Cutaneous Human Papillomavirus Infection and Risk of Incident External Genital Le

阴茎癌是一种死亡率高、对身体和性心理造成严重后果的疾病。我们 关于人乳头瘤病毒（HPV）在阴茎癌发生中的作用的知识主要是 来源于HPV 16属之一的α属（α-HPV）中粘膜HPV类型的研究。粘膜 α-HPV感染导致每年阴茎癌发病率的大约50%。知之甚少 HPV类型的多样性参与了阴茎癌前病变的发展。意义 皮肤HPV的β属（β-HPV），一组HPV普遍和持续存在于健康人 人类皮肤或其与粘膜α-HPV的组合暴露在阴茎癌发生中的作用尚未评估。 本项目的目标是对一个新的假设进行前瞻性流行病学调查： 暴露于皮肤β-HPV，无论是单独或联合粘膜α-HPV，增加了外部感染的风险。 生殖器病变（EGL），具有阴茎癌的恶性潜力。这项研究的两个具体目标是： (1)估计皮肤β-HPV和粘膜α-HPV暴露的基线患病率，并调查因素 与任何β-HPV暴露以及与粘膜α-HPV的联合暴露相关;（2）确定是否 皮肤β-HPV的基线暴露，单独或联合粘膜α-HPV暴露， 随着EGL的发展。 我们提出了一个病例队列设计嵌套在一个已建立和正在进行的纵向队列4072 男性（HIM研究）。研究人群将由随机选择的550名男性子队列组成， 来自母队列的EGL事件病例（迄今为止n=230）。将检测基线血清样本， 针对多种皮肤β-HPV和粘膜α-HPV类型的类型特异性血清抗体作为 使用高通量多重血清学测定的HPV暴露。事件EGL案例将从 基于活检证实的病理诊断（EGL诊断的金标准）的母队列。 该项目是第一个流行病学研究，以评估时间的联系， 皮肤β-HPV感染和具有恶性潜能的EGL的风险。它利用现有的资源， 大型NIH资助的研究，是开发可验证假设的成本效益策略。这项研究将使 通过早期了解皮肤β-HPV暴露的患病率， 一般男性群体，皮肤β-HPV在阴茎癌发生中的意义。如果皮肤β- HPV被发现在EGL中起着潜在的导致阴茎癌的病因学作用，我们的研究结果可以 为未来HPV相关癌症预防策略和疫苗开发提供信息，以预防beta-HPV感染 和相关病变，从而降低阴茎癌的发病率，特别是在年龄较大的成年男性中， 增加的风险，但缺乏常规获得目前的预防性疫苗。

Penile cancer is a disease with a high mortality, serious physical and psychosexual consequences. Our knowledge on the role of Human Papillomavirus (HPV) in penile carcinogenesis has been predominantly derived from studies of mucosal HPV types in the alpha genus (alpha-HPV), one of the 16 genera of HPV. Mucosal alpha-HPV infection is responsible for approximately 50% of annual penile cancer incidence. Little is known about the diversity of HPV types involved in the development of precursor lesions to penile cancer. The significance of cutaneous HPV in the beta-genus (beta-HPV), a group of HPV ubiquitously and persistently present on healthy human skin, or its combined exposures with mucosal alpha-HPV in penile carcinogenesis has not been evaluated. The goal of this project is to conduct a prospective epidemiologic investigation of a new hypothesis: exposures to cutaneous beta-HPV, either individually or jointly with mucosal alpha-HPV, increase the risk of external genital lesions (EGLs) that have malignant potential for penile cancer. The two specific aims of the study are: (1) estimate baseline prevalence of cutaneous beta-HPV and mucosal alpha-HPV exposures, and investigate factors associated with any beta-HPV exposure as well as joint exposures with mucosal alpha-HPV; (2) determine whether baseline exposures to cutaneous beta-HPV, individually or jointly with mucosal alpha-HPV exposures, are associated with subsequent development of EGLs. We propose a case-cohort design nested within an established and ongoing longitudinal cohort of 4072 men (the HIM Study). The study population will consist of a randomly selected sub-cohort of 550 men and all incident EGL cases (n=230 to date) arising from the parent cohort. Baseline serum samples will be tested for type-specific serum antibodies to a wide array of cutaneous beta-HPV and mucosal alpha-HPV types as the marker of HPV exposures using high throughput multiplex serology assays. Incident EGL cases will be enumerated from the parent cohort based on biopsy-confirmed pathologic diagnosis, the gold standard for EGL diagnosis. The proposed project is the first epidemiologic study to evaluate the temporal association between cutaneous beta-HPV infection and risk of EGLs with malignant potential. It utilizes the existing resources of a large NIH-funded study and is a cost-effective strategy to develop testable hypotheses. This study will make a significant contribution by generating early knowledge of the prevalence of cutaneous beta-HPV exposures in the general male community, and the significance of cutaneous beta-HPV in penile carcinogenesis. If cutaneous beta- HPV is found to play an aetiological role in EGLs potentially leading to penile carcinoma, our findings can inform future HPV-related cancer prevention strategies and vaccine development to prevent beta-HPV infection and associated lesions, and in turn reduce penile cancer incidence, especially in older adult men who are at increased risk but lack routine access to the current prophylactic vaccines.