Genetic & Epigenetic Events in Papillary Thyroid 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，具有几种重要的致癌事件，包括BRAF突变、Ras突变、RET/PTC重排和甲基化诱导的肿瘤抑制基因RASSF 1A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）的基因，是一些PTC患者对放射性碘治疗反应失败的原因。据推测，致癌事件，通过激活MAP激酶途径，导致表观遗传改变，负责甲状腺特异性基因沉默。为了检验这一假设，将首先在PTC的特定亚型中检验致癌事件的互斥性，以支持每个致癌事件能够通过激活其共享的MAP激酶途径引起PTC的概念。随后将在相同的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甲状腺肿瘤细胞系，无论是天然存在的还是实验创建的，将用于研究致癌事件和甲状腺基因甲基化之间的功能关系。还将在细胞系中研究表观遗传组蛋白修饰及其与沉默甲状腺基因的DNA甲基化和致癌改变的关系。在这些研究中，特异性激酶抑制剂和癌蛋白和siRNA的细胞转染将用于改变MAP激酶途径活性。BRAF突变，PTC中最常见的致癌事件，以及相关的MAP激酶通路畸变在甲状腺特异性基因的表观遗传改变和沉默中的作用将是这些研究的主要焦点。我们期望发现PTC发病机制的重要分子信息和这种最常见的内分泌癌的新治疗靶点。

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.