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.

口腔鳞状细胞癌（OSCC）是一种毁灭性的恶性肿瘤，可能由前体粘膜引起 病变，称为口腔癌前病变（OPL）。 OPL 包括低度和高度不典型增生 (OD)。 尽管大多数低级 OD 可以保持稳定多年，有些甚至会自发消退，但 其中少数（4-11%）迅速发展为 OSCC。目前，尚无可用于筛查低血糖的生物标志物。 OD 等级可识别罹患 OSCC 的高风险人群，以实施循证癌症预防 管理。多项研究报告了口腔癌发生过程中 DNA 甲基化的变化，但未能解决这一问题 渐进与静态低级 OD 之间的差异或生成全基因组覆盖 足够的宽度和深度以实现最大的新发现。我们的长期目标是了解表观遗传 驱动癌前病变恶性进展的机制。 R21 的目标是 使用整体发现与 OPL 进展相关的新差异甲基化区域 (DMR) 基因组单核苷酸分辨率方法，创建新的基于 DMR 的模型，并验证其能力 预测低级别 OD 进展为 OSCC。该 R21 的中心假设指出 OPL 进展为 OSCC 是由全基因组发现的 DNA 甲基化变化驱动的 进行性 OPL 与静态 OPL 的 DMR 分析，用于预测 OPL 的癌症风险以进行管理 决定。该假设是基于以下科学前提提出的：1）表观遗传修饰是一种 捕获早期致癌环境基因相互作用事件的关键疾病驱动机制 在整个疾病进展过程中忠实地保存，并且 2) DNA 甲基化变化已被证明 与正常口腔上皮相比，发生在 OD 和 OSCC 中。进行拟议研究的理由 是一旦基于高质量识别出渐进式 OD 和静态 OD 之间的 DMR 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 位点 低等级 OD，否则会被错过。目标 1 将发现差异基因组区域 使用全基因组亚硫酸氢盐测序 (WGBS) 进行渐进性与静态低级 OD 甲基化 具有纵向跟踪的样本。目标 2 将创建基于 DMR 的模型并验证其功能 预测低级别 OD 进展为 OSCC 的风险。成功完成预计会发现 新的 DMR 能够区分渐进式 OD 与静态 OD，并创建新颖的风险预测 DMR 模型。 该结果将满足对敏感且可靠的筛查方法的迫切需求，以预测 OPL 风险 在早期阶段成为 OSCC，此时医疗干预措施更有效且破坏性更小，这 将直接影响减少 OSCC 和相关健康问题的发生率，并发现 驱动 OSCC 恶性进展的新型 DNA 甲基化机制可能是可药物化的。它可能 对推进其他与烟草相关的 HNSCC 的研究也具有广泛的影响。