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

总结 口腔鳞状细胞癌（OSCC）是头颈部癌（HNSCC）最常见的亚型， 很少有靶向治疗，总体生存率低。基于高通量的新策略 分析为改善风险评估、早期癌症检测、治疗干预和 肿瘤监测，但这些策略的影响受到对肿瘤的不完全理解的限制。 口腔癌的生物学，特别是在其早期发展阶段。与其他实体恶性肿瘤一样，OSCC开始 作为肿瘤前细胞增殖，由遗传和表观遗传的连续获得驱动， 改变。近20%的口腔鳞状细胞癌患者有多处癌前病变，表现为异型增生的迹象， 通常在视觉上被识别为白斑病或红斑病。随着这些病变中的一些发展为恶性肿瘤， 它们代表OSCC进展的中间步骤。从正常上皮细胞到早期上皮细胞的多步骤过程 癌前病变为原位癌（CIS）和完全浸润性癌，提供了合理的框架， 研究口腔鳞状细胞癌进展背后的分子变化。然而，相对较少的致癌突变 目前认识到对OSCC的发展至关重要，阻碍了新的靶向治疗剂的发现。 此外，突变本身不足以解释基因表达变化的广泛范围， 表征OSCC。 增强子（染色质的功能元件）的全基因组分布与 多种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。尽管增强子是其功能的关键调节剂， 靶基因和增强子基因组元件正迅速成为抗癌的有效靶点 在治疗方面，OSCC中染色质修饰与基因表达模式之间的联系尚不清楚 定义，没有全面的分子信息可用于口腔癌前病变。该项目将 使用新的生物信息学和实验方法来测试核心假设，即转录变化， 在口腔鳞状细胞癌发生过程中出现，是由动态染色质改变。我们的综合分析 将把基因表达和甲基化景观与癌症的相应评估结合起来， 特异性增强子表型在整个OSCC进展的连续性。描述时间和 基因表达改变与染色质组织标志物相一致的方式， 口腔内的进行性病变（例如轻度发育不良、中度发育不良、重度发育不良/CIS，以及 侵袭性OSCC）将产生HNSCC进化的第一个全面的表观遗传图谱，并将定义HNSCC进化的关键。 表观遗传调控基因驱动OSCC致癌。此外，评估其生物学和 临床相关性可能为开发针对这些基因的新干预策略开辟了一条肥沃的途径 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.