Genetic & Epigenetic Events in Papillary Thyroid Cancer

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• 批准号: 7034799
• 负责人: MICHAEL Mingzhao XING
• 金额: $ 27.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034799
• 关键词: clinical research; epigenetics; gene mutation; genes; genetics; methylation; mitogen activated protein kinase; neoplasm /cancer; thyroid neoplasm

DESCRIPTION (provided by applicant): Papillary thyroid cancer (PTC), the most common endocrine malignancy, harbors several important oncogenic events, including BRAF mutation, Ras mutation, RET/PTC rearrangements, and methylation- induced silencing of the tumor suppressor gene RASSF1 A. Silencing of the thyroid-specific genes that are involved in iodide metabolism, such as the genes for thyroid-stimulating hormone receptor (TSHR) and sodium/iodide symporter (NIS), is responsible for the failure of some PTC patients to respond to radioiodine treatment. It is hypothesized that the oncogenic events, by activating the MAP kinase pathway, result in epigenetic alterations that are responsible for thyroid-specific gene silencing. To test this hypothesis, mutual exclusivity of the oncogenic events will first be tested in specific subtypes of PTC to support the concept that each oncogenic event is able to cause PTC through activating their shared MAP kinase pathway. Methylation status of thyroid-specific genes will be subsequently examined in the same tumors, with a focus on the TSHR and NIS genes, to define the relationship of oncogenic events with thyroid gene methylation. Human thyroid tumor cell lines with various oncogenic alterations, either naturally existing or experimentally created, will be used to study the functional relationship between the oncogenic events and thyroid gene methylation. Epigenetic histone modification and its relationship to DNA methylation in silencing thyroid genes and to oncogenic alterations will also be studied in cell lines. Specific kinase inhibitors and cell transfection with oncoproteins and siRNAs will be used to alter MAP kinase pathway activities in these studies. The role of BRAF mutation, the most common oncogenic event in PTC, and related MAP kinase pathway aberration in the epigenetic alteration and silencing of thyroid-specific genes will be the primary focus of these studies. We expect to discover important molecular information on the mechanisms of PTC pathogenesis and novel therapeutic targets for this most common endocrine cancer.

描述（由申请人提供）：甲状腺乳头状癌（PTC）是最常见的内分泌恶性肿瘤，具有多种重要的致癌事件，包括 BRAF 突变、Ras 突变、RET/PTC 重排以及甲基化诱导的抑癌基因 RASSF1 A 沉默。参与碘代谢的甲状腺特异性基因的沉默，例如 促甲状腺激素受体 (TSHR) 和钠/碘同向转运体 (NIS) 基因是导致某些 PTC 患者对放射性碘治疗失败的原因。据推测，致癌事件通过激活 MAP 激酶途径，导致表观遗传改变，从而导致甲状腺特异性基因沉默。为了检验这一假设，首先将在 PTC 的特定亚型中测试致癌事件的相互排他性，以支持每个致癌事件都能够通过激活其共享的 MAP 激酶途径导致 PTC 的概念。随后将在同一肿瘤中检查甲状腺特异性基因的甲基化状态，重点是 TSHR 和 NIS 基因，以确定致癌事件与甲状腺基因甲基化的关系。具有各种致癌改变的人类甲状腺肿瘤细胞系（无论是自然存在的还是实验创建的）将用于研究致癌事件与甲状腺基因甲基化之间的功能关系。表观遗传组蛋白修饰及其与甲状腺基因沉默中的 DNA 甲基化和致癌改变的关系也将在细胞系中进行研究。在这些研究中，将使用特定激酶抑制剂以及用癌蛋白和 siRNA 进行细胞转染来改变 MAP 激酶途径活性。 BRAF 突变（PTC 中最常见的致癌事件）的作用，以及相关 MAP 激酶通路畸变在表观遗传改变和甲状腺特异性基因沉默中的作用将是这些研究的主要焦点。我们期望发现有关 PTC 发病机制的重要分子信息以及这种最常见内分泌癌的新治疗靶点。