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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

基本信息

批准号：
10390319
负责人：
Daria A Gaykalova
金额：
$ 40.72万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
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/10390319
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 DNA Binding DNA Binding Domain DNA methylation profiling Dependence Detection Development Diagnosis Disease Dysplasia Elements Enhancers Epigenetic Process Epithelial 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 Lesion Leukoplakia Malignant - descriptor Malignant Neoplasms Maps Mediating Methylation Mild Dysplasia Moderate Dysplasia Molecular 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 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 Tissues anti-cancer therapeutic base 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 preventive intervention targeted treatment transcriptome sequencing tumor tumor initiation tumor progression whole genome

项目摘要

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.

总结