Identification and Classification of Epigenetic Changes in Head and Neck Cancer

头颈癌表观遗传变化的鉴定和分类

• 批准号: 8097673
• 负责人: THOMAS J. BELBIN
• 金额: $ 7.31万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097673
• 关键词: Aberrant DNA Methylation; Aggressive behavior; Anatomic Sites; Anatomy; Awareness; Behavior; Biological Markers; Biopsy; Characteristics; Classification; Clinical; Computer software; Contralateral; Coupled; CpG Island Methylator Phenotype; CpG Islands; DNA; DNA Methylation; Data; Diagnosis; Disease; Distant; Early Diagnosis; Epigenetic Process; Etiology; Event; Excision; Exhibits; Exons; Gene Expression; Gene Silencing; Genes; Genome; Genomics; Goals; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Histologic; Histopathology; Human Genome; Hypermethylation; Intervention; Larynx; Link; Location; Malignant Neoplasms; Measures; Methods; Methylation; Microarray Analysis; Molecular; Molecular Profiling; Nasopharynx; Neoplasm Metastasis; Neoplasms; Normal tissue morphology; Oral cavity; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Outcome; Patient Care; Patients; Pattern; Phenotype; Play; Population; Primary Neoplasm; Prognostic Marker; Recurrence; Research; Research Project Grants; Risk Factors; Role; Side; Site; Specimen; Statistical Models; Testing; Tissue Banks; Tissues; Tumor Tissue; base; cancer cell; genome-wide; hypopharynx; improved; lymph nodes; minimally invasive; molecular marker; mortality; neoplastic; outcome forecast; prognostic; promoter; public health relevance; tumor; tumor progression

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.

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有关。人们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发挥着关键作用。这些 DNA 甲基化事件代表了肿瘤进展早期发生的一种重要的肿瘤特异性标志物，并且可以通过基于 PCR 的方法以对患者微创的方式轻松检测到。头颈鳞状细胞癌（HNSCC）是一种多因素病因学且危险因素变异性很大的疾病，肿瘤群体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 疾病预后表观遗传标记的有趣方法。因此，该研究项目的目标是对口咽鳞状细胞癌 (OPSCC)（HNSCC 的一种亚型）中的 DNA 甲基化事件模式进行分类，并确定可用于预测肿瘤行为和患者结果的特定 DNA 甲基化“特征”。该项目的具体目标是： 1) 检验 OPSCC 临床标本中整体 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）检验OPSCC存在CpG岛甲基化表型（CIMP）的假设，并且该表型对该疾病具有预后价值。 3) 测试目标1中确定的异常甲基化事件是否在肿瘤邻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：尽管采取了干预措施，但仍有约 50% 的患者出现头颈部鳞状细胞癌复发，无论是局部、区域还是远处部位，相关死亡率很高。迄今为止，很少有分子标志物能够可靠地用于头颈部鳞状细胞癌的早期检测或作为预后指标。因此，越来越有必要对头颈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。

项目成果

Unique DNA methylation loci distinguish anatomic site and HPV status in head and neck squamous cell carcinoma.

• DOI: 10.1158/1078-0432.ccr-12-3280
• 发表时间: 2013-10-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Lleras RA;Smith RV;Adrien LR;Schlecht NF;Burk RD;Harris TM;Childs G;Prystowsky MB;Belbin TJ
• 通讯作者: Belbin TJ