Oral Dysplasias to Carcinomas: Multi-omics Study of Progression

口腔发育不良到癌症：进展的多组学研究

• 批准号: 10770832
• 负责人: LAURA ROZEK
• 金额: $ 70.66万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10770832
• 关键词: Accounting; Address; Affect; Alcohol consumption; Apoptosis; Bioinformatics; Biological; Biological Markers; Board Certification; Cancer Biology; Candidate Disease Gene; Carcinoma; Cell Adhesion; Cell Cycle Checkpoint; Characteristics; Clinic; Clinical; Collaborations; DNA Methylation; DNA Repair; DNA copy number; DNA sequencing; Data; Diagnosis; Disease; Doctor of Philosophy; Dysplasia; Early Diagnosis; Early identification; Epidemiology; Epigenetic Process; Frequencies; Funding; Gene Expression; Genes; Genetic; Genomics; Goals; Growth Factor; Head and neck structure; Heterogeneity; Hospitals; Individual; Intraepithelial Neoplasia; Lesion; Lesion by Stage; Light; Longitudinal Studies; Longitudinal cohort; Malignant Neoplasms; Manuscripts; Methods; Michigan; Molecular; Molecular Profiling; Monitor; Mutation; Operative Surgical Procedures; Oral; Oral Diagnosis; Oral cavity; Oral mucous membrane structure; Pathologic; Pathologist; Pathway interactions; Patients; Phenotype; Population; Prevention approach; Preventive measure; Progressive Disease; Proliferating; Publishing; Quality of life; Recurrence; Reporting; Research; Risk; Risk Marker; Sample Size; Sampling; Scientist; Signal Transduction; Site; Smoking; Somatic Mutation; Survival Rate; T-Lymphocyte; Technology; Testing; The Cancer Genome Atlas; Time; Tissues; Training; Transcript; United States National Institutes of Health; Universities; Validation; Work; biomarker discovery; biomarker identification; candidate identification; candidate marker; carcinogenesis; cohort; colon carcinogenesis; data integration; detection test; disability; early detection biomarkers; epigenetic marker; exome sequencing; follow-up; histone methyltransferase; improved; individualized prevention; innovation; insight; keratinocyte; malignant mouth neoplasm; maxillofacial; molecular marker; mouth squamous cell carcinoma; multiple omics; oral carcinogenesis; oral cavity epithelium; oral dysplasia; oral lesion; patient subsets; personalized medicine; predictive marker; premalignant; progression marker; progression risk; prospective; risk prediction; sex; standard care; standard of care; success; transcriptome sequencing; transcriptomics; tumor

Abstract Oral squamous cell carcinomas (OSCCs) account for 35-38% of head and neck SCC, the 6th most common cancer worldwide, and have a disappointing 5-year survival rate of ~50%. Oral epithelial dysplasia (OED) are precursors to OSCC, but many go undiagnosed. Studies of OED allow characterization of the aberrant molecular changes that lead to cancer. Yet due to inconsistencies in standard care and a lack of sufficient longitudinal data, few studies have examined the molecular characteristics that drive the transformation of OED to OSCC across time in the same patients to identify features unique to recurrence with progression. There are very few longitudinal studies of OED progression, and those that exist have little epidemiologic characterization and lack data integration from multi-omics. Additionally, existing reports concentrate on a few common candidate genes and/or are limited to a small sample size. We will use our uniquely detailed longitudinal cohort of OED to integrate clinical, histopathologic, epidemiologic and multiple molecular characteristics of OED lesions to identify those hallmarks of OED lesions that lead to OSCC. This will benefit patients by leading to improved risk prediction, more effective preventive measures, and insight into OSCC biomarkers that indicate carcinogenesis. Use of a large, highly-characterized longitudinal cohort for this type of multi-omics study, while using a second, independent population to validate generalizability, is highly innovative. Viewed in light of the molecular profiles of OSCCs identified from our current set of tumors and from TCGA HNSC data, this study will enable us to focus on the most relevant, recurrent changes, and understand how OSCCs that proceed OED fit into the heterogeneity of overall OSCCs. Identification of biomarkers predictive of progression will enable clinicians to provide more targeted preventive measures, and vary the extensiveness of surgery and frequency of monitoring to increase quality of life. In Aim 1, we will use existing samples identify genomic, transcriptomic, and epigenetic profile signatures distinguishing progressors from non-progressors at diagnosis for each OED stage. Our approach allows us to identify a set of candidate biomarkers that distinguish high from low risk lesions, accounting for important biologic variables. The goal of Aim 2 is to chart the timing of key genomic, transcriptomic, and epigenetic changes associated with progression to OSCC, using extensive longitudinal cases, and comparing observed changes to genes and pathways known to be aberrant in OSCC. In Aim 3, we will validate the characterization of our unique longitudinal clinical cohort in OED with and without a subsequent diagnosis of OSCC from the University of Michigan to identify clinicopathologic and epidemiologic predictors of recurrence with progression.

摘要 口腔鳞状细胞癌(OSCC)占头颈部鳞状细胞癌的35-38%，居第六位 癌症在全世界范围内都是如此，而且令人失望的是5年存活率只有50%。口腔上皮异型增生(OED)是 口腔鳞状细胞癌的前驱症状，但许多没有被诊断出来。《牛津英语词典》的研究可以刻画这种异常 导致癌症的分子变化。然而，由于标准护理的不一致和缺乏足够的 在纵向数据中，很少有研究考察驱动细胞转化的分子特征 OED检查同一患者的口腔鳞状细胞癌的时间跨度，以确定复发和进展的独特特征。 关于牛津英语学习障碍进展的纵向研究很少，那些存在的研究也几乎没有流行病学 定性和缺乏多组学的数据集成。此外，现有报告集中在以下几个方面 常见的候选基因和/或仅限于小样本大小。我们将用我们独一无二的细节 整合临床、组织病理学、流行病学和多分子的OED纵向队列 以确定导致口腔鳞状细胞癌的OED病变的特征。这将使我们受益 通过改进风险预测、更有效的预防措施和对口腔鳞状细胞癌的洞察来帮助患者 指示致癌的生物标记物。对这种类型的大的、高度特征化的纵向队列的使用 多组学研究，同时使用第二个独立的群体来验证泛化，是高度 创新。根据我们目前发现的一组肿瘤和口腔鳞状细胞癌的分子图谱 从TCGA hNSC数据中，这项研究将使我们能够专注于最相关的、反复发生的变化，以及 了解OSCC如何适应整体OSCC的异质性。身份识别 预测进展的生物标志物将使临床医生能够提供更有针对性的预防措施，以及 改变手术的广泛性和监测的频率，以提高生活质量。 在目标1中，我们将使用现有样本确定基因组、转录和表观遗传学特征 在诊断每个OED阶段时区分进步者和非进步者的特征。我们的方法 使我们能够识别一组区分高风险和低风险损害的候选生物标志物，解释 重要的生物变量。目标2的目标是绘制关键基因组、转录本和 与进展为口腔鳞癌相关的表观遗传学改变，使用广泛的纵向病例，并比较 观察到口腔鳞状细胞癌中已知异常的基因和通路的变化。在目标3中，我们将验证 我们独特的纵向临床队列特征在有和没有随后诊断的OED中 密歇根大学口腔鳞状细胞癌的临床病理和流行病学复发预测因素 与时俱进。