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.

抽象的 口服鳞状细胞癌（OSCC）占头颈SCC的35-38％，这是第六个最常见的 全球癌症，令人失望的5年生存率约为50％。口腔上皮发育不良（OED）为 OSCC的前体，但许多人未被诊断。 OED的研究允许异常表征 导致癌症的分子变化。然而，由于标准护理的不一致，缺乏足够的 纵向数据，很少有研究检查了驱动转化的分子特征 在同一患者中，OED向OSCC到OSCC，以识别随着进展的复发特征。 OED进展的纵向研究很少，并且存在的流行病学很少 表征和缺乏来自多词的数据集成。此外，现有报告集中于一些 普通候选基因和/或仅限于较小的样本量。我们将使用我们独特的详细信息 OED的纵向队列以整合临床，组织病理学，流行病学和多个​​分子 OED病变的特征，以识别导致OSCC的OED病变的标志。这将受益 通过改善风险预测，更有效的预防措施以及对OSCC的洞察力，通过改善患者 表明癌变的生物标志物。使用这种类型的大型，高度特征的纵向队列 多词的研究虽然使用第二个独立人群来验证普遍性，但高度 创新的。根据我们当前一组肿瘤和 从TCGA HNSC数据中，这项研究将使我们能够专注于最相关的，经常性的变化和 了解如何将OSCC符合整体OSCC的异质性。识别 预测进展的生物标志物将使临床医生能够提供更多针对性的预防措施，并 改变手术和监测频率以提高生活质量的频率。 在AIM 1中，我们将使用现有样品识别基因组，转录组和表观遗传概况 在每个OED阶段，在诊断时将进步者与非培训者区分开的特征。我们的方法 允许我们确定一组将高风险病变区分开的候选生物标志物 重要的生物学变量。目标2的目的是绘制关键基因组，转录组和 使用广泛的纵向案例，与向OSCC发展相关的表观遗传学变化，并比较 在OSCC中观察到的基因和途径的变化。在AIM 3中，我们将验证 表征我们在OED中有和没有随后诊断的独特纵向临床队列的表征 密歇根大学的OSCC识别复发的临床病理学和流行病学预测因子 随着进展。