Identification and Classification of Epigenetic Changes in Head and Neck Cancer

描述（由申请人提供）：在许多癌症中，所谓的“CpG岛”（通常与启动子或第一外显子相关的富含CpG的序列）的异常DNA甲基化与关键基因的不适当转录沉默相关。人们也越来越认识到基因组DNA甲基化的总体模式在肿瘤疾病的分子特征中起着关键作用。这些DNA甲基化事件代表了在肿瘤进展早期发生的重要肿瘤特异性标志物，并且可以通过基于PCR的方法以对患者微创的方式容易地检测到。在头颈部鳞状细胞癌（HNSCC）的情况下，一种多因素病因学和风险因素变异性很大的疾病，在肿瘤人群中启动子甲基化事件也存在相当大的变异性。这使得高通量方法成为鉴定HNSCC疾病中的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）（HNSCC的一种亚型）中DNA甲基化事件的模式进行分类，并确定可用于预测肿瘤行为和患者结局的特定DNA甲基化“签名”。该项目的具体目的是：1）检验OPSCC临床标本中的总体DNA甲基化模式包含可用作该疾病的预后生物标志物和分子分类器的信息的假设。2)为了验证OPSCC存在CpG岛甲基化表型（CIMP）的假设，以及该表型对该疾病具有预后价值。3)测试目标1中鉴定的异常甲基化事件是否在肿瘤附近的组织学正常组织以及对侧正常组织中观察到。公共卫生相关性：尽管进行了干预，但在约50%的患者中观察到头颈部鳞状细胞癌复发，无论是局部、区域还是远处，相关死亡率很高。到目前为止，很少有分子标记物被发现可以可靠地用于HNSCC的早期检测或作为预后的指标。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，从而改善患者护理。

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.