Genetic & Epigenetic Events in Papillary Thyroid Cancer

描述(申请人提供)：甲状腺癌，特别是乳头状甲状腺癌(PTC)，是一种常见的内分泌恶性肿瘤，近年来发病率迅速上升。目前在其临床诊断、预测和治疗中遇到了几个主要的难题。要解决这些问题并改善目前的甲状腺癌医学实践，需要更好地了解甲状腺癌发生的分子机制。为此，这个由R01资助的项目的主要目标一直是发现和表征甲状腺癌的遗传和表观遗传学改变，并将它们转移到临床。这个项目在最初的五年资助中取得了巨大的成功。 尤其是与BRAF突变(BRAFV600E)相关的区域，BRAF突变是PTC中MAP激酶信号通路中的一个重要癌基因。为了继续这个项目的主题和强劲的势头，在这个更新的应用中，我们建议基于最近强劲的新数据来测试我们的新假设，即由BRAFV600E信号促进的广泛的基因组范围的甲基化异常，从而促进重要功能基因的表达，是甲状腺癌发病机制中以前未知的基本分子机制。我们建议验证这一假说，并通过实现三个具体目标将其应用于临床：1)检测由BRAFV600E/MAP激酶信号驱动的全基因组DNA甲基化改变，并确定其启动子甲基化和表达改变的基因；2)直接测试由BRAFV600E信号引起的表观遗传改变的基因在甲状腺肿瘤发生中的功能和作用；3)检查在特定目标1和2中发现的新的DNA甲基化标记的诊断和预后价值。我们将应用最近建立的新的和目前最广泛的450K CpG甲基化微阵列系统。随着对甲状腺癌基因甲基化的广泛研究，特别是关于BRAFV600E驱动的甲状腺肿瘤发生的表观遗传学机制的研究，我们预计将识别许多基因，这些基因将首次被证明在甲状腺肿瘤发生中发挥关键作用，从而成为甲状腺癌潜在的新治疗靶点。我们还希望在基因组中发现许多新的DNA甲基化标记，从这些标记中，我们将通过在甲状腺肿瘤组织、血液样本和甲状腺细针活检标本上进行检测，确定对甲状腺癌诊断和预后最敏感和最特异的标记。该项目的更新将使我们能够利用我们成熟的专业知识、技术和研究资源实现这些新的研究目标，我们相信这将对甲状腺癌领域产生重大影响。

DESCRIPTION (provided by applicant): Thyroid cancer, particularly papillary thyroid cancer (PTC), is a common endocrine malignancy that has been rising rapidly in incidence in recent years. There are currently several major dilemmas encountered in its clinical diagnosis, prognostication, and treatment. To tackle them and improve the current practice of thyroid cancer medicine requires a better understanding of molecular mechanisms in the tumorigenesis of thyroid cancer. To this end, the main goal of this R01-supported project has been to discover and characterize genetic and epigenetic alterations in thyroid cancer and to move them toward clinical translation. This project has been a tremendous success for this initial five-year funding cycle, particularly in the areas related to the BRAF mutation (BRAFV600E), a prominent oncogene in the MAP kinase signaling pathway in PTC. To continue the main theme and the strong momentum of this project, in this renewal application we propose to test our novel hypothesis, based on strong recent new data, that extensive genome-wide aberration in the methylation and hence expression of functionally important genes promoted by the BRAFV600E signaling is a previously unrecognized fundamental molecular mechanism in the pathogenesis of thyroid cancer. We propose to test this hypothesis and move it to clinic by achieving three Specific Aims: 1) To examine genome-wide DNA methylation alterations driven by the BRAFV600E/MAP kinase signaling and identify genes whose promoter methylation and expression are altered; 2) To directly test the function and role of genes epigenetically altered by the BRAFV600E signaling in thyroid tumorigenesis; 3) To examine the diagnostic and prognostic value of novel DNA methylation markers identified in Specific Aims 1 and 2. We will apply the recently established novel and currently most extensive 450K CpG methylation microarray system to this project. With this extensive gene methylation study of thyroid cancer, particularly on the epigenetic mechanisms involved in the BRAFV600E-driven thyroid tumorigenesis, we expect to identify many genes that will be for the first time shown to play a key role in thyroid tumorigenesis and are therefore potential novel therapeutic targets for thyroid cancer. We also expect to uncover many novel DNA methylation markers in the genome from which we will identify the most sensitive and specific ones for the diagnosis and prognostication of thyroid cancer by testing them on thyroid tumor tissues, blood samples, and thyroid fine needle aspiration biopsy specimens. Renewal of this project will allow us to achieve these novel study aims using our well-established expertise, techniques, and research resources, which we believe will have a significant impact on the field of thyroid cancer.