Investigation of Oral HPV Infection Natural History and Biomarkers of Persistent Infection: The HIM Study

摘要 2013年，美国42,440名成年人被诊断出口咽癌(OPC)，大多数是在晚期 分期，估计五年存活率为50%，复发率高。在幸存下来的人中， 手术和放化疗给患者留下长期的疼痛、毁容和残疾，进一步 增加了疾病的负担。每年，OPC造成约10,000人死亡，130,000年 潜在寿命损失，以及约30亿美元的生产力损失。早期的OPC诊断增加了单纯性- 治疗方式，降低死亡风险，减少医疗费用，提高生活质量。 在美国，约70%的OPC是由HPV引起的，HPV引起的OPC所占比例每年都在增加。 男性HPV相关OPC的发病率也是女性的~3倍。趁有机会 关于生殖器HPV感染和宫颈癌进展的自然病史的大量文献， 有关口腔HPV感染的自然病史的文献很少，因此限制了OPC的发展。 预防干预措施。与宫颈癌和肛门癌不同，OPC没有筛查测试，也没有 目前的HPV疫苗已被评估对这些癌症的疗效。因此，在这份赠款申请中，我们 建议通过建立一个中等风险男性的前瞻性队列来研究口腔HPV的自然历史， 为制定未来预防战略而急需的信息，包括临床 相关筛查工具。HIM研究是唯一一项具有队列基础结构的男性前瞻性研究 和存档的口腔标本来填补这一关键的研究空白。 这项研究的总体目标是确定口腔hpv感染的自然历史，以便为未来提供信息。 制定OPC预防和筛查干预措施。中心假设是病毒、宿主和 行为因素是口腔HPV感染的预测因素，这种感染最有可能持续≥12个月(替代 癌症终点)，感染最有可能进展为癌症。我们将估计口腔的发病率和持续时间。 人乳头瘤病毒感染及相关因素。新病毒(病毒甲基化、整合、变异)、宿主(甲基化)、 和行为因素(烟草使用、口腔卫生和健康、性行为)将根据以下方面进行评估 口腔HPV自然病史。拟议的研究是创新的，因为它将是第一个前瞻性地解决 与口腔HPV自然病史相关的基本问题。我们的研究建立在现有的大量数据和 生物标本库，以有效地解决识别标记的及时和重要问题 对未来的HPV-OPC筛查/预防干预措施的设计有帮助的感染。我们的 由流行病学家、生物统计学家、肿瘤学家和病毒学家组成的跨学科团队具有经验和 成功实施拟议研究的专业知识。

ABSTRACT In 2013, 42,440 adults in the U.S. were diagnosed with oropharyngeal cancer (OPC), the majority at late stages, with an estimated five-year survival of 50% and a high rate of recurrence. Among those who survive, surgery and chemoradiotherapy leave patients with long-term pain, disfigurement, and disability that further add to the burden of the disease. Each year, OPCs are responsible for ~10,000 deaths, 130,000 years of potential life lost, and ~$3 billion in productivity loss. Earlier OPC diagnoses increase likelihood of single- modality treatment, lower the risk of mortality, decrease medical expenditures, and improve quality of life. HPV causes ~70% of OPCs in the US, with the proportion of OPCs due to HPV increasing each year. Incidence rates of HPV-related OPCs are also ~3-fold higher in males compared to females. While there is substantial literature regarding the natural history of genital HPV infection and progression to cervical cancer, little has been published on the natural history of oral HPV infection, thus limiting the development of OPC prevention interventions. Unlike cervical and anal cancers, no screening tests are available for OPC, nor have current HPV vaccines been evaluated for efficacy against these cancers. Therefore, in this grant application we propose to study oral HPV natural history through an established prospective cohort of average risk men, information urgently needed to inform the development of future prevention strategies, including clinically relevant screening tools. The HIM Study is the only male prospective study that has the cohort infrastructure and archived oral specimens to fill this critical research void. The overall goal of this research is to define the natural history of oral HPV infection to inform future development of OPC prevention and screening interventions. The central hypothesis is that viral, host, and behavioral factors are predictive of oral HPV infections that are most likely to persist ≥12 months (surrogate cancer endpoint), infections most likely to progress to cancer. We will estimate incidence and duration of oral HPV infections and associated factors. Novel viral (viral methylation, integration, variants), host (methylation), and behavioral (tobacco use, oral hygiene and health, sexual behavior,) factors will be evaluated in relation to oral HPV natural history. The proposed research is innovative, as it will be the first to prospectively address fundamental questions related to oral HPV natural history. Our study builds on an existing large data and biological specimen repository to efficiently address timely and significant questions identifying markers of infection that have utility for the design of future HPV-OPC screening/prevention interventions. Our transdisciplinary team of epidemiologists, biostatisticians, oncologists, and virologists has the experience and expertise to successfully implement the proposed study.