Circulating HPV DNA as a Prediagnostic Marker of Oropharyngeal Cancer

循环 HPV DNA 作为口咽癌的诊断前标志物

• 批准号: 10526797
• 负责人: Daniel Faden
• 金额: $ 28.38万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-29 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526797
• 关键词: Aftercare; Antibodies; Archives; Biological Assay; Biological Markers; Blood; Blood Volume; Blood specimen; Cancer Patient; Clinical; Cohort Studies; Colorectal; Communities; Custom; DNA; Data; Detection; Development; Diagnosis; Diagnostic; Early Diagnosis; Genotype; Gold; HPV oropharyngeal cancer; Head and Neck Cancer; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papillomavirus 16; Incidence; Individual; Joints; Kinetics; Lead; Logistic Regressions; Lung; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of nasopharynx; Methods; Monitor; Monitoring for Recurrence; Morbidity - disease rate; National Cancer Institute; National Institute of Dental and Craniofacial Research; Nested Case-Control Study; Ovarian; Patients; Plasma; Prospective cohort; Prospective cohort study; Prostate; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Research; Risk; Sampling; Screening for cancer; Specificity; Testing; Time; Tumor Burden; United States; Virus; Woman; Work; base; biological specimen archives; cancer cell; cancer diagnosis; cancer recurrence; case control; cohort; digital; early detection biomarkers; experience; high risk; innovation; interest; liquid biopsy; malignant oropharynx neoplasm; men; middle age; novel; response; screening; seroconversion; seropositive; tool; tumor; validation studies; viral DNA; viral detection; virtual

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.

项目摘要 HPV驱动的口咽癌（HPV-OPC）的发生率是一种类型的头颈癌，正在迅速增加 美国（美国）。 HPV-OPC最近超越了宫颈癌，是最常见的HPV相关恶性肿瘤。 与宫颈癌不同，HPV-OPC没有早期检测方法。 HPV16 E6抗体阳性已经 被确定为HPV-OPC的有前途的早期生物标志物。我们小组的先前工作表明HPV16 E6抗体 最多有90％的HPV-OPC患者出现，并在诊断前10年出现。但是，给定 HPV16 E6血清转化与癌症诊断之间的滞后时间，HPV16 E6血清阳性个体可能需要是 在癌症可以诊断出癌症之前，紧随其后的十年或更多。因此，提示的早期检测生物标志物 在考虑HPV16 E6抗体测试以进行临床使用之前，需要存在或不存在肿瘤。循环 肿瘤（CT）HPV DNA检测是用于检测HPV-OPC的有希望的标记。我们小组的工作已证明 诊断时，该CTHPVDNA的灵敏度为98.4％，针对HPV-OPC的98.6％。 cthpvDNA的先前研究 专注于CTHPVDNA诊断HPV-OPC和监测后处理后的效用。到 日期，尚未探索CTHPVDNA早期检测HPV-OPC的潜力。评估的主要障碍 在诊断前的环境中的CTHPVDNA是迄今为止开发的测定需要大量的血液（> 1ml） 鉴于在HPV-OPC诊断之前收集的血液样本是，排除了前瞻性人群中的嵌套研究 有限而珍贵。利用我们在ctDNA的经验，我们重新优化了基于液滴数字PCR（DDPCR） 用于在少量存档标本中检测CTHPVDNA的测定。这项研究的目的是进行第一个 大型研究在诊断之前评估CTHPVDNA的动力学，并将该生物标志物与HPV16 E6进行比较 血清阳性。嵌套的病例对照研究将在前列腺肺结直肠和卵巢（PLCO）内进行 癌症筛查试验，一项对来自美国各地的154,935名中年男女的前瞻性队列研究。 pre 将测试来自81例OPC病例和162个匹配对照的诊断血液样本（1：2）的CTHPVDNA。全部序列 CTHPVDNA阳性病例的样品还将进行测试，以评估导致诊断的标记动力学。我们 假设CTHPVDNA将在癌症诊断之前被检测到，并且CTHPVDNA将比 HPV16 E6血清阳性。考虑到专门针对专门优化的新型CTHPVDNA分析，该建议具有创新性 少量的存档标本，这将使我们能够进行首次研究，以评估cthpvdna 诊断设置。这项研究可能会导致更好的方法来早日检测HPV-OPC，并直接对 美国国家癌症研究所（NCI）和国家牙科研究所发出的特别利益通知 颅面研究（NIDCR）：前进的头颈癌早期检测研究（前方）；非CA-20-031。