The role of promoter hypermethylation in adenoid cystic carcinoma

描述(由申请人提供)：候选人，哈博士，已经证明了长期致力于研究和学术耳鼻咽喉科的历史。该职业发展奖由David Sidransky博士和Joseph Califano博士指导，重点研究腺样囊性癌(ACC)的基本机制。 ACC是一种涎腺恶性肿瘤，其特征是持续的局部、局部和远处复发，尽管完全手术切除和辅助放射治疗。通过化疗改善局部区域控制的尝试一直令人失望，到目前为止，还没有系统性药物改善区域或远处转移的控制。更好地描述与ACC肿瘤发生有关的基因改变将使我们深入了解选择有效的辅助治疗或开发新的治疗方法。 启动子高甲基化作为肿瘤抑制基因沉默的一种手段，是实体瘤发生的重要因素。我们有初步证据表明，启动子高甲基化是ACC中抑癌基因失活的重要途径。候选人建议评估扩展的ACC样本队列中常见的甲基化肿瘤抑制基因，并在ACC细胞系中进行全基因组筛选，以努力识别新的甲基化基因。然后将应用功能和临床相关性来评估这些失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超甲基化在ACC中的作用。对公众健康的影响在于建立这一基础工作，这将导致识别肿瘤行为的重要生物标记物，以及治疗这种疾病的治疗干预的可能途径。进行这些实验的过程将为候选人提供必要的指导、课程安排和实践培训，使其成为一名独立的调查者，并进一步加深对腺样囊性癌的基本科学知识。

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.