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.

摘要口腔鳞状细胞癌(OSCC)是一种可能起源于粘膜前体的破坏性恶性肿瘤。 病变，称为口腔癌前病变(OPLS)。OPLS由低度和高度异型增生(OD)组成。 尽管大多数低级别OD保持稳定多年，有些甚至自发退化，但显著的 少数(4%-11%)口腔鳞癌进展迅速。目前，还没有可用于筛查低血压病的生物标志物 识别口腔鳞癌高危人群的ODs，以实施循证癌症预防 管理层。几项研究报告了口腔癌变过程中DNA甲基化的变化，但未能解决 渐进性和静止性低级别OD或生成全基因组覆盖之间的差异 有足够的宽度和深度来最大限度地进行新发现。我们的长期目标是了解表观遗传学 推动癌前病变恶性进展的机制。这款R21的目标是 使用完整的-发现与OPL进展相关的新的差异甲基化区域(DMR)- 基因组单核苷酸解析方法，创建基于DMR的新模型，并验证其在 预测低级别OD向口腔鳞状细胞癌的进展。这个R21的中心假设是 全基因组可发现的DNA甲基化改变推动了OPLS向OSCC的进展 进展型与静止型OPLS的DMR分析及用于预测OPLS癌风险的管理 决定。这一假说是基于以下科学前提提出的：1)表观遗传修饰是一种 捕捉早期致癌环境-基因相互作用事件的关键致病机制 在疾病发展过程中被忠实地保存下来，2)DNA甲基化变化已被证明 与正常口腔上皮相比，发生在口腔鳞癌和口腔鳞癌中。进行拟议研究的理由 是一旦基于高质量识别了渐进和静态OD之间的DMRS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ODD，否则就会被错过。目标1将以不同的方式发现基因组区域 在进行性和静止性低等级OD中使用全基因组亚硫酸氢盐测序(WGBS)进行甲基化 有纵向随访的样本。AIM 2将创建基于DMR的模型，并在 预测进展为口腔鳞癌的低级别口服避孕药的风险。如果成功完成，预计会发现 新的DMR能够区分渐进性和静态OD，并创建新的风险预测DMR模型。 这一结果将满足对敏感和可靠的筛查方法的迫切需求，以预测OPLS的风险 在早期阶段成为口腔鳞状细胞癌，此时医疗干预更有效，破坏性更小， 将对减少口腔鳞状细胞癌和相关健康问题的发生率产生直接影响，以及 新的DNA甲基化机制推动口腔鳞状细胞癌的恶性进展，可能是可药物治疗的。它可能 对推进其他烟草相关HNSCC的研究也有广泛的影响。