Delineating chromatin-related gene expression signatures as a function of HNSCC progression

摘要 口腔鳞状细胞癌(OSCC)是头颈部癌(HNSCC)最常见的亚型，具有 可用的靶向治疗很少，总体存活率很低。基于高吞吐量的新策略 分析为改进风险评估、癌症早期发现、治疗干预和 肿瘤监测，但这些策略的影响一直有限，因为对 口腔癌的生物学，特别是在其早期发展阶段。像其他实体恶性肿瘤一样，口腔鳞状细胞癌始于 作为由遗传和表观遗传的一系列获取所驱动的肿瘤前细胞增殖 改装。近20%的口腔鳞状细胞癌患者有多个癌前病变，显示出不典型增生的迹象， 通常在视觉上被识别为白斑或红斑。随着这些病变中的一些演变为恶性肿瘤， 它们代表了口腔鳞癌进展的中间步骤。从正常上皮到早期的这个多步骤的过程 癌前病变为原位癌(CIS)和完全浸润性癌提供了合理的框架 研究口腔鳞癌进展过程中的分子变化。然而，相对较少的致癌突变 对口腔鳞状细胞癌的发展至关重要的是目前公认的，阻碍了新的靶向治疗的发现。 此外，单靠突变不足以解释基因表达的广谱变化。 描述OSCC的特征。 增强子的全基因组分布是染色质的功能元件，与 多发性实体恶性肿瘤的发展，并介导广泛的基因组变化，包括表达 已知的癌症驱动基因。尽管越来越明显的是，增强剂是其 靶基因和增强子基因组元件正迅速成为抗癌的有效靶点 治疗学：口腔鳞状细胞癌染色质修饰和基因表达模式之间的联系尚不清楚 在口腔癌前病变中没有全面的分子信息可用。这个项目将 使用新的生物信息学和实验方法来验证核心假设，即转录变化， 在口腔鳞状细胞癌发生过程中，由动态染色质改变所致。我们的综合分析 会将基因表达和甲基化情况与相应的癌症评估相结合- 口腔鳞癌进展过程中特有的增强子表型。描述了时间和时间 基因表达变化与染色质组织标志顺序一致的方式 口腔内进行性病变(如轻度异型增生、中度异型增生、重度异型增生/CIS，以及 侵袭性口腔鳞状细胞癌)将产生第一个全面的HNSCC进化表观遗传学图谱，并将定义关键 表观遗传调控的基因，驱动口腔鳞癌的发生。此外，评估它们的生物学和 临床相关性可能为开发针对这些基因的新干预策略开辟一条肥沃的途径 在HNSCC的不同发育阶段。

Summary Oral squamous cell carcinoma (OSCC), the most common subtype of head and neck carcinoma (HNSCC), has very few targeted therapies available and poor overall survival. Novel strategies based on the high-throughput analyses offer new hope for improved risk assessment, early cancer detection, therapeutic intervention and tumor surveillance, but the impact of these strategies has been limited by an incomplete understanding of the biology of oral cancer, particularly in its early developmental stages. Like other solid malignancies, OSCCs begin as pre-neoplastic cellular proliferation that are driven by the serial acquisition of genetic and epigenetic alterations. Nearly 20% of patients with OSCC harbor multiple pre-malignant lesions showing signs of dysplasia, often visually identified as leukoplakia or erythroplakia. As some of these lesions evolve to malignant neoplasms, they represent intermediate steps in OSCC progression. This multi-step process from normal epithelium to early premalignant change to carcinoma in situ (CIS) and fully invasive carcinoma, provides a rational framework for studying molecular alterations underlying the OSCC progression. However, relatively few oncogenic mutations critical to the development of OSCC are currently recognized, impeding discovery of novel targeted therapeutics. Moreover, mutations alone are insufficient to explain the broad spectrum of gene expression changes that characterize OSCC. Whole-genome distribution of enhancers, the functional elements of the chromatin, is associated with the development of multiple solid malignancies, and mediates widespread genomic changes including expression of known cancer driver genes. Although it is becoming apparent that enhancers are the critical regulators of their target genes, and enhancer genomic elements are rapidly emerging as potent targets for anti-cancer therapeutics, the association between chromatin modifications and gene expression patterns in OSCC is not yet defined, and no comprehensive molecular information is available in oral pre-neoplastic lesions. This project will use novel bioinformatics and experimental approaches to test the central hypothesis that transcriptional changes, which arise during OSCC carcinogenesis, are enabled by dynamic chromatin alterations. Our integrated analysis will couple the gene expression and methylation landscape with a corresponding evaluation of the cancer- specific enhancer phenotype throughout the continuum of OSCC progression. Characterizing the timing and manner by which gene expression alterations coincide with markers of chromatin organization in sequentially progressive lesions within the oral cavity (e.g. mild dysplasia, moderate dysplasia, severe dysplasia/CIS, and invasive OSCC) will yield the first comprehensive epigenetic map of HNSCC evolution, and will define the key epigenetically regulated genes that drive OSCC carcinogenesis. Furthermore, evaluating their biological and clinical relevance may open up a fertile avenue for developing novel intervention strategies targeting these genes at various developmental stages of HNSCC.