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: 10620313
• 负责人: Daria A Gaykalova
• 金额: $ 32.59万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620313
• 关键词: Affect; Algorithms; Apoptosis; Bioinformatics; Biological; Biology; Carcinoma; Carcinoma in Situ; Cell Line; Cell Proliferation; ChIP-seq; Chromatin; Chromatin Structure; Computer software; Coupled; DNA Binding; DNA Binding Domain; DNA Methylation; DNA analysis; DNA methylation profiling; Dependence; Detection; Development; Diagnosis; Disease; Dysplasia; Elements; Enhancers; Epigenetic Process; Epithelium; Erythroplasia; Evaluation; Event; Evolution; Excision; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genomics; Head and Neck Squamous Cell Carcinoma; Histologic; Histones; Intervention; Invaded; Lesion; Leukoplakia; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Methylation; Mild Dysplasia; Moderate Dysplasia; Molecular; Mouth Carcinoma; Mouth Neoplasms; Multiomic Data; Mutation; Oncogenic; Oral; Oral Characters; Oral Surgical Procedures; Oral cavity; Oral mucous membrane structure; Pathway interactions; Patients; Pattern; Phenotype; Premalignant Cell; Premalignant Change; Prevention; Prevention strategy; Primary Neoplasm; Process; Proteins; Protocols documentation; Public Health; RNA; Reader; Recurrence; Residual state; Risk Assessment; Role; Sampling; Screening for cancer; Severe dysplasia; Signal Pathway; Solid; Specimen; Testing; Therapeutic Intervention; Tissue Microarray; Visual; anti-cancer therapeutic; carcinogenesis; chromatin modification; clinically relevant; clinically significant; design; epigenomics; follow-up; gene discovery; genome-wide; high throughput analysis; improved; inhibitor; malignant mouth neoplasm; migration; mouth squamous cell carcinoma; neoplastic; new therapeutic target; novel; novel strategies; oral dysplasia; oral lesion; oral tumorigenesis; premalignant; targeted treatment; transcriptome sequencing; tumor; tumor initiation; tumor progression; whole genome

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）是头和颈癌最常见的亚型（HNSCC） 很少有针对性疗法可用，总生存率差。基于高通量的新型策略 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 口腔癌的生物学，特别是在其早期发育阶段。像其他坚实的恶性肿瘤一样，OSCC开始 作为由遗传和表观遗传学的连续采集驱动的肿瘤前细胞增殖 改变。 OSCC患者中，近20％的患者携带多个恶性病变，显示出发育不良的迹象， 通常在视觉上被识别为白细胞或赤型紫罗兰氏菌。随着其中一些病变演变为恶性肿瘤， 它们代表OSCC进程中的中间步骤。从正常上皮到早期的多步骤过程 对原位癌（CI）和完全侵入性癌的预立法变化为合理的框架提供了合理的框架 研究OSCC进展的基础分子改变。但是，相对较少的致癌突变 目前对OSCC的发展至关重要，这阻碍了对新颖的靶向治疗剂的发现。 此外，仅突变不足以解释基因表达的广泛变化，这些变化 特征OSCC。 增强子的全基因组分布（染色质的功能元素）与 发展多种固体恶性肿瘤，并介导广泛的基因组变化，包括表达 已知的癌症驱动基因。尽管显而易见的是增强剂是其关键调节者 靶基因和增强子基因组元素迅速成为抗癌的有效靶标 疗法，OSCC中染色质修饰与基因表达模式之间的关联尚未 定义，并且在口服肿瘤前病变中没有全面的分子信息。这个项目将 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， 在OSCC癌变期间出现的，由动态染色质改变启用。我们的综合分析 将将基因表达和甲基化景观与癌症的相应评估融入 在OSCC进展的整个过程中，特定的增强子表型。表征时间和 基因表达改变与伴有染色质组织标记的方式依次 口腔内的进行性病变（例如，轻度发育不良，中等异常，严重的发育不良/顺染和 Invasive OSCC）将产生HNSCC进化的第一张全面的表观遗传图，并将定义密钥 驱动OSCC癌变的表观遗传调节基因。此外，评估其生物学和 临床相关性可能会为制定针对这些基因的新型干预策略开辟肥沃的途径 在HNSCC的各个发展阶段。