Oral Dysplasias to Carcinomas: Multi-omics Study of Progression

摘要 口腔鳞状细胞癌（OSCC）占头颈部鳞状细胞癌的35-38%，是第六常见的 癌症，并且具有令人失望的~ 50%的5年存活率。口腔上皮发育不良（OED）是 口腔鳞状细胞癌的前体，但许多未被诊断。OED的研究允许描述异常的 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 纵向数据，很少有研究探讨了推动转型的分子特征， 同一患者不同时间的OED到OSCC，以确定复发与进展的独特特征。 很少有关于OED进展的纵向研究，而且那些存在的研究几乎没有流行病学研究。 表征和缺乏来自多组学的数据集成。此外，现有的报告集中在几个方面， 共同的候选基因和/或限于小样本量。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、流行病学和多分子 OED病变的特征，以确定导致OSCC的OED病变的标志。这将有利于 通过改善风险预测，更有效的预防措施和对OSCC的了解， 指示致癌作用的生物标志物。使用一个大型的，高度特征化的纵向队列， 多组学研究，而使用第二个，独立的人口来验证普遍性，是高度 新颖啊从我们目前的肿瘤组中鉴定出的OSCC的分子谱来看， 根据美国技术中心全球大气局的HNSC数据，这项研究将使我们能够把重点放在最相关的、经常性的变化上， 理解OED的OSCC如何适应整体OSCC的异质性。鉴定 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， 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，我们将使用现有的样品鉴定基因组、转录组和表观遗传谱 在每个OED阶段的诊断时区分进展者和非进展者的特征。我们的方法 使我们能够识别一组区分高风险病变和低风险病变的候选生物标志物， 重要的生物学变量。目标2的目标是绘制关键基因组、转录组和 表观遗传学变化与OSCC进展相关，使用广泛的纵向病例，并比较 观察到的变化，基因和途径已知是异常的口腔鳞状细胞癌。在目标3中，我们将验证 我们独特的纵向OED临床队列的特征，有和没有随后的诊断 密歇根大学的OSCC，以确定复发的临床病理学和流行病学预测因子 有进步。

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.