Discovery of New DNA Methylation Biomarkers for Predicting the Malignant Outcome of Low-Grade Oral Dysplasia

发现新的 DNA 甲基化生物标志物，用于预测低度口腔发育不良的恶性结果

• 批准号: 10641351
• 负责人: ROBERT Y TSAI
• 金额: $ 22.79万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641351
• 关键词: Address; Appearance; Automobile Driving; Biological Markers; Biopsy; DNA Methylation; Data; Dental; Disease; Disease Progression; Epigenetic Process; Event; Gene Targeting; Genomic Segment; Genomics; Goals; Head and Neck Squamous Cell Carcinoma; Health; High grade dysplasia; Human; Incidence; Intervention; Knowledge; Left; Lesion; Logistic Regressions; Longitudinal Studies; Longterm Follow-up; Malignant - descriptor; Malignant Neoplasms; Medical; Methods; Methylation; Minority; Modeling; Modification; Morphology; Mucous Membrane; Mutation; Nucleotides; Oral; Outcome; Output; Patients; Prevention strategy; Proteins; Public Health; Reporting; Research; Resolution; Risk; Risk Assessment; Sampling; Site; Testing; Tobacco; Training; Treatment Side Effects; Validation; Visit; Width; bisulfite sequencing; cancer prevention; cancer risk; carcinogenicity; evidence base; gene environment interaction; gene function; high risk; improved; learning algorithm; machine learning algorithm; malignant mouth neoplasm; methylome; mouth squamous cell carcinoma; novel; oral cancer prevention; oral carcinogenesis; oral cavity epithelium; oral dysplasia; personalized strategies; predictive marker; predictive modeling; premalignant; preservation; programs; random forest; risk prediction; risk prediction model; screening; sequencing platform; side effect; whole genome

Oral squamous cell carcinoma (OSCC) is a devastating malignancy that may arise from precursor mucosal lesions, called oral premalignant lesions (OPLs). OPLs consist of low- and high-grade dysplasia (ODs). Although most low-grade ODs remain stable for years and some even regress spontaneously, a significant minority of them (4-11%) rapidly develop OSCC. Currently, there is no biomarker available for screening low- grade ODs to identify those at high risk of developing OSCC to implement evidence-based cancer prevention management. Several studies reported DNA methylation changes in oral carcinogenesis, but failed to address the differences between progressive vs. static low-grade ODs or generate whole genome coverage with sufficient width and depth for maximal new discoveries. Our long-term goal is to understand the epigenetic mechanisms that drive the malignant progression of precancerous lesions. The objective of this R21 is to discover new differentially methylated regions (DMRs) associated with OPL progression using a whole- genome single-nucleotide-resolution approach, create novel DMR-based models, and validate their power in predicting the progression of low-grade ODs to OSCC. The central hypothesis of this R21 states that the progression of OPLs to OSCC is driven by DNA methylation changes that can be discovered by whole-genome DMR analysis of progressive vs. static OPLs and used to predict the cancer risk of OPLs for management decision. This hypothesis is formulated based on the scientific premises that: 1) epigenetic modification is a key disease-driving mechanism that captures early carcinogenic environment-gene interaction events and is faithfully preserved throughout disease progression, and 2) DNA methylation changes have been shown to occur in ODs and OSCC compared to normal oral epithelium. The rationale for pursuing the proposed research is that once the spectrum of DMRs between the progressive and static ODs are identified based on high quality data and powerful analysis, we will discover key DMR sites that drive and predict the malignant progression of low-grade ODs, which would otherwise be missed. Aim 1 will discover genomic regions differentially methylated in progressive vs. static low-grade ODs using whole genome bisulfite sequencing (WGBS) on samples with longitudinal follow-ups. Aim 2 will create DMR-based models and validate their power in predicting the risk of low-grade ODs in progression to OSCC. A successful completion is expected to discover new DMRs capable of differentiating progressive vs. static ODs and create novel risk-prediction DMR models. The outcome will fill the critical need for a sensitive and reliable screening method to predict the risk of OPLs in becoming OSCCs at an early stage, when medical interventions are more effective and less damaging, which will lead to a direct impact on reducing the incidence of OSCC and related health issues, as well as finding novel DNA methylation mechanisms driving the malignant progression of OSCC that may be druggable. It may also have a broad impact on advancing research on other tobacco-related HNSCC.

口服鳞状细胞癌（OSCC）是一种毁灭性的恶性肿瘤，可能是由前体粘膜引起的 病变，称为口服前病变（OPLS）。 OPL由低级和高级发育不良（ODS）组成。 尽管大多数低级OD保持稳定多年，有些甚至自发地退化，但很重要 其中少数（4-11％）迅速发展OSCC。目前，尚无生物标志物可用于筛查低 - 识别出高风险的ODS等级OSCC来实施基于证据的癌症预防 管理。几项研究报道了口服癌变的DNA甲基化变化，但未能解决 渐进性与静态低度OD之间的差异或与 最大新发现的足够宽度和深度。我们的长期目标是了解表观遗传 促进癌前病变的恶性进展的机制。 R21的目的是 发现与OPL进展相关的新的差异甲基化区域（DMR） 基因组单核苷酸分辨率方法，创建基于DMR的新型模型，并在 预测低级ODS对OSCC的发展。该R21的中心假设指出 OPL向OSCC的进展是由DNA甲基化变化驱动的，全基因组可以发现这些变化 DMR进行了进行性和静态OPL的分析，用于预测OPL的癌症风险用于管理 决定。该假设是基于科学前提提出的：1）表观遗传修饰是 捕获早期致癌环境相互作用事件的关键疾病驱动机制，是 忠实保存在整个疾病进展中，2）DNA甲基化变化已显示为 与正常的口服上皮相比，发生在ODS和OSCC中。追求拟议研究的理由 是，一旦根据高质量确定了渐进式和静态OD之间的DMR频谱 数据和强大的分析，我们将发现驱动和预测恶性进展的关键DMR站点 低级ODS，否则会错过。 AIM 1会差异发现基因组区域 使用整个基因组亚硫酸盐测序（WGB）上的甲基化与静态低度OD在渐进的和静态的低度OD中 纵向随访的样品。 AIM 2将创建基于DMR的模型并验证其功率 预测向OSCC发展中低级OD的风险。预计成功完成 能够区分渐进式和静态OD并创建新型风险预测DMR模型的新DMR。 结果将满足对敏感和可靠的筛选方法的关键需求，以预测OPL的风险 在早期阶段成为OSCC，当医疗干预措施更加有效且破坏性较小时， 将导致直接影响减少OSCC及相关健康问题的发病率，并发现 新型的DNA甲基化机制推动了可能可药物的OSCC的恶性进展。可能 对其他与烟草相关的HNSCC的研究也有广泛的影响。