Fanconi Anemia as a Model for Susceptibility to Human Papillomavirus Infection

描述（由申请人提供）：该R 01申请的总体目标是描述范科尼贫血（FA）患者及其家人中人乳头瘤病毒（HPV）感染的流行病学特征和宿主免疫反应。目前，对异常FA相关DNA修复和免疫失调在多大程度上有助于早期HPV获得、维持和/或对癌症的易感性仍有不完全的理解。由于FA是由14个基因中的一个突变引起的，这些基因各自的蛋白质产物在细胞核中组装以修复DNA损伤，因此这些患者具有相当大的基因组不稳定性，进行性骨髓衰竭以及头颈部和妇科鳞状细胞癌（SCC）的易感性。因此，FA是一个很好的模型，可以用来了解HPV相关癌症风险的潜在机制，特别是在脆弱人群中。虽然在一般人群中HPV感染和SCC之间存在已知的相关性，但这些SCC与FA个体中HPV感染的相关程度尚不清楚。我们的初步数据表明，FA相关DNA修复途径的激活在正常情况下限制了HPV的生命周期，并防止恶性转化。此外，与对照组相比，观察到的FA患者口腔HPV患病率增加表明FA相关基因缺陷的角质形成细胞独特地支持HPV感染和/或复制。重要的是，异常免疫学研究指出FA儿童存在特异性免疫缺陷，这也可能导致观察到的HPV倾向。为了验证我们的中心假设，即FA个体对HPV感染具有独特的易感性，我们将追求以下两个具体目标：1）确定FA个体及其父母中37种HPV亚型感染的患病率、发生率和类型特异性持续性（专性杂合子）和兄弟姐妹（潜在的杂合子; HPV的可能来源）; 2）描述免疫学基础（主要是自然杀伤细胞、细胞毒性T淋巴细胞和B细胞表型/功能）用于患有FA的个体中的HPV感染。该研究利用了辛辛那提、明尼苏达州和巴西独特的FA临床小组的强有力合作，与范科尼贫血研究基金建立了关系，并在HPV分型、免疫表型和流行病学分析方面获得了公认的专业知识。这项创新研究无疑将深入了解在脆弱个体（如FA患者）中观察到的SCC风险的可能机制，以及调节FA相关DNA修复途径的基因如何代表一般人群中HPV感染的遗传修饰剂。这些重大贡献预计将导致为更容易感染诱发癌症的个体开发更好的癌症预防和治疗策略。重要的是，我们的研究将通过为FA患者的HPV疫苗接种建议提供证据，对儿童健康产生积极影响。 公共卫生相关性：拟议的R 01申请对公共卫生具有重要意义，因为它将指出在遗传易感人群中观察到的典型人乳头瘤病毒（HPV）相关鳞状细胞癌风险增加的可能机制，例如范可尼贫血（FA），以及帮助研究人员了解FA相关DNA修复途径中蛋白质在普通人群中修饰HPV感染的作用。因此，拟议的研究与NIH的使命相关，即开发基础知识，以增强健康，延长寿命，并减少疾病负担，如鳞状细胞恶性肿瘤的高风险疾病。

DESCRIPTION (provided by applicant): The overall objective of this R01 application is to characterize the epidemiology of and host immunological responses to human papillomavirus (HPV) infection in individuals with Fanconi anemia (FA) and their families. Currently, there remains an incomplete understanding of the extent to which abnormal FA-related DNA repair and immune dysregulation contribute to early HPV acquisition, maintenance and/or susceptibility to cancer. As FA results from mutations in one of 14 genes whose respective protein products assemble in the nucleus to repair DNA damage, those afflicted have considerable genome instability, progressive bone marrow failure and predisposition to head and neck and gynecological squamous cell carcinomas (SCC). FA therefore is an excellent model in which to understand the mechanisms underlying the risk of typically HPV-related cancers particularly in vulnerable populations. While there are known associations between HPV infection and SCC in the general population, the degree to which these SCCs are associated with HPV infection in individuals with FA is unclear. Our preliminary data indicate that activation of the FA-related DNA repair pathway limits the HPV life cycle under normal circumstances and prevents malignant transformation. Further, the observed increased oral HPV prevalence in individuals with FA compared to controls indicates that keratinocytes deficient in FA-related genes uniquely support HPV infection and/or replication. Importantly, abnormal immunologic studies point to the presence of specific immune deficiencies in children with FA that may also contribute to the observed propensity to HPV. To test our central hypothesis that individuals with FA are uniquely susceptible to HPV infection, we will pursue the following two Specific Aims: 1) determine the prevalence, incidence and type-specific persistence of infection with 37 HPV subtypes in individuals with FA and their parents (obligate heterozygotes) and siblings (potential heterozygotes; possible sources of HPV); and 2) characterize the immunological basis (primarily natural killer cell, cytotoxic T-lymphocyte, and B cell phenotype/function) for HPV infection in individuals with FA. The study capitalizes on the strong collaboration of distinctive FA clinical groups in Cincinnati, Minnesota and Brazil, established relationships with the Fanconi Anemia Research Fund, and proven expertise in HPV typing, immunophenotyping and epidemiological analyses. This innovative research will undoubtedly provide insight into the possible mechanisms underlying the observed risks of SCC in vulnerable individuals such as those with FA as well as how genes modulating the FA-related DNA repair pathway may represent genetic modifiers of HPV infection in the general population. These significant contributions are expected to lead to development of improved cancer prevention and treatment strategies for individuals more susceptible to infection-induced cancers. Importantly, our study will positively impact child health now by providing evidence for recommendations for HPV vaccination in individuals with FA. PUBLIC HEALTH RELEVANCE: The proposed R01 application is significant to public health because it will point to possible mechanisms underlying the observed increased risk of typically human papillomavirus (HPV)-associated squamous cell cancers in genetically vulnerable populations such as those with Fanconi anemia (FA) as well as help researchers understand the role(s) of proteins in the FA-related DNA repair pathway in modifying HPV infection in the general population. Consequently, the proposed research is relevant to the NIH mission of developing fundamental knowledge that will enhance health, lengthen life, and reduce the burden of illnesses such as those at high risk for squamous cell malignancies.