Developing a HPV-mediated DNA methylation panel in HNSCC

开发 HNSCC 中 HPV 介导的 DNA 甲基化组合

• 批准号: 8625532
• 负责人: THOMAS J. BELBIN
• 金额: $ 25.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625532
• 关键词: Affect; Atlases; Biological Assay; Biological Markers; CDKN2A gene; Cancer Research Project; Cell Line; Cells; Clinical; Clinical Research; Complex; Computing Methodologies; DNA; DNA Methylation; Data; Detection; Diagnosis; Disease; Epigenetic Process; Event; Freezing; Future; Gene Expression; Genes; Genetic Transcription; Genomics; Genotype; Gold; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histopathology; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Individual; Infection; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measures; Mediating; Methods; Methylation; Molecular; Molecular Profiling; Mutation; Normal tissue morphology; Oncogene Proteins; Oncogenes; Oropharyngeal Squamous Cell Carcinoma; Outcome; Pathologic; Patients; Protein p53; Proteins; RNA; Recurrence; Research; Sampling; Sensitivity and Specificity; Site; Testing; Time; Tissue Sample; Tumor Suppressor Proteins; Viral; Viral Oncogene; base; cancer genome; clinically relevant; high risk; improved; insight; malignant oropharynx neoplasm; novel; outcome forecast; public health relevance; research study; response; tumor; tumor progression; vector

Molecular characterization of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinomas (OPSCC) is genetically complex but has provided some promising insight into individual genetic changes that contribute to improved cancer survival and tumor progression. However, current commercial methods for detecting HPV in tumors by histopathology have shown poor sensitivity and specificity when compared to the more labor intensive gold standard methods for detecting HPV RNA. Our research group has recently developed a novel 22 CpG loci panel whose methylation status distinguishes between OPSCC with and without HPV16 infections expressing the E6/E7 oncogenes. This has potential clinical relevance as detection of HPV16 E6/E7 RNA in tumors has been associated with significantly improved cancer survival in OPSCC. In this study, we propose to validate this host DNA methylation panel and test the novel epigenetic events that may regulate key effector proteins, including for four panel loci downstream of the transcriptional start site of CDKN2A(p16) that, despite being hypermethylated in tumor compared to normal tissues, are associated with increased expression of the cellular gene. In this study, we propose to test and validate this signature. We will: 1) test the hypothesis that changes in host DNA methylation status of the HPV panel have functional consequences in altering expression of their corresponding genes; 2) the hypothesis that HPV viral oncogenes E6 and E7 are sufficient to induce host DNA methylation and corresponding gene expression changes seen in the HPV panel, including the novel changes observed for CDKN2A(p16); and 3) test the clinical relevance of our HPV-driven methylation panel in clinical samples to determine which are most predictive of clinical outcome. Combined with our experiments establishing functional and clinical relevance, this study will lay the groundwork for future clinical studies to test clinical utility of an HPV-specific methylation panel.

人乳头瘤病毒相关口咽鳞状细胞的分子特征 癌（OPSCC）是遗传复杂的，但提供了一些有前途的洞察个人遗传 有助于改善癌症生存和肿瘤进展的变化。目前，商业 通过组织病理学检测肿瘤中HPV的方法显示出低的灵敏度和特异性， 与检测HPV RNA的劳动密集型金标准方法相比。我们的研究小组 最近开发了一种新的22个CpG基因座面板，其甲基化状态区分OPSCC与 并且没有表达E6/E7癌基因的HPV 16感染。这具有潜在的临床相关性， 在肿瘤中检测到HPV 16 E6/E7 RNA与显著提高癌症存活率相关， OPSCC。在这项研究中，我们建议验证这个宿主DNA甲基化小组，并测试新的表观遗传学。 可能调节关键效应蛋白的事件，包括转录因子下游的四个基因座。 CDKN 2A（p16）起始位点尽管与正常组织相比在肿瘤中高度甲基化， 与细胞基因表达增加有关。在这项研究中，我们建议测试和验证这一点， 签名.我们将：1）检验HPV组的宿主DNA甲基化状态的变化与HPV感染相关的假设。 改变其相应基因表达的功能后果; 2）HPV病毒 癌基因E6和E7足以诱导宿主DNA甲基化和相应的基因表达 HPV组中观察到的变化，包括CDKN 2A（p16）观察到的新变化;以及3）检测 我们的HPV驱动的甲基化组在临床样本中的临床相关性，以确定哪些是最常见的 预测临床结果。结合我们建立功能和临床相关性的实验， 这项研究将为未来的临床研究奠定基础，以测试HPV特异性甲基化的临床效用。 面板