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

项目摘要 降低浸润性宫颈癌（ICC）的发病率和死亡率是全球卫生的优先事项， 部分是通过改善宫颈癌前病变的及时发现和管理来实现的。癌前 宫颈病变的特征性进展是从低级别到高级别的宫颈上皮内瘤变（从 CIN-1至CIN-2/3）。低级别CIN-1可自发恢复正常，随时间持续，或进展为CIN-1。 2/3，但没有足够的证据来预测哪些CIN-1病例会进展。DNA的表观遗传改变 在子宫颈癌前病变中观察到胞嘧啶-p-鸟嘌呤（CpG）位点的甲基化等序列， 和癌症因此，甲基化模式已被提议作为用于检测高-甲基化的潜在生物标志物。 分级宫颈病变。然而，它们作为宫颈疾病进展的预测因子的效用是有限的， 研究已经调查了甲基化对从低级别CIN-1进展到高级别CIN-1的风险的影响， CIN-2/3。此外，虽然已知高危型人乳头瘤病毒（HPV）会引起ICC，但对ICC的发生知之甚少。 HPV感染与宫颈癌发生中宿主甲基化模式之间的关系。 需要结合纵向临床数据的表观遗传学研究来理解DNA的影响。 甲基化对HPV相关宫颈癌前病变进展风险的影响。 本研究将评估早期DNA甲基化、高危型HPV感染和 CIN-1的进展或持续。拟议的研究将利用收集的数据，从妇女在子宫颈 入组时CIN-1的上皮内瘤样病变队列研究（CINCS），基线甲基化为450，000 GpG， 相关的临床和行为暴露，以及一年的临床随访数据。使用这种独特而强大的 数据集，本提案的具体目标是1。评估基线DNA甲基化对CIN的影响- 在1年随访时，151名女性中有1例进展/持续存在，2.）评估之间的关联 151例CIN-1妇女的基线HPV感染状态和DNA甲基化。 研究结果有可能发现宫颈疾病进展的新甲基化标志物，改善宫颈癌的预后。 低度宫颈癌前病变的临床管理，并有助于我们对HPV相关的知识， 致癌作用通过完成这些研究目标，申请人将获得一套独特的技能， 先进的流行病学方法和临床研究，包括分析和解释复杂的 表观遗传学和纵向临床数据。癌症和遗传流行病学、甲基化 分析，统计和妇科肿瘤学将支持申请人成功完成拟议的 研究，相关的培训计划，并在查佩尔山的北卡罗来纳州大学获得MD-博士学位。这 F30奖学金将对申请人作为未来跨学科医生-科学家的发展起到关键性的帮助作用 在癌症护理、表观遗传学和妇女健康的交叉点上实践。

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.