HPV: Biology, Clinical Significance and Epidemiology

HPV：生物学、临床意义和流行病学

• 批准号: 7298629
• 负责人: DENISE A. GALLOWAY
• 金额: $ 195.82万
• 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/7298629
• 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(申请人提供)：我们的长期目标是了解人类乳头瘤病毒(HPV)在癌症病因中所起的作用，并识别仅导致部分HPV感染者进展为癌症的其他危险因素。在此之前，我们重点研究了一组高危的甲型HPV，并证明它们在肛门生殖器癌中起着因果作用。此外，我们还确定了影响宫颈癌发生发展的免疫遗传因素。我们还确定了一些已知或被认为与免疫抑制有关的因素，如吸烟和皮质类固醇的使用，这些因素在鳞状细胞肛门癌中很常见。这促使我们将注意力转移到另一组不同的HPV，即所谓的贝塔病毒或EV HPV的可能性上(连同免疫抑制和紫外线 皮肤鳞状细胞癌(SCSC)的病因学。为了验证这一假设，项目1将建立一项器官移植受者中SCSC的嵌套病例对照研究。我们将确定SCSC肿瘤组织中存在的β-HPV类型，病例和对照患者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标志物的相关性将考虑到其他SCSC危险因素，如免疫抑制药物、阳光暴露和其他特征。在一项平行的纵向研究中，项目1还将检查OTR人群中贝塔病毒属的自然历史。项目2将通过研究βE6和E7蛋白绕过紫外线损伤检查点、抑制细胞凋亡、干扰P53功能和刺激增殖的能力，重点研究βE6和E7蛋白促进恶性肿瘤的机制。我们假设感染β属HPV可以促进鳞状细胞的增殖，并且HPV癌蛋白抑制了对紫外线诱导的DNA损伤的正常反应，即修复或凋亡，允许肿瘤抑制基因或癌基因突变的细胞积累导致癌症的变化。项目3将侧重于确定HPV相关癌症的遗传风险因素。对于OTRs中的SCSC，将询问先天和获得性免疫反应途径中的基因多态性，以及紫外线诱导的DNA损伤修复途径中的基因多态性。我们还将研究宫颈癌和外阴癌中Toll样受体途径基因的多态性，利用我们在之前的资助时期积累的基于人群的大型病例和对照。四个核心将支持这三个项目：分子生物学， 病理学、数据管理、生物统计学和行政管理。如果特定的HPV类型和SCSC之间的强烈联系能够在我们所建议的研究中得到证实，这一信息将在诊断、治疗和预防方面具有重要的翻译益处。我们带来了一支经验丰富、高度整合的多学科团队来解决这一重要问题。