Oral Biomarkers for HPV-related Head and Neck Cancer

描述(申请人提供)：本申请是响应PA-11-159：感染相关癌症的生物标记物而提交的。本研究的目的是确定人乳头瘤病毒相关头颈部鳞状细胞癌(HPV-HNSCC)的特异性生物标志物，以开发一种敏感和特异的筛查工具来检测早期癌症，并识别HPV暴露的亚群，这些人可能是患HPV-HNSCC的高危人群。我们计划通过评估HPV-HNSCC患者口腔冲洗样本(ORS)中HPV基因的甲基化来实现这一目标。病毒DNA整合到宿主基因组中是由于病毒调控基因无意中缺失而导致癌症进展过程中的第一个分子步骤之一。在病毒整合后，HPV基因组也变得容易被宿主表观遗传机制修改。因此，检测到甲基化的HPV基因表明病毒整合已经发生。由于病毒整合可以导致细胞转化，因此在ORS中检测整合或甲基化的病毒基因可以成为诊断早期癌症和/或识别HPV暴露者患头颈癌风险增加的有用生物标记物。甲基化特异性聚合酶链式反应(MSP)是一种检测组织和体液中甲基化基因的成熟方法。通过MSP检测ORS中的甲基化HPV基因可能是我们在本研究中建议开发的一种新的筛查工具。在开发生物标记物时，通过识别和筛查那些罹患癌症风险最高的受试者，通常可以提高成功率。被诊断为HPV-HNSCC的患者的伴侣是有持续口腔HPV-16暴露和感染风险的个人，这是发生HPV-HNSCC的已知风险因素。因此，我们计划评估HPV-HNSCC患者和配对伴侣ORS中的HPV基因甲基化。我们将比较患者、配对伴侣和非癌症对照组ORS中甲基化或整合的HPV-16基因的检测频率，以确定甲基化的病毒基因，如L1，是否可以作为HPV-HNSCC的生物标记物，并确定HPV-HNSCC患者的伴侣是否代表了一组暴露于HPV的人，与匹配的对照组相比，这些人患HPV-HNSCC的风险可能会增加，因为持续或整合的口腔HPV感染的频率更高。来自患者、伴侣和配对对照的ORS已经收集完毕，准备用于这项拟议的研究。

DESCRIPTION (provided by applicant): This application is submitted in response to PA-11-159: Biomarkers of Infection-Associated Cancers. The objective of this study is to identify a biomarker specific for Human Papillomavirus-associated Head and Neck Squamous Cell Carcinoma (HPV-HNSCC) in order to develop a sensitive and specific screening tool to detect early stage cancers as well as to identify subpopulations of HPV-exposed individuals who may be at increased risk for developing HPV-HNSCC. We plan to achieve this goal by evaluating methylation of HPV genes in Oral Rinse Samples (ORS) of HPV-HNSCC patients. Integration of viral DNA into the host genome is one of the first molecular steps that occurs in the progression to cancer due to the inadvertent deletion of viral regulatory genes. After viral integration, the HPV genome also becomes susceptible to modification by the host epigenetic machinery. Therefore, the detection of methylated HPV genes indicates viral integration has occurred. Since viral integration can lead to cellular transformation, the detection of integrated, or methylated, viral genes in ORS can be a useful biomarker to diagnose early stage cancers and/or to identify HPV-exposed individuals at increased risk for developing head and neck cancer. Methylation-specific PCR (MSP) is an established method to detect methylated genes in tissue and body fluids. The detection of methylated HPV genes in the ORS via MSP may be a novel screening tool that we propose to develop in this study. When developing biomarkers, the success rate is often improved through the identification and screening of those subjects at highest risk for developing cancer. The partners of patients diagnosed with HPV-HNSCC are individuals at risk for persistent oral HPV- 16 exposure and infection, which is a known risk factor for the development of HPV-HNSCC. Therefore, we plan to evaluate for HPV gene methylation in the ORS of both HPV-HNSCC patients and matched partners. We will compare the frequency of detection of methylated, or integrated, HPV-16 genes in the ORS of patients, matched partners, and non-cancer controls to determine if methylated viral genes, such as L1, can serve as a biomarker for HPV-HNSCC and to determine if the partners of HPV-HNSCC patients represent a subpopulation of HPV-exposed individuals who may be at increased risk for developing HPV-HNSCC due to a higher frequency of persistent, or integrated, oral HPV infection as compared to a matched control group. The ORS from patients, partners, and matched controls already have been collected and are ready to be used for this proposed study.