5-hydroxymethylcytosine in HPV(+) and HPV(-) oral and oropharyngeal cancers

HPV( ) 和 HPV(-) 口腔癌和口咽癌中的 5-羟甲基胞嘧啶

• 批准号: 8958840
• 负责人: Maureen Agnes Sartor
• 金额: $ 23.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958840
• 关键词: Affect; Bioinformatics; Biological Markers; Clinical; Clinical Data; Copy Number Polymorphism; DNA; DNA Methylation; DNA Sequence Alteration; Data; Databases; Diagnosis; Diet; Epidemiology; Epigenetic Process; Event; Freezing; Future; Gene Expression; Genome; Genomics; Goals; Grant; HPV-High Risk; Head and Neck Squamous Cell Carcinoma; Head and neck structure; High-Throughput Nucleotide Sequencing; Human Papillomavirus; Human papillomavirus 18; Laboratories; Lead; Light; Link; Malignant Neoplasms; Measurement; Measures; Methods; Methylation; Molecular; Mouth Neoplasms; Normal tissue morphology; Oral cavity; Oropharyngeal; Oropharyngeal Neoplasms; Oropharyngeal Squamous Cell Carcinoma; Outcome; Patients; Pattern; Play; Population; Process; Prognostic Marker; Research; Role; Sample Size; Sampling; Side; Signal Transduction; Site; Subgroup; Testing; The Cancer Genome Atlas; Tissues; Tobacco use; Transcriptional Regulation; Translating; Viral; base; bead chip; bisulfite; bisulfite sequencing; carcinogenesis; clinically relevant; deep sequencing; demethylation; epigenomics; follow-up; genome-wide; insight; leukemia; malignant mouth neoplasm; malignant oropharynx neoplasm; novel; outcome forecast; programs; promoter; public health relevance; response; targeted treatment; tool; transcriptome sequencing; transcriptomics; tumor

 DESCRIPTION (provided by applicant): Differences in molecular mechanisms between human papillomavirus (HPV)-induced oral cavity and oropharyngeal squamous cell carcinomas (OC/OP SCCs) and those associated with tobacco use lead to different responses to therapy, with patients having HPV-positive tumors having a better prognosis than those with HPV-negative tumors. We and others have shown that site-specific and global differences in DNA methylation exist between HPV(+) and HPV(-) tumors. 5-hydroxymethylcytosine (5hmC), once thought of as simply a transient step in the demethylation process, is now known to be aberrant with functional consequences in multiple cancers, however it has not yet been studied in OC/OP SCCs. Given suggestive evidence that 5hmC may also play a role in oral and oropharyngeal tumors, we propose to study 5hmC, its interactions with DNA methylation, and how these translate to functional changes in gene expression in HPV(+) and HPV(-) OC/OP SCCs. The goal of Aim 1 of this proposal will be to determine the extent and form of 5hmC involvement in HPV(+) and HPV(-) tumors by performing whole-genome 5hmC deep sequencing on a current set of OC/OP SCC frozen tumors and matched controls. In Aim 2, we will integrate the 5hmC data with whole-genome bisulfite sequencing data (which does not distinguish between 5hmC and 5mC marks), transcriptomics data measured via RNA-seq, and copy number variation data on the same tumors to determine how DNA methylation (5mC) and 5hmC deregulation affect the transcriptional programming in OC/OP SCCs and their relationship with clinical outcome. To help accomplish our goals, we will develop a bioinformatics method and tool for concurrent analysis and interpretation of 5mC and 5hmC deep sequencing data.

 描述（由申请人提供）：人乳头瘤病毒（HPV）诱导的口腔和口咽鳞状细胞癌（OC/OP SCC）与烟草使用相关癌之间的分子机制差异导致对治疗的不同反应，HPV阳性肿瘤患者的预后优于HPV阴性肿瘤患者。我们和其他人已经表明，HPV（+）和HPV（-）肿瘤之间存在DNA甲基化的位点特异性和整体差异。5-羟甲基胞嘧啶（5 hmC），曾经被认为是简单的去甲基化过程中的一个短暂步骤，现在已知是异常的，在多种癌症中具有功能性后果，然而，尚未在OC/OP SCC中进行研究。鉴于提示性证据表明5 hmC也可能在口腔和口咽肿瘤中发挥作用，我们建议研究5 hmC，其与DNA甲基化的相互作用，以及这些如何转化为HPV（+）和HPV（-）OC/OP SCC中基因表达的功能变化。本提案的目标1是通过对当前一组OC/OP SCC冷冻肿瘤和匹配对照进行全基因组5 hmC深度测序，确定5 hmC参与HPV（+）和HPV（-）肿瘤的程度和形式。在目标2中，我们将整合5 hmC数据与全基因组亚硫酸氢盐测序数据（不区分5 hmC和5 mC标记），通过RNA-seq测量的转录组学数据以及相同肿瘤的拷贝数变异数据，以确定DNA甲基化（5 mC）和5 hmC失调如何影响OC/OP SCC中的转录编程及其与临床结局的关系。为了帮助实现我们的目标，我们将开发一种生物信息学方法和工具，用于同时分析和解释5 mC和5 hmC深度测序数据。