The effect of epigenetic DNA methylation on the progression of HPV-associated precancerous cervical lesions

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PROJECT SUMMARY Reducing morbidity and mortality due to invasive cervical cancer (ICC) is a global health priority, which can be accomplished in part by improving the timely detection and management of cervical precancer. Precancerous cervical lesions characteristically progress from low-grade to high-grade cervical intraepithelial neoplasia (from CIN-1 to CIN-2/3). Low-grade CIN-1 can spontaneously regress to normal, persist over time, or progress to CIN- 2/3, but there is insufficient evidence to predict which CIN-1 cases will progress. Epigenetic alterations of DNA sequences, such as methylation at cytosine-p-guanine (CpG) sites, have been observed in cervical precancer and cancer. As such, methylation patterns have been proposed as potential biomarkers for the detection of high- grade cervical lesions. However, their utility as predictors of cervical disease progression is limited, as few studies have investigated the effect of methylation on the risk of progression from low-grade CIN-1 to high-grade CIN-2/3. In addition, while high-risk human papillomavirus (HPV) is known to cause ICC, little is known about the relationship between HPV infection and the host methylation patterns seen in cervical carcinogenesis. Epigenetic studies incorporating longitudinal clinical data are needed to understand the effect of DNA methylation on the risk of progression of HPV-associated precancerous cervical lesions. This study will assess relationships between early-stage DNA methylation, high-risk HPV infection, and the progression or persistence of CIN-1. The proposed research will utilize collected data from women in the Cervical Intraepithelial Neoplasia Cohort Study (CINCS) with CIN-1 at enrollment, baseline methylation at 450,000 GpGs, pertinent clinical and behavioral exposures, and one year of clinical follow-up data. Using this unique and robust dataset, the Specific Aims of this proposal are to 1.) assess the effect of baseline DNA methylation on CIN- 1 progression/persistence in 151 women at one-year follow-up and 2.) assess the association between baseline HPV infection status and DNA methylation in 151 women with CIN-1. Study findings have the potential identify novel methylation markers of cervical disease progression, improve the clinical management of low-grade cervical precancer, and contribute to our knowledge of HPV-related carcinogenesis. Through the completion of these research aims, the applicant will gain a unique set of skills in advanced epidemiologic methods and clinical research, including the analysis and interpretation of complex epigenetic and longitudinal clinical data. Expert mentors in cancer and genetic epidemiology, methylation analysis, statistics, and gynecologic oncology will support the applicant’s successful completion of the proposed research, associated training plan, and MD-PhD degree at the University of North Carolina at Chapel Hill. This F30 fellowship will critically aid the applicant’s development as a future interdisciplinary physician-scientist practicing at the intersection of cancer care, epigenetics, and women’s health.