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

HPV 甲基化作为病毒持久性和宫颈疾病风险的生物标志物

• 批准号: 8627150
• 负责人: MICHAEL D. WYATT
• 金额: $ 15.04万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627150
• 关键词: Affect; Age; Am 80; Appearance; Attention; Base Excision Repairs; Biological Markers; Biopsy; Cancer Etiology; Caring; Cells; Cervical; Cervical Intraepithelial Neoplasia; Clinical; Cohort Studies; Collecting Cell; Colposcopy; Cytology; Cytosine; DNA; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; DNA Sequence; Diet; Disease; Dysplasia; Economics; Emotional; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Epigenetic Process; Folate; Genes; Genetic; Genetic Polymorphism; Genome; Genomic DNA; Goals; HPV-High Risk; Host Defense Mechanism; Human Papillomavirus; Human papilloma virus infection; Infection; Institutes; Lead; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mammals; Measures; Medical; Methionine; Methylation; Modification; Morbidity - disease rate; No Evidence of Disease; Open Reading Frames; Outcome; Pap smear; Participant; Positioning Attribute; Prevalence; Procedures; Process; Reading; Recruitment Activity; Reporting; Resources; Risk; Sampling; Sampling Studies; Site; South Carolina; System; Taxes; Testing; Tetrahydrofolates; Time; Universities; Viral; Virus Diseases; Visit; Woman; base; cohort; college; demethylation; experience; folic acid metabolism; follow-up; health disparity; methyl group; minority health; psychologic; public health relevance; repair enzyme; screening; viral DNA

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.

描述（由申请人提供）：美国女性人乳头瘤病毒 (HPV) 感染率估计超过 1000 万，每年新增感染人数约为 620 万，但大多数 HPV 感染都是短暂的，且会在 24 个月内消失。美国每年报告约 12,000 例新发宫颈癌病例，只有持续感染高危 HPV 的女性才有患不典型增生 (CIN) 并最终发展为宫颈癌的风险。目前尚不清楚为什么 HPV 感染在大多数女性中已清除，但在其他女性中却持续存在。目前子宫颈抹片检查的假阳性率（大约十分之一是“异常”），导致后续阴道镜检查和活检在经济和情感上代价高昂。因此，临床迫切需要确定能够预测少数持续和进展的高危HPV感染的生物标志物，以便将医疗资源用于真正面临宫颈疾病风险的女性。病毒 DNA 序列（尤其是 L1 和 L2 ORF）的甲基化作为宿主防御机制正在引起人们的关注。甲基化过程依赖于膳食叶酸，去甲基化依赖于碱基切除修复 (BER) 以恢复 CpG 序列中的天然胞嘧啶。很少有研究以测量病毒持久性为具体目标，对女性进行前瞻性跟踪。我们为拟议的研究提供了 DNA 样本，这些样本是从一个名为卡罗莱纳州妇女护理研究 (CWCS) 的独特队列中收集的，该队列由国家少数族裔健康和健康差异研究所 (P20 MD001770) 支持。该研究的目的是确定大学女性中 HPV 持久性的生物标志物。从 CWCS 中纵向收集的脱落宫颈细胞中分离出的 DNA 将使我们能够根据以下假设发现候选生物标志物。 HPV DNA 甲基化的改变最终决定病毒的持久性或清除，并且 HPV 序列的表观遗传甲基化受叶酸代谢和/或 DNA 修复过程控制。因此，参与叶酸代谢和/或碱基切除修复的基因多态性将作为 HPV 持久性的极好生物标志物，从而最终确定宫颈癌的风险。目标 1 将确定作为 CWCS 一部分收集的脱落宫颈细胞中病毒 L1 和 L2 基因的甲基化状态，该研究对大学年龄的女性进行了长达四年的跟踪，并确定了快速清除 HPV 病毒感染的参与者以及其他患有持续性 HPV 感染。目标 2 将确定 CWCS 队列中叶酸代谢酶和 DNA 修复酶的多态性 (SNP) 患病率，并将特定 SNP 与高危 HPV DNA 甲基化、病毒持久性和病毒清除水平相关联。这项研究的临床和转化影响将是确定 HPV 甲基化、叶酸代谢酶和 DNA 修复酶之间的遗传相互作用，这些酶将作为 HPV 持久性的生物标志物，从而确定宫颈癌的风险。