HPV Methylation as a Biomarker of Viral Persistence and Risk of Cervical Disease

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DESCRIPTION (provided by applicant): The estimated prevalence of human papillomavirus (HPV) infection for women in the U.S. is over 10 million, with approximately 6.2 million new infections annually, yet most HPV infections are transient and clear within 24 months. About 12,000 new cases of cervical cancer are reported annually in the U.S., and only women with persistent high-risk HPV infection are at risk of dysplasia (CIN) that ultimately progresses to cervical cancer. It is unknown why HPV infections clear in most women yet persist in others. The current false positive rate of pap test screening (~1 in 10 are "abnormal"), results in follow up colposcopy and biopsy that are financially and emotionally costly. Thus, there is a great clinical need to identify biomarkers that are predictive of the small number of high-risk HPV infections that will persist and progress, so that medical resources can be directed at the women truly at risk of cervical disease. Methylation of viral DNA sequences (especially in the L1 and L2 ORF) as a host defense mechanism is gaining attention. The process of methylation depends on dietary folate and the demethylation depends on base excision repair (BER) to restore native cytosine in CpG sequences. Rarely have studies prospectively followed women over time with the specific goal of measuring viral persistence. We have available for the proposed study samples of DNA collected from a unique cohort called the Carolina Women's Care Study (CWCS) supported by the National Institute on Minority Health and Health Disparities (P20 MD001770). The study was initiated to identify biomarkers of HPV persistence in college-age women. DNA isolated from exfoliated cervical cells collected longitudinally in the CWCS will allow us to uncover candidate biomarkers based on the following hypothesis. Alterations in the methylation of HPV DNA ultimately determine viral persistence or clearance, and epigenetic methylation of HPV sequences is controlled by folate metabolism and/or DNA repair processes. Accordingly, polymorphisms in genes involved in folate metabolism and/or base excision repair will serve as excellent biomarkers for HPV persistence, and thus, risk ultimately for cervical cancer. Aim 1 will determine the methylation status of the viral L1 and L2 genes in exfoliated cervical cells collected as part of the CWCS, which followed college age women prospectively for up to four years and identified participants who rapidly cleared the HPV viral infection along with others who had persistent HPV infections. Aim 2 will determine the prevalence of polymorphisms (SNPs) in folate metabolizing enzymes and DNA repair enzymes in the CWCS cohort and will correlate specific SNPs with the levels of high- risk HPV DNA methylation, viral persistence, and viral clearance. The clinical and translational impact of this study will be to identify genetic interactions between methylation of HPV, folate metabolizing enzymes and DNA repair enzymes that will serve as biomarkers for HPV persistence, and thus, risk for cervical cancer.