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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：人乳头瘤病毒（HPV）诱导的口腔和口咽型鳞状细胞癌（OC/OP SCC）与烟草使用相关的分子乳头瘤病毒（HPV）诱导的分子机制差异，导致对治疗的反应不同，导致对HPV稳定性肿胀的患者具有更好的预后症。我们和其他人表明，HPV（+）和HPV（ - ）肿瘤之间存在位点特异性和全局DNA甲基化的差异。 5-羟基甲基胞嘧啶（5HMC）曾经被认为仅仅是脱甲基化过程中的短暂步骤，现在已知在多种癌症中具有功能后果，但是在OC/OP SCC中尚未研究它。如果有暗示的证据表明5HMC也可能在口腔和口咽肿瘤中发挥作用，我们建议研究5HMC，其与DNA甲基化的相互作用，以及它们如何转化为HPV（+）和HPV（ - ）OC/OP/OP SCC中基因表达的功能变化。该提案的目标1的目的是通过在当前的OC/OP SCC冷冻肿瘤集和匹配的对照组上进行全基因组深度测序，以确定HPV（+）和HPV（ - ）肿瘤中5HMC参与的程度和形式。 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.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5MC和5HMC深度测序数据。