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: 9196582
• 负责人: THOMAS J. BELBIN
• 金额: $ 9.01万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9196582
• 关键词: Developing; HPV; mediated; DNA; methylation

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：人乳头瘤病毒（HPV）相关口咽鳞状细胞癌（OPSCC）的分子特征在遗传上很复杂，但为有助于改善癌症生存和肿瘤进展的个体遗传变化提供了一些有前景的见解。然而，与检测 HPV RNA 的劳动密集型金标准方法相比，目前通过组织病理学检测肿瘤中 HPV 的商业方法显示出较差的敏感性和特异性。我们的研究小组最近开发了一种新型 22 CpG 位点组，其甲基化状态可区分表达 E6/E7 癌基因的 HPV16 感染和未感染的 OPSCC。这具有潜在的临床意义，因为肿瘤中 HPV16 E6/E7 RNA 的检测与 OPSCC 癌症存活率的显着改善相关。在这项研究中，我们建议验证这个宿主 DNA 甲基化组，并测试可能调节关键效应蛋白的新表观遗传事件，包括转录组下游的四个组基因座。 CDKN2A(p16) 的起始位点，尽管与正常组织相比在肿瘤中高度甲基化，但与细胞基因表达增加相关。在本研究中，我们建议测试和验证此签名。我们将：1) 检验 HPV 组宿主 DNA 甲基化状态的变化在改变其相应基因的表达方面具有功能性影响的假设； 2) HPV 病毒癌基因 E6 和 E7 足以诱导宿主 DNA 甲基化和 HPV 组中观察到的相应基因表达变化的假设，包括在 CDKN2A(p16) 中观察到的新变化； 3) 在临床样本中测试我们的 HPV 驱动的甲基化组的临床相关性，以确定哪些最能预测临床结果。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，以测试临床 HPV 特异性甲基化组的实用性。