HPV: Biology, Clinical Significance and Epidemiology

HPV：生物学、临床意义和流行病学

• 批准号: 7883494
• 负责人: DENISE A. GALLOWAY
• 金额: $ 227.89万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883494
• 关键词: HPV; Biology; Clinical; Significance; Epidemiology

DESCRIPTION (provided by applicant): Our long-standing goal is to understand the role that human papillomaviruses (HPVs) play in the etiology of cancer, and to identify other risk factors that cause only some HPV infected individuals to progress to cancer. Previously we have focused on a group of high-risk genus alpha HPVs and have showed that they have a causal role in anogenital cancers. In addition, we identified immunogenetic factors that influenced the development of cervical cancer. We also identified a number of factors that were known or thought to be associated with immunosuppression, such as smoking and corticosteroid use that were common among the squamous cell anogenital cancers. This prompted us to direct our attention to the possibility that a different set of HPVs, known as genus beta- or EV HPVs, are involved (together with immunosuppression and UV damage) in the etiology of squamous cell cancer of the skin (SCSC). To test this hypothesis Project 1 will establish a nested case control study of SCSC among organ transplant recipients (OTR). We will identify the genus beta HPV types present in SCSC tumor tissue, the types and viral load resident in hair follicles of cases and controls, and HPV antibodies in blood samples drawn prior to transplantation. Associations with HPV markers will be estimated accounting for other SCSC risk factors such as immunosuppressive drugs, sunlight exposure and other characteristics. In a parallel longitudinal study, Project 1 will also examine the natural history of genus beta HPVs in the OTR population. Project 2 will focus on the mechanisms by which the genus beta E6 and E7 proteins contribute to malignancy by studying their ability to bypass UV damage checkpoints, inhibit apoptosis, disrupt p53 function and stimulate proliferation. We hypothesize that infection with genus beta HPVs can lead to increased proliferation of squamous cells, and that the HPV oncoproteins inhibit the normal response to UV-induced DNA damage, i.e. repair or apoptosis, allowing cells with mutations in tumor suppressors or oncogenes to accumulate changes that lead to cancer. Project 3 will focus on identifying genetic risk factors for HPV related cancers. For SCSC in OTRs, polymorphisms in genes in both the innate and adaptive immune response pathways will be interrogated, as well as genes in the UV-induced DNA damage repair pathway. We will also study polymorphisms in genes in the Toll-like receptor pathway in cervical and vulvar cancers, taking advantage of our large population-based cases and controls accrued in prior funding periods. Four cores will support these three projects: Molecular Biology, Pathology, Data Management and Biostatistics, and Administration. If a strong link between specific HPV types and SCSC can be verified in studies such as the ones we propose, this information will have important translational benefit in diagnosis, therapy and prevention. We bring an experienced, highly integrated, multidisciplinary team to address this important problem.

描述（由申请人提供）：我们的长期目标是了解人乳头瘤病毒 (HPV) 在癌症病因学中所起的作用，并确定仅导致某些 HPV 感染者进展为癌症的其他风险因素。此前，我们重点关注了一组高危 α HPV 属，并表明它们在肛门生殖器癌症中具有因果作用。此外，我们还确定了影响宫颈癌发展的免疫遗传因素。我们还确定了许多已知或被认为与免疫抑制相关的因素，例如鳞状细胞肛门生殖器癌中常见的吸烟和皮质类固醇的使用。这促使我们将注意力转向一种可能，即涉及一组不同的 HPV，即 β 型或 EV HPV（与免疫抑制和紫外线一起）。 损伤）在皮肤鳞状细胞癌（SCSC）的病因学中。为了检验这一假设，项目 1 将在器官移植受者 (OTR) 中建立 SCSC 巢式病例对照研究。我们将鉴定 SCSC 肿瘤组织中存在的 β HPV 类型、病例和对照毛囊中驻留的类型和病毒载量，以及移植前抽取的血液样本中的 HPV 抗体。与 HPV 标记物的关联将根据其他 SCSC 危险因素（例如免疫抑制药物、阳光照射和其他特征）进行估计。在一项平行的纵向研究中，项目 1 还将检查 OTR 人群中 β HPV 属的自然史。项目 2 将重点研究 β E6 和 E7 属蛋白导致恶性肿瘤的机制，研究其绕过紫外线损伤检查点、抑制细胞凋亡、破坏 p53 功能和刺激增殖的能力。我们假设感染 β HPV 会导致鳞状细胞增殖增加，并且 HPV 癌蛋白会抑制对紫外线诱导的 DNA 损伤的正常反应，即修复或凋亡，从而使肿瘤抑制基因或癌基因发生突变的细胞积累导致癌症的变化。项目 3 将重点确定 HPV 相关癌症的遗传风险因素。对于 OTR 中的 SCSC，将询问先天性和适应性免疫反应途径中基因的多态性，以及紫外线诱导的 DNA 损伤修复途径中的基因的多态性。我们还将利用之前资助期间积累的大量基于人群的病例和对照研究宫颈癌和外阴癌中 Toll 样受体途径基因的多态性。四个核心将支持这三个项目：分子生物学、 病理学、数据管理和生物统计学以及管理。如果特定 HPV 类型和 SCSC 之间的密切联系可以在我们提出的研究中得到证实，那么这些信息将在诊断、治疗和预防方面具有重要的转化效益。我们拥有一支经验丰富、高度整合的多学科团队来解决这一重要问题。