DNA Methylation as a Risk Factor for Cervical Neoplasia

DNA 甲基化是宫颈肿瘤的危险因素

• 批准号: 7292742
• 负责人: LONG FU XI
• 金额: $ 28.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292742
• 关键词: Aberrant DNA Methylation; Address; Adenocarcinoma In Situ; Apoptosis; Biological Assay; Biological Markers; Biopsy; CDH1 gene; CDH13 gene; Cancer Control; Candidate Disease Gene; Carcinoma in Situ; Cell Cycle Regulation; Cells; Cervical; Cervical Cancer Screening; Cervical Intraepithelial Neoplasia; Clinic; Clinical; CpG Islands; CpG dinucleotide; Cyclin-Dependent Kinase Inhibitor 2A; Cytology Histology; Cytosine; DNA; DNA Methylation; Data; Detection; Development; Drug Metabolic Detoxication; Effectiveness; Endopeptidases; Epigenetic Process; Eukaryotic Cell; Evaluation; FHIT gene; Funding; Future; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Histology; Housekeeping Gene; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Hypermethylation; Individual; Infection; Interview; Invasive; Lead; Lesion; Light; MGMT gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Maps; Messenger RNA; Methods; Methylation; Modeling; Modification; Neoplasm Metastasis; Neoplasms; Normal Cell; Oncogenic; Pap smear; Papillomavirus; Pathogenesis; Pattern; Peptide Hydrolases; Performance; Personal Satisfaction; Play; Population; Predictive Value; Promoter Regions; Publishing; RARB gene; Recruitment Activity; Regulation; Relative (related person); Research Design; Research Personnel; Risk; Risk Factors; Role; SYK gene; Sampling; Screening procedure; Sensitivity and Specificity; Specificity; Swab; TWIST1 gene; Testing; Tumor Suppression; Visit; Washington; Woman; base; bisulfite; carcinogenesis; case control; cost effectiveness; design; genital infection; high throughput screening; improved; interest; loss of function; performance tests; programs; promoter; tumor; tv watching

DESCRIPTION (provided by applicant): Although a central role of human papillomavirus (HPV) in risk for cervical cancer and its precursor, cervical intraepithelial neoplasia grades ll-lll or carcinoma in situ (greater than or equal to CIN2-3) has been well established, most of the HPV infections resolve spontaneously and only few progress to cervical cancer. Thus, an HPV-based screening usually suffers from a low specificity for identification of women with SCIN2-3. Clearly, factors other than HPV infection also play an important role in pathogenesis of cervical neoplasia. A loss of function of certain critical genes by methylation of CpG islands in promoter region has been found in a variety of cancers, including cancer of the cervix. Almost every tumor type appears to have CpG hypermethylation in multiple genes and a unique hypermethylation profile exists for different tumors. We hypothesize that aberrant DNA methylation is associated with risk of cervical neoplasia and its detection in the exfoliated cell sample obtained at the routine screening can serve as a biomarker for identification of women who are at high risk of greater than or equal to CIN2-3. We propose to efficiently address our hypotheses by performing additional analyses on a subset of samples collected in the ongoing NCI-funded project entitled "Evaluation of Cervical Cancer Screening Methods (EVA)," a study designed to evaluate a variety of screening strategies for detection of greater than or equal to CIN3. Interview data, cytology and histology, and HPV results will be available to the planned study. We plan to define a panel of genes that are closely related to risk of greater than or equal to CIN2-3 (Aim one) by mapping methylation patterns of CpG islands of the 12 or more candidate genes between women with greater than or equal to CIN2-3 (cases) and those with CIN1 or normal histology (controls). Based on the methylation patterns between the cases and controls, we will design a high throughput assay (MethyLight) for detecting the hypermethylated genes in cervical swab samples. In Aim two, we will examine performance of testing the panel of hypermethylated genes for identification of women with greater than or equal to CIN2-3. Lastly (Aim three), among women with HPV16 infection, we will determine whether CpG hypomethylation in the long control region of HPV16 genome is associated with an increased risk of greater than or equal to CIN2-3, high level of E7 mRNA, and repeated HPV16-positive visits. Data from the proposed study will not only shed light on our understanding of the role of CpG methylation in development of cervical neoplasia but also help to better design future cervical cancer control programs.

描述（由申请人提供）：尽管人类乳头瘤病毒（HPV）在宫颈癌及其前体，颈椎上皮内肿瘤级ll-lll或癌（或癌症）上的核心作用（大多数是HPV Infections spontane cancer spontaney spontane cance cancerally spontane cancerally spontane spontane contoncane contoical concove spontane and contoinal cancinallal ll-lll或癌症（大于或等于CIN2-3）。因此，基于HPV的筛查通常患有较低的特异性，以鉴定SCIN2-3的女性。显然，除HPV感染以外的其他因素在宫颈肿瘤的发病机理中也起着重要作用。在包括子宫颈癌在内的各种癌症中发现了通过CPG岛甲基化CPG岛的甲基化来丧失某些关键基因的功能。几乎每种肿瘤类型似乎都具有多种基因中的CpG高甲基化，并且对于不同的肿瘤存在独特的高甲基化谱。我们假设异常的DNA甲基化与宫颈肿瘤的风险有关，并且在常规筛查中获得的去角质细胞样品中的检测可以作为鉴定患有高度或等于CIN2-3的高风险的女性的生物标志物。我们建议通过对正在进行的NCI资助的项目中收集的样本的一部分进行其他分析来有效地解决我们的假设，这些样本名为“评估宫颈癌筛查方法（EVA）”，该研究旨在评估多种筛选策略，以检测大于或等于CIN3。访谈数据，细胞学和组织学以及HPV结果将用于计划的研究。我们计划通过绘制大于或等于CIN2-3（病例）和具有CIN1或正常组织学（对照组）的女性的CPG岛的甲基化模式，定义与大于或等于CIN2-3（AIM ON）的风险密切相关的基因面板。基于病例和对照之间的甲基化模式，我们将设计一个高通量测定（Methlight），用于检测宫颈拭子样品中的高甲基化基因。在目标二中，我们将检查测试高甲基化基因小组的性能，以鉴定大于或等于CIN2-3的女性。最后（AIM三），在HPV16感染的女性中，我们将确定在HPV16基因组长期控制区域中CpG低甲基化是否与大于或等于CIN2-3的风险增加或等于CIN2-3，高水平的E7 mRNA，高水平的E7 mRNA，并反复反复使用HPV16阳性访问。拟议研究的数据不仅会揭示我们对CpG甲基化在宫颈肿瘤发展中的作用的理解，而且还有助于更好地设计未来的宫颈癌控制程序。