The role of promoter hypermethylation in adenoid cystic carcinoma

描述（由申请人提供）：候选人，哈博士，已证明了长期致力于研究和学术耳鼻喉科的历史。该职业发展奖在大卫·西德兰斯基（David Sidransky）和约瑟夫·卡利法诺（Joseph Califano）博士的指导下，重点关注腺样囊性癌（ACC）的基本机制。 ACC是一种唾液腺恶性肿瘤，其特征是尽管完全手术切除和辅助放疗，但仍存在持续的局部、区域和远处复发。用化疗改善局部区域控制的尝试令人失望，迄今为止，没有全身性药物改善对区域或远处转移的控制。更好地表征ACC肿瘤发生中涉及的遗传改变将使我们深入了解有效辅助治疗的选择或新疗法的开发。 启动子甲基化作为抑制肿瘤基因表达的一种手段，在实体瘤的发生发展中起着重要作用。我们有初步证据表明，启动子超甲基化是ACC中肿瘤抑制基因失活的重要手段。候选人建议在扩大的ACC样本队列中评估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，以识别新的甲基化基因。功能和临床相关性，然后将应用于评估这些失活基因的生物学意义和预后价值。 这项工作的目标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，这将导致识别肿瘤行为的重要生物标志物和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，课程和实践培训，以成为一名独立的研究者，并进一步提高腺样囊性癌的基础科学知识。

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.