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

项目总结 减少浸润性宫颈癌(ICC)的发病率和死亡率是全球卫生优先事项，这可以是 这在一定程度上是通过改进宫颈癌前病变的及时检测和管理来实现的。癌前病变 宫颈病变的特点是从低级别进展到高度上皮内瘤变(从 CIN-1至CIN-2/3)。低级别CIN-1可自发退化至正常，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的表观遗传学改变 已在宫颈癌前病变中观察到胞嘧啶对鸟嘌呤(CpG)位点的甲基化等序列 和癌症。因此，甲基化模式已被认为是检测高密度脂蛋白的潜在生物标志物。 宫颈病变分级。然而，它们作为宫颈疾病进展的预测指标的效用是有限的，因为很少 研究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 此外，尽管已知高危人乳头瘤病毒(HPV)可引起ICC，但人们对此知之甚少 宫颈癌变过程中HPV感染与宿主甲基化模式的关系 需要结合纵向临床数据的表观遗传学研究来了解DNA的作用 甲基化对HPV相关癌前病变进展风险的影响。 这项研究将评估早期DNA甲基化、高危HPV感染和 CIN-1的进展或持续性。这项拟议的研究将利用从宫颈疾病妇女那里收集的数据 上皮内瘤变队列研究(CINCS)在登记时使用CIN-1，基线甲基化水平为450,000 Gpgs， 相关的临床和行为暴露，以及一年的临床随访数据。使用这一独特而健壮的 数据集，这项提案的具体目标是1。)评估基线DNA甲基化对CIN-1的影响 1在一年的随访中，151名妇女的进展/持续和2。)评估两者之间的关联 151例CIN-1妇女的HPV感染状态和DNA甲基化的基线研究 研究结果有可能发现宫颈疾病进展的新的甲基化标志物，改善 低级别宫颈癌前病变的临床处理，有助于我们对HPV相关的认识 致癌。通过完成这些研究目标，申请者将获得一套独特的技能 先进的流行病学方法和临床研究，包括复杂疾病的分析和解释 表观遗传学和纵向临床数据。癌症和基因流行病学、甲基化方面的专家导师 分析、统计和妇科肿瘤学将支持申请人成功完成建议的 北卡罗来纳大学教堂山分校的研究、相关培训计划和医学博士学位。这 F30奖学金将极大地帮助申请者发展成为未来的跨学科医生-科学家 在癌症护理、表观遗传学和女性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.