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

描绘染色质相关基因表达特征作为 HNSCC 进展的函数

• 批准号: 10331096
• 负责人: Daria A Gaykalova
• 金额: $ 47.57万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331096
• 关键词: Delineating; chromatin; related; gene; expression

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.

概括 口腔鳞状细胞癌（OSCC）是头颈癌（HNSCC）最常见的亚型， 可用的靶向治疗很少，总体生存率较差。基于高通量的新策略 分析为改进风险评估、早期癌症检测、治疗干预和 肿瘤监测，但这些策略的影响因对肿瘤监测的不完全了解而受到限制 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 变更。近 20% 的 OSCC 患者存在多个恶变前病变，显示出不典型增生的迹象， 通常通过视觉识别为白斑或红斑。随着其中一些病变演变为恶性肿瘤， 它们代表 OSCC 进展的中间步骤。这个从正常上皮细胞到早期细胞的多步骤过程 癌前变化为原位癌（CIS）和完全浸润性癌，为 研究 OSCC 进展的分子改变。然而，致癌突变相对较少 目前认识到对 OSCC 的发展至关重要，这阻碍了新型靶向治疗方法的发现。 此外，仅突变不足以解释广泛的基因表达变化 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。尽管增强子是其关键调节剂已变得越来越明显 靶基因和增强子基因组元件正在迅速成为抗癌的有效靶标 治疗方面，OSCC 中染色质修饰与基因表达模式之间的关联尚不清楚 定义，并且在口腔肿瘤前病变中没有全面的分子信息。该项目将 使用新颖的生物信息学和实验方法来测试转录变化的中心假设， 它是在 OSCC 癌变过程中出现的，是由动态染色质改变引起的。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 整个 OSCC 进展过程中的特定增强子表型。表征时间和 基因表达改变与染色质组织标记顺序一致的方式 口腔内进行性病变（例如轻度不典型增生、中度不典型增生、重度不典型增生/CIS 和 侵袭性 OSCC）将产生第一个 HNSCC 进化的全面表观遗传图谱，并将定义关键 驱动 OSCC 癌变的表观遗传调控基因。此外，评估他们的生物学和 临床相关性可能为开发针对这些基因的新型干预策略开辟一条肥沃的途径 HNSCC 的各个发展阶段。