Integrative epigenomic/genomic profiling and biomarker discovery in HPV+ and HPV-

HPV 和 HPV- 的综合表观基因组/基因组分析和生物标志物发现

• 批准号: 8193428
• 负责人: LAURA ROZEK
• 金额: $ 49.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-14 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193428
• 关键词: Accounting; Automobile Driving; Behavior; Benchmarking; Bioinformatics; Biological Markers; Carcinogens; Cell Line; Cervical Squamous Cell Carcinoma; Clinical; Clinical Trials; Communities; Complex; DNA Methylation; DNA Modification Process; Data; Development; Employee Strikes; Epidemiological Factors; Epigenetic Process; Etiology; Excision; Gene Expression; Genome; Genomics; Goals; HPV-High Risk; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human Papillomavirus; Incidence; Individual; Knowledge; Life; Light; Link; Malignant Epithelial Cell; Malignant Neoplasms; Methods; Michigan; Molecular; Molecular Epidemiology of Cancer; National Center for Integrative Biomedical Informatics; Normal Cell; Oral; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Pathway interactions; Patients; Persons; Population Sciences; Primary Neoplasm; Recurrence; Research; Risk; Risk Factors; Role; Sampling; Site; Smoker; Smoking; Specialized Program of Research Excellence; Specimen; Squamous cell carcinoma; Survival Rate; The Cancer Genome Atlas; Therapeutic; Tobacco; Tobacco-Associated Carcinogen; Translational Research; Tumor Cell Line; Universities; Validation; advanced disease; base; carcinogenesis; chemical carcinogenesis; clinically relevant; epigenomics; experience; functional genomics; genome-wide; high throughput technology; histone modification; improved; innovation; keratinocyte; malignant oropharynx neoplasm; malignant tongue neoplasm; malignant tonsil neoplasm; neoplastic cell; next generation; non-genetic; non-smoker; novel; outcome forecast; patient population; protein expression; response; tool; transcriptomics; tumor

DESCRIPTION (provided by applicant): It is clear that differences exist between the molecular mechanisms in HPV-induced squamous cell carcinomas (SCCs) and those linked to tobacco carcinogens. Currently, treatment of head and neck SCC (HNSCC) is not based on HPV status. The incidence of tonsil and tongue cancers have been increasing annually and many contain high risk HPV. It is important to understand differing factors of carcinogenesis in HPV(+) and HPV(-) HNSCC to develop personalized treatment approaches. To do this requires more knowledge of the molecular mechanisms that drive tumor behavior and response to therapy in HPV(+) vs HPV(-) SCCs. Our preliminary data indicate that there are striking epigenetic differences between HPV+ and HPV- tumors, but to appreciate these differences, they must be considered in light of gene expression and other somatic changes. We propose to use gene expression, DNA methylation and histone modifications, and copy number changes to identify molecular mechanisms that define and differentiate HPV-induced from carcinogen-induced HNSCC. The overall objective of this proposal is to understand the differences in the aberrant molecular pathways leading to carcinogenesis in HPV(+) and HPV(-) HNSCCs taking into account smoking and additional epidemiological factors. Our central hypothesis is that by using advanced, integrative bioinformatics methods on the genomic and epigenomic profiles of HPV+ and HPV- tumor cells, we will be able to subdivide HPV+ and HPV- tumors into high and low risk subsets. Our long term goal is to accurately predict and apply the most appropriate treatment regimes for individual HPV+ and HPV- HNSCCs based on smoking, molecular factors and new targets identified in this study. In the first aim, whole-genome analyses will be performed on a well-characterized panel of HPV+ and HPV- oropharyngeal cell lines and primary oral/oropharyngeal (OPSCC) tumors from HPV+ smokers, HPV+ non-smokers, and HPV- ever smokers, and relevant normal cells to define and distinguish aberrant molecular pathways for each etiology. Aim 2 will integrate and characterize genomic, epigenomic and corresponding gene expression changes to prioritize results based on clinical relevancy by developing, validating, and applying integrative methods for the analysis of multifaceted deep sequencing data. Aim 3 will identify and validate top prioritized findings in a larger sample of primary tumor samples. This will confirm clinically important biomarkers and identify aberrant changes associated with etiology, recurrence, or survival in tumor cells from clinical specimens. Our tiered approach from high-throughput technologies to validation in a patient population together with innovative bioinformatics approaches will pave the way to understanding and exploiting somatic differences for optimal therapeutic application. Collectively, our proposed studies will bring us closer to personalized treatment regimes for OPSCCs, as well as provide valuable, accessible tools to the research community for integrative analysis and interpretation of deep sequencing data. PUBLIC HEALTH RELEVANCE: Certain types of squamous cell carcinomas can be caused by the human papillomavirus (HPV), while others are not. In this proposal, we will study the non-genetic DNA modifications that modify protein expression and cellular behavior between HPV+ and HPV- cancers using advanced bioinformatics methods to understand the survival differences between these two types of tumors.

