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，尤其是乳头状甲状腺癌（PTC），是一种常见的内分泌恶性肿瘤，近年来发病率一直在迅速上升。目前，其临床诊断，预后和治疗中遇到了一些主要困境。为了解决它们并改善当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中的分子机制。为此，这个R01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学改变，并将其转移到临床翻译中。对于最初的五年资金，这个项目取得了巨大的成功 循环，特别是在与BRAF突变有关的区域（BRAFV600E），这是PTC中MAP激酶信号通路中的突出癌基因。为了继续主要的主题和该项目的强大动力，在这种续签应用中，我们建议基于最新的新数据来检验我们的新假设，该数据是基于甲基化基因组的广泛诸如甲基化的广泛差异，因此BRAFV600E信号传达了功能重要的基因，这是一种先前未识别的基本分子机制，是一种未经识别的基础机制。我们建议通过实现三个特定目的来检验该假设并将其移至临床：1）检查由BRAFV600E/MAP激酶信号传导驱动的全基因组DNA甲基化改变并识别改变启动子甲基化和表达的基因； 2）直接测试甲状腺肿瘤发生中BRAFV600E信号传导表观遗传学改变基因的功能和作用； 3）要检查特定目标1和2中确定的新型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型新颖，目前最广泛的450K CPG甲基化微阵列系统。通过对甲状腺癌的这项广泛的基因甲基化研究，尤其是在BRAFV600E驱动的甲状腺肿瘤发生的表观遗传机制上，我们期望确定许多将首次证明的基因，这些基因首次证明在甲状腺肿瘤中起着关键作用，因此是潜在的新型甲状腺甲状腺癌症靶标。我们还期望在基因组中揭示许多新型的DNA甲基化标记，我们将通过对甲状腺肿瘤组织，血液样本和甲状腺细针药物抽吸活检标本进行测试，从中确定甲状腺癌的诊断和预测最敏感和特异性。该项目的续签将使我们能够使用我们公认的专业知识，技术和研究资源来实现这些新型研究的目的，我们认为这将对甲状腺癌领域产生重大影响。