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

表观遗传DNA甲基化对HPV相关宫颈癌前病变进展的影响

• 批准号: 10331004
• 负责人: Alexandra Bukowski
• 金额: $ 3.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331004
• 关键词: Address; Behavioral; Biological Markers; Biological Process; Cancer Control; Cell Cycle; Cells; Cervical; Cervical Intraepithelial Neoplasia; Cervical spinal cord injury; Cessation of life; Characteristics; Clinical; Clinical Data; Clinical Management; Clinical Research; Cohort Studies; Complex; Cross-Sectional Studies; Cytosine; DNA Methylation; DNA Sequence Alteration; Data; Data Set; Detection; Development; Disease Outcome; Disease Progression; Doctor of Philosophy; Early treatment; Enrollment; Epidemiologic Methods; Epidemiology; Epigenetic Process; Exhibits; Fellowship; Future; Gene Expression; Genes; Genome; Goals; Guanine; Guidelines; Gynecologic Oncology; HPV-High Risk; Health Priorities; Human Papilloma Virus Vaccination; Human Papillomavirus; Human papilloma virus infection; Hypermethylation; Learning; Lesion; London; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Maps; Mentors; Methods; Methylation; Morbidity - disease rate; North Carolina; Outcome; Pathway Analysis; Physicians; Postdoctoral Fellow; Premature Birth; Research; Risk; Risk Factors; Risk Management; Sampling; Scientist; Site; Specimen; Testing; The Cancer Genome Atlas; Time; Training; Universities; Viral Proteins; Woman; Women' s Health; cancer care; cancer epidemiology; carcinogenesis; carcinogenicity; career; cervical carcinogenesis; clinically significant; cohort; experience; follow-up; genetic epidemiology; global health; high risk; improved; methylation biomarker; methylation pattern; mortality; novel; potential biomarker; premalignant; prospective; public health priorities; screening; skills; statistics

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.

项目概要 降低浸润性宫颈癌 (ICC) 的发病率和死亡率是全球卫生优先事项，可以 部分实现是通过改善宫颈癌前病变的及时检测和管理来实现的。癌前期 宫颈病变的特征是从低度宫颈上皮内瘤变进展为高度宫颈上皮内瘤变（从 CIN-1 至 CIN-2/3）。低级别 CIN-1 可自发恢复正常、持续一段时间或进展为 CIN- 2/3，但没有足够的证据来预测哪些 CIN-1 病例将会进展。 Epigenetic alterations of DNA 在宫颈癌前病变中观察到了一些序列，例如胞嘧啶-p-鸟嘌呤 (CpG) 位点的甲基化 和癌症。因此，甲基化模式已被提议作为检测高水平的潜在生物标志物。 级宫颈病变。然而，它们作为宫颈疾病进展预测因子的效用有限，因为很少有 研究调查了甲基化对从低级别 CIN-1 进展为高级别 CIN-1 的风险的影响 CIN-2/3。此外，虽然已知高危人乳头瘤病毒 (HPV) 会导致 ICC，但人们对它知之甚少。 HPV 感染与宫颈癌发生过程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了解 DNA 的影响 甲基化对 HPV 相关宫颈癌前病变进展风险的影响。 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。拟议的研究将利用从女性宫颈中收集的数据 入组时使用 CIN-1 的上皮内肿瘤队列研究 (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。利用这种独特而强大的 数据集，该提案的具体目标是 1.) 评估基线 DNA 甲基化对 CIN-的影响 1 151 名女性在一年的随访中病情进展/持续，2.) 评估之间的关联 151 名 CIN-1 女性的基线 HPV 感染状态和 DNA 甲基化。 研究结果有可能识别宫颈疾病进展的新甲基化标志物，改善 低级别宫颈癌前病变的临床管理，并有助于我们了解 HPV 相关知识 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，包括复杂的分析和解释 表观遗传学和纵向临床数据。癌症和遗传流行病学、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拟议的 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人发展成为未来的跨学科医师科学家 在癌症护理、表观遗传学和女性健康的交叉领域进行实践。