描述(由申请人提供)：很明显，在HPV诱导的鳞状细胞癌(SCCs)和那些与烟草致癌物有关的分子机制之间存在差异。目前，头颈部鳞状细胞癌(HNSCC)的治疗不是基于HPV状态。扁桃体和舌癌的发病率一直在逐年上升，其中许多都含有高危HPV。了解HPV(+)和HPV(-)HNSCC的不同致癌因素对于开发个性化的治疗方法非常重要。要做到这一点，需要更多地了解在HPV(+)与HPV(-)SCC中驱动肿瘤行为和治疗反应的分子机制。我们的初步数据表明，HPV+和HPV-肿瘤之间存在显著的表观遗传学差异，但要理解这些差异，必须结合基因表达和其他躯体变化来考虑。我们建议使用基因表达、DNA甲基化和组蛋白修饰以及拷贝数变化来确定定义和区分HPV诱导和致癌物诱导的HNSCC的分子机制。这项建议的总体目标是在考虑吸烟和其他流行病学因素的情况下，了解导致HPV(+)和HPV(-)HNSCC致癌的异常分子途径的差异。我们的中心假设是，通过使用先进的综合生物信息学方法对HPV+和HPV-肿瘤细胞的基因组和表观基因组图谱进行分析，我们将能够将HPV+和HPV-肿瘤细分为高风险和低风险亚组。我们的长期目标是根据吸烟、分子因素和本研究确定的新靶点，准确预测和应用最合适的治疗方案来治疗单个HPV+和HPV-HNSCC。在第一个目标中，将对HPV+和HPV-口咽细胞系以及来自HPV+吸烟者、HPV+非吸烟者和曾经吸烟者的原发口腔/口咽(OPSCC)肿瘤以及相关的正常细胞进行全基因组分析，以确定和区分每种病因的异常分子通路。目标2将整合和表征基因组、表观基因组和相应的基因表达变化，通过开发、验证和应用综合方法来分析多方面的深度测序数据，以基于临床相关性来确定结果的优先顺序。AIM 3将在更大的原发肿瘤样本样本中识别和验证最优先的发现。这将确认临床上重要的生物标志物，并从临床标本中识别与肿瘤细胞的病因、复发或生存相关的异常变化。我们从高通量技术到在患者群体中进行验证的分级方法，以及创新的生物信息学方法，将为理解和利用体细胞差异以实现最佳治疗应用铺平道路。总体而言，我们建议的研究将使我们更接近OPSCC的个性化治疗制度，并为研究界提供有价值的、可获得的工具，用于对深度测序数据进行综合分析和解释。 与公共卫生相关：某些类型的鳞状细胞癌可能是由人类乳头瘤病毒(HPV)引起的，而其他类型的鳞癌不是。在这个提案中，我们将利用先进的生物信息学方法研究改变HPV+和HPV-癌症之间蛋白质表达和细胞行为的非遗传DNA修饰，以了解这两种类型肿瘤之间的生存差异。