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）：美国妇女的人乳头瘤病毒（HPV）感染的估计患病率超过1000万，每年大约有620万新的新感染，但大多数HPV感染是短暂的，并且在24个月内均明显。每年在美国每年有大约12,000例新的宫颈癌病例，只有持续的高风险HPV感染的女性才有最终发展为宫颈癌的发育不良风险（CIN）。尚不清楚为什么大多数女性中的HPV感染在其他女性中仍然存在。当前的PAP测试筛查的假阳性速率（10分之一是“异常”），导致经济和情感上的后续阴道镜检查和活检。因此，有很大的临床需要确定可以预测少量的高风险HPV感染的生物标志物，这些高危HPV感染将持续和进展，以便可以将医疗资源针对妇女真正面临宫颈疾病的风险。病毒DNA序列（尤其是在L1和L2 ORF中）作为宿主防御机制的甲基化正在引起人们的注意。甲基化的过程取决于饮食叶酸，脱甲基取决于基础切除修复（BER）以恢复CpG序列中天然胞嘧啶。随着时间的流逝，很少有研究对妇女进行前瞻性跟踪，其特定目标是测量病毒持久性。我们已经提供了从美国国家少数民族健康与健康差异（P20 MD001770）支持的独特队列中收集的DNA的研究样本。该研究旨在确定大学时代女性HPV持久性的生物标志物。从CWC中纵向收集的去角质宫颈细胞中分离出的DNA将使我们能够根据以下假设来发现候选生物标志物。 HPV DNA甲基化的改变最终确定了病毒持续性或清除率，并且HPV序列的表观遗传甲基化受叶酸代谢和/或DNA修复过程的控制。因此，与叶酸代谢和/或碱基切除修复有关的基因中的多态性将是HPV持久性的极好的生物标志物，因此，最终风险对宫颈癌有风险。 AIM 1将确定作为CWC的一部分收集的去角质宫颈细胞中病毒L1和L2基因的甲基化状态，该细胞最多可前瞻性四年，并确定了迅速清除HPV病毒感染的参与者以及其他患有HPV感染的参与者。 AIM 2将确定CWCS队列中叶酸代谢酶和DNA修复酶中多态性（SNP）的患病率，并将特定的SNP与高风险HPV DNA甲基化，病毒持久性和病毒清除率相关。这项研究的临床和翻译影响将是确定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，从而成为宫颈癌的风险。