Genetic & Epigenetic Events in Papillary Thyroid Cancer

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• 批准号: 8577313
• 负责人: MICHAEL Mingzhao XING
• 金额: $ 27.12万
• 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 2016-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577313
• 关键词: Accounting; Area; BRAF gene; Biopsy Specimen; Blood specimen; Cancer cell line; Cell Proliferation; Cessation of life; Characteristics; Clinic; Clinical; DNA; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Disease; Endocrine; Epigenetic Process; Event; Fine needle aspiration biopsy; Funding; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Growth; In Vitro; Incidence; Journals; Laboratories; Lead; Legal patent; Life; MAP Kinase Gene; MAP Kinase Signaling Pathways; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Medicine; Methylation; Mitogen-Activated Protein Kinases; Molecular; Mutation; Oncogenes; Papillary thyroid carcinoma; Pathogenesis; Patients; Play; Primary Neoplasm; Principal Investigator; Protocols documentation; Publications; Publishing; Ras/Raf; Recurrence; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Role; Seminal; Serum; Signal Pathway; Signal Transduction; Specimen; System; Techniques; Testing; Thyroid Gland; Time; Translations; Tumor Tissue; Work; base; cancer cell; clinical Diagnosis; effective therapy; genome-wide; improved; in vivo; molecular marker; new therapeutic target; novel; novel diagnostics; prognostic; promoter; public health relevance; success; thyroid neoplasm; tumor; tumorigenesis

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.

描述（由申请人提供）：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、鉴别诊断和治疗中遇到了几个主要的难题。为了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肿瘤发生的分子机制。为此，这个R 01支持的项目的主要目标是发现和表征甲状腺癌的遗传和表观遗传改变，并将其推向临床转化。这个项目在最初的五年资助中取得了巨大的成功 周期，特别是在与BRAF突变（BRAFV 600 E）相关的区域，BRAFV 600 E是PTC中MAP激酶信号通路中的一个突出癌基因。为了延续该项目的主题和强劲势头，在本次更新申请中，我们提出基于最近强有力的新数据来检验我们的新假设，即BRAFV 600 E信号传导促进的功能重要基因的甲基化和表达中的广泛基因组畸变是甲状腺癌发病机制中先前未被认识到的基本分子机制。我们拟通过以下三个具体目标来验证这一假说并将其应用于临床：1）检测BRAFV 600 E/MAP激酶信号转导所驱动的全基因组DNA甲基化改变，并鉴定启动子甲基化和表达改变的基因; 2）直接检测BRAFV 600 E信号转导所引起的表观遗传学改变基因在甲状腺肿瘤发生中的功能和作用; 3）检查特异性目的1和2中鉴定的新型DNA甲基化标志物的诊断和预后价值。我们将应用最近建立的新的和目前最广泛的450 K CpG甲基化微阵列系统到这个项目。通过这项广泛的甲状腺癌基因甲基化研究，特别是关于BRAFV 600 E驱动的甲状腺肿瘤发生中涉及的表观遗传机制的研究，我们希望能够鉴定出许多基因，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，因此是甲状腺癌的潜在新治疗靶点。我们还希望在基因组中发现许多新的DNA甲基化标记，通过在甲状腺肿瘤组织、血液样本和甲状腺细针穿刺活检标本上进行测试，我们将从中确定最敏感和特异的标记，用于甲状腺癌的诊断和鉴别。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。