Identification and Classification of Epigenetic Changes in Head and Neck Cancer

描述(申请人提供)：在许多癌症中，所谓的“CpG岛”的异常DNA甲基化，即经常与启动子或第一外显子相关的富含CpG的序列，与关键基因的不适当转录沉默有关。人们也越来越意识到基因组DNA甲基化的总体模式在肿瘤疾病的分子特征中发挥着关键作用。这些DNA甲基化事件代表了在肿瘤进展早期发生的一个重要的肿瘤特异性标记物，并且可以通过基于聚合酶链式反应的方法以对患者最小的侵袭方式容易地检测到。在头颈部鳞状细胞癌(HNSCC)中，启动子甲基化事件在肿瘤人群中也存在相当大的差异。HNSCC是一种多因素病因和危险因素差异很大的疾病。这使得高通量方法成为识别HNSCC疾病预后表观遗传标记的有趣手段。因此，本研究项目的目标是对口咽鳞状细胞癌(OPSCC)中DNA甲基化事件的模式进行分类，并识别可用于预测肿瘤行为和患者预后的特定DNA甲基化“信号”。该项目的具体目标是：1)测试假设，即OPSCC临床标本中的全球DNA甲基化模式包含可用作该病预后生物标记物和分子分类器的信息。2)验证OPSCC存在CpG岛甲基化表型(CIMP)的假设，该表型对本病有预后价值。3)检测目的1中发现的甲基化异常事件是否存在于癌旁正常组织和对侧正常组织中。公共卫生相关性：尽管采取了干预措施，头颈部鳞状细胞癌的复发在大约50%的患者中观察到，无论是局部的、地区性的还是远距离的，相关死亡率都很高。到目前为止，还没有发现能可靠地用于HNSCC早期检测或作为预后指标的分子标志物。因此，越来越有必要对头颈部肿瘤进行更好的分子分类，以提供预后和预测信息，以改善患者护理。

DESCRIPTION (provided by applicant): In many cancers, aberrant DNA methylation of so called "CpG islands", CpG-rich sequences frequently associated with promoters or first exons, is associated with the inappropriate transcriptional silencing of critical genes. There is also a growing awareness that overall patterns of genomic DNA methylation play a critical role in the molecular characteristics of neoplastic disease. These DNA methylation events represent an important tumor-specific marker occurring early in tumor progression and one that can be easily detected by PCR based methods in a manner that is minimally invasive to the patient. In the case of head and neck squamous cell carcinoma (HNSCC), a disease of multifactorial etiology and great variability in risk factors, there is also considerable variability in promoter methylation events among the tumor population. This makes a high- throughput approach an intriguing means to identify prognostic epigenetic markers in HNSCC disease. The goal of this research project is therefore to classify the patterns of DNA methylation events in oropharyngeal squamous cell carcinoma (OPSCC), one subtype of HNSCC, and to identify specific DNA methylation "signatures" that can be used to predict tumor behavior and patient outcome. The specific aims of the project are: 1) To test the hypothesis that the pattern of global DNA methylation in a OPSCC clinical specimen contains information that can be used as a prognostic biomarker and a molecular classifier of this disease. 2) To test the hypothesis that there exists a CpG island methylator phenotype (CIMP) for OPSCC, and that this phenotype has prognostic value for this disease. 3) To test whether the aberrant methylation events identified in Aim 1 are observed in histologically normal tissues adjacent to the tumor, as well as in contralateral normal tissue. PUBLIC HEALTH RELEVANCE: Despite interventions, recurrence of the head and neck squamous cell carcinoma is observed in about 50% of patients, either locally, regionally or at a distant site with high rates of associated mortality. To date, few molecular markers have been found that can be reliably used in early detection of HNSCC or as indicators of prognosis. There is therefore an increasing necessity for better molecular classification of head and neck tumors to provide prognostic as well as predictive information to improve patient care.