Circulating HPV DNA as a Prediagnostic Marker of Oropharyngeal Cancer

循环 HPV DNA 作为口咽癌的预诊断标志物

• 批准号: 10674048
• 负责人: Daniel Faden
• 金额: $ 14.73万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674048
• 关键词: Aftercare; Antibodies; Archives; Biological Assay; Biological Markers; Blood; Blood Volume; Blood specimen; Cancer Detection; Cancer Patient; Clinical; Cohort Studies; Colorectal; Communities; Custom; DNA; Data; Detection; Development; Diagnosis; Diagnostic; Early Diagnosis; Genotype; HPV oropharyngeal cancer; Head and Neck Cancer; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papillomavirus 16; Incidence; Individual; Joints; Kinetics; 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; Recurrence; Recurrent Malignant Neoplasm; Research; Risk; Sampling; Screening for cancer; Specificity; Testing; Time; Tumor Burden; United States; Virus; Woman; Work; biological specimen archives; cancer cell; cancer diagnosis; cancer recurrence; cohort; comparison control; detection assay; diagnostic biomarker; 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.

项目概要 HPV 驱动的口咽癌 (HPV-OPC)（一种头颈癌）的发病率在 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，HPV-OPC 没有早期检测方法。 HPV16 E6 抗体阳性 被确定为 HPV-OPC 有前途的早期生物标志物。我们课题组之前的工作表明，HPV16 E6 抗体 高达 90% 的 HPV-OPC 患者中存在这种病毒，并且在诊断前 10 多年就出现了。然而，鉴于 HPV16 E6 血清转化和癌症诊断之间存在较长的滞后时间，HPV16 E6 血清阳性个体可能需要进行 在癌症被临床诊断之前，需要跟踪十年或更长时间。因此，早期检测生物标志物表明 在考虑临床使用 HPV16 E6 抗体检测之前，需要了解是否存在肿瘤。循环 肿瘤 (ct)HPV DNA 检测是检测 HPV-OPC 的一个有前景的标记物。我们小组的工作已经证明 在诊断时，ctHPVDNA 对 HPV-OPC 的敏感性为 98.4%，特异性为 98.6%。 ctHPVDNA 的先前研究 重点关注 ctHPVDNA 在诊断 HPV-OPC 和监测治疗后复发方面的用途。到 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 ctHPVDNA 在预诊断环境中的特点是，迄今为止开发的检测方法需要大量血液 (>1ml)，这已 鉴于在 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 PCR (ddPCR) 的技术 用于检测少量存档样本中的 ctHPVDNA 的测定。本研究的目的是进行第一个 大型研究在诊断前评估 ctHPVDNA 的动力学并将该生物标志物与 HPV16 E6 进行比较 血清阳性。将在前列腺、肺、结直肠和卵巢（PLCO）内进行巢式病例对照研究 癌症筛查试验是一项针对美国各地 154,935 名中年男性和女性的前瞻性队列研究。预 来自 81 个 OPC 病例和 162 个匹配对照（1:2 比例）​​的诊断血样将进行 ctHPVDNA 检测。全系列 还将测试 ctHPVDNA 阳性病例的样本，以评估导致诊断的标记物动力学。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。鉴于使用了专门针对以下情况进行优化的新型 ctHPVDNA 检测，该提案具有创新性： 少量的存档样本，这将使我们能够进行第一项研究，以预评估 ctHPVDNA 诊断设置。这项研究可能会带来更好的 HPV-OPC 早期检测方法，并直接应对 美国国家癌症研究所 (NCI) 和美国国家牙科研究所联合发布的特别关注通知 颅面研究 (NIDCR)：推进头颈癌早期检测研究 (AHEAD)；不是-CA-20-031。