Fanconi Anemia as a Model for Susceptibility to Human Papillomavirus Infection

描述（由申请人提供）：本R01申请的总体目标是表征范可尼贫血（FA）患者及其家庭中人乳头瘤病毒（HPV）感染的流行病学和宿主免疫反应。目前，对于异常fa相关的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，人们仍然不完全了解。由于FA是由14种基因中的一种突变引起的，这些基因各自的蛋白产物在细胞核中组装以修复DNA损伤，因此患者具有相当大的基因组不稳定性，进行性骨髓衰竭，易患头颈部和妇科鳞状细胞癌（SCC）。因此，FA是一个很好的模型，可以用来理解hpv相关癌症的发病机制，尤其是在易感人群中。虽然已知一般人群中HPV感染与SCC之间存在关联，但这些SCC与FA患者中HPV感染的关联程度尚不清楚。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，并阻止了恶性转化。此外，与对照组相比，观察到FA患者口腔HPV患病率增加，这表明缺乏FA相关基因的角化细胞独特地支持HPV感染和/或复制。重要的是，异常免疫学研究指出，FA儿童中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患者对HPV感染易感，我们将追求以下两个具体目标：1)确定FA患者及其父母（专性杂合子）和兄弟姐妹（潜在杂合子；可能的HPV来源）中37种HPV亚型感染的患病率、发病率和类型特异性持续性；2)确定FA患者HPV感染的免疫学基础（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）。该研究利用了辛辛那提、明尼苏达州和巴西不同FA临床小组的强大合作，与范可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证实了专业知识。毫无疑问，这项创新研究将深入了解易感个体（如FA患者）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普通人群中HPV感染的遗传修饰因子。这些重大贡献预计将导致为更容易感染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患者接种HPV疫苗的建议提供证据，对儿童健康产生积极影响。

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.