls (1:2 ratio) will be tested for ctHPVDNA. All serial samples from ctHPVDNA positive cases will also be tested to evaluate kinetics of the marker leading up to diagnosis. We hypothesize that ctHPVDNA will be detectable prior to cancer diagnosis and that ctHPVDNA will be more sensitive than HPV16 E6 seropositivity. This proposal is innovative given the use of a novel ctHPVDNA assay specifically optimized for small volumes of archived specimen, which will allow us to conduct the first study to evaluate ctHPVDNA in a pre- diagnostic setting. This research may lead to better methods for early detection of HPV-OPC and directly responds to the joint Notice of Special Interest issued by the National Cancer Institute (NCI) and National Institute for Dental and Craniofacial Research (NIDCR): Advancing Head and Neck Cancer Early Detection Research (AHEAD); NOT-CA-20-031.