The role of promoter hypermethylation in adenoid cystic carcinoma

启动子高甲基化在腺样囊性癌中的作用

• 批准号: 7624213
• 负责人: Patrick Kyongmin Ha
• 金额: $ 13.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624213
• 关键词: Adenoid Cystic Carcinoma; Adjuvant Radiotherapy; Adjuvant Therapy; Affect; Basic Science; Behavior; Biological Assay; Biological Markers; Candidate Disease Gene; Cell Line; Clinical; Data; Development; Disease; Distant; Distant Metastasis; Epigenetic Process; Event; Excision; Fingerprint; Foundations; Future; Gene Silencing; Gene Targeting; Genes; Genetic; Goals; Hypermethylation; Indolent; K-Series Research Career Programs; Knowledge; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mentorship; Methylation; Minor salivary gland structure; Molecular; Mutation; Operative Surgical Procedures; Otolaryngology; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Primary Neoplasm; Process; Public Health; Publishing; Radiation therapy; Recording of previous events; Recurrence; Research; Research Personnel; Resistance; Role; Salivary; Salivary Glands; Sampling; Serum; Solid Neoplasm; Techniques; Testing; Therapeutic Intervention; Tissue Sample; Training; Tumor Suppressor Genes; Tumor-Suppressor Gene Inactivation; Work; carcinogenesis; chemotherapeutic agent; chemotherapy; clinically relevant; cohort; genome wide association study; improved; insight; novel; novel therapeutics; prognostic; programs; promoter; research study; skills training; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The candidate, Dr. Ha, has demonstrated a long standing history of commitment to research and academic otolaryngology. This career development award, under the mentorship of Drs. David Sidransky and Joseph Califano is focused on the basic mechanisms underlying adenoid cystic carcinoma (ACC). ACC is a salivary gland malignancy characterized by persistent local, regional, and distant recurrence despite complete surgical resection and adjuvant radiotherapy. Attempts at improving loco regional control with chemotherapy have been disappointing, and to date, no systemic agent improves control of regional or distant metastases. Better characterization of the genetic alterations involved in ACC tumorigenesis will give us insight into the selection of effective adjuvant therapies or the development of novel therapy. Promoter hypermethylation as a means of tumor suppressor gene silencing is a significant factor in solid tumor carcinogenesis. We have preliminary evidence that promoter hypermethylation is an important means of tumor suppressor gene inactivation in ACC. The candidate proposes to evaluate commonly methylated tumor suppressor genes in an expanded cohort of ACC samples as well as perform genome wide screening in ACC cell lines in an effort to identify novel methylated genes. Functional and clinical correlation will then be applied to evaluate the biologic significance and prognostic value of these inactivated genes. The goal of this work is to comprehensively analyze the role of promoter hypermethylation in ACC. The impact on public health lies in establishing this groundwork that will lead to the identification of important biomarkers of tumor behavior and possible avenues of therapeutic intervention in the treatment of this disease. The process of performing these experiments will provide the candidate with the necessary guidance, coursework, and practical training towards becoming an independent investigator as well as furthering the basic science knowledge of adenoid cystic carcinoma.

描述（由申请人提供）：候选人HA博士表现出了长期以来对研究和学术耳鼻喉科的承诺的历史。在Drs的指导下，该职业发展奖。戴维·西德兰斯基（David Sidransky）和约瑟夫·卡利亚诺（Joseph Califano）专注于腺样囊性癌的基本机制（ACC）。 ACC是一种唾液腺恶性肿瘤，尽管完全手术切除和辅助放射疗法，但具有持续的局部，区域和远处复发的特征。通过化学疗法改善机车区域控制的尝试一直令人失望，迄今为止，尚无系统性药物可以改善对区域或遥远转移的控制。对ACC肿瘤发生涉及的遗传变量的更好表征将使我们深入了解有效的辅助疗法或新疗法的发展。 启动子高甲基化作为肿瘤抑制基因沉默的一种手段是实体瘤致癌的重要因素。我们有初步的证据表明启动子高甲基化是ACC中肿瘤抑制基因失活的重要手段。候选人建议在扩展的ACC样品中评估普遍甲基化的肿瘤抑制基因，并在ACC细胞系中进行基因组宽筛查，以鉴定新型甲基化基因。然后，将应用功能和临床相关性来评估这些灭活基因的生物学意义和预后价值。 这项工作的目的是全面分析启动子高甲基化在ACC中的作用。对公共卫生的影响在于建立这一基础，这将导致鉴定肿瘤行为的重要生物标志物以及治疗这种疾病的治疗干预途径。进行这些实验的过程将为候选人提供必要的指导，课程和实践培训，以成为独立研究者，并进一步发展腺样囊性癌的基础科学知识。