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.
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.
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