TERT Promoter Mutations in Thyroid Cancer

甲状腺癌中的 TERT 启动子突变

基本信息

  • 批准号:
    9029307
  • 负责人:
  • 金额:
    $ 36.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-03-05 至 2020-02-29
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are the most common thyroid malignancies and a subgroup of them can become aggressive and incurable, creating significant prognostic and therapeutic challenges. Our group has made an award-winning landmark discovery of TERT promoter mutations in thyroid cancer (Liu X et al. Endocr Relat Cancer 2013;20:603-610) and has recently published two more articles partially documenting the pathologic role and clinical relevance of these mutations in thyroid cancer (Liu et al. J Clin Endocrinol Metab 2014; Xing et al. J Clin Oncol 2014). In this early phase of this exciting new research area, however, much is unknown about the TERT promoter mutations; their pathologic roles and clinical significance in thyroid cancer remain to be fully defined and the molecular mechanisms remain to be elucidated. Based on our strong preliminary data, we hypothesize that TERT promoter mutations play an important role in the tumorigenesis and aggressiveness of thyroid cancer, particularly when in cooperation with classical driver genetic alterations activating the MAP kinase pathway in PTC and the PI3K pathway in FTC, which is further modified by a common polymorphism rs2853669 T>C in the TERT promoter; this has two important clinical implications, 1) co-existence of TERT promoter mutations with classical genetic alterations, depending on the rs2853669 status, may be associated with particularly poor outcomes of PTC and FTC and therefore has a unique prognostic value; and 2) therapeutically targeting both TERT and the signaling pathway harboring the co-existing genetic alterations in such thyroid cancer may be particularly effective. We propose to pursue the following three Specific Aims to test this hypothesis: 1) To extensively explore TERT promoter mutations 1,295,228 C>T and 1,295,250 C>T and SNP rs2853669 in PTC, their relationship with classical genetic alterations in the MAPK pathway and clinicopathological outcomes, and their prognostic value for PTC; 2) To similarly explore these TERT promoter variants in FTC, their relationship with genetic alterations in the PI3K pathway and clinico-pathological outcomes, and their prognostic value for FTC; and 3) To use in vitro and in vivo approaches to functionally test the role of TERT promoter variants in cooperation with classical oncogenes as well as the mechanistic role of the EST system in thyroid tumorigenesis and the therapeutic potential of targeting them. These studies are among our strongest research areas and will likely have a major impact on the field of thyroid cancer by unveiling new genetic patterns and mechanisms, based on which novel prognostic and therapeutic strategies may be developed for thyroid cancer.
描述(由申请人提供):甲状腺乳头状癌(PTC)和滤泡性甲状腺癌(FTC)是最常见的甲状腺恶性肿瘤,其中一个亚组可能会变得侵袭性和不可治愈,造成重大的预后和治疗挑战。我们的小组已经在甲状腺癌中发现了一个获奖的具有里程碑意义的TERT启动子突变(Liu X et al. Endocr Relat Cancer 2013;20:603-610),最近又发表了两篇文章,部分记录了这些突变在甲状腺癌中的病理作用和临床相关性(Liu et al. J Clin Endocrinol Metab 2014; Xing et al. J Clin Oncol 2014)。然而,在这一令人兴奋的新研究领域的早期阶段,关于TERT启动子突变的许多情况尚不清楚;它们在甲状腺癌中的病理作用和临床意义仍有待完全确定,分子机制仍有待阐明。基于我们强有力的初步数据,我们假设TERT启动子突变在甲状腺癌的肿瘤发生和侵袭性中起重要作用,特别是当与激活PTC中的MAP激酶途径和FTC中的PI 3 K途径的经典驱动基因改变合作时,其进一步被TERT启动子中的常见多态性rs 2853669 T>C修饰;这具有两个重要的临床意义,1)依赖于rs 2853669状态,TERT启动子突变与经典遗传改变的共存可能与PTC和FTC的特别差的结果相关,因此具有独特的预后价值;和2)在治疗上靶向这种甲状腺癌中携带共存遗传改变的TERT和信号通路可能特别有效。 本研究拟从以下三个方面来验证这一假设:1)深入研究PTC中TERT启动子1,295,228 C>T和1,295,250 C>T突变及SNP rs 2853669与MAPK通路经典遗传学改变和临床病理结果的关系,以及它们对PTC的预后价值; 2)类似地探讨FTC中这些TERT启动子变异体,它们与PI 3 K通路中的遗传改变和临床病理结果的关系,以及它们对FTC的预后价值;和3)为了使用体外和体内方法来功能性地测试TERT启动子变体与经典癌基因协作的作用,以及其机制,EST系统在甲状腺肿瘤发生中的作用以及靶向治疗的潜力。这些研究是我们最强的研究领域之一,可能会对甲状腺癌领域产生重大影响,揭示新的遗传模式和机制,在此基础上可能会为甲状腺癌开发新的预后和治疗策略。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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MICHAEL Mingzhao XING其他文献

MICHAEL Mingzhao XING的其他文献

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{{ truncateString('MICHAEL Mingzhao XING', 18)}}的其他基金

Genome-wide Exploration of DNA Methylation Markers for Thyroid Cancer
甲状腺癌 DNA 甲基化标记的全基因组探索
  • 批准号:
    8634084
  • 财政年份:
    2013
  • 资助金额:
    $ 36.49万
  • 项目类别:
Genome-wide Exploration of DNA Methylation Markers for Thyroid Cancer
甲状腺癌 DNA 甲基化标记的全基因组探索
  • 批准号:
    8492305
  • 财政年份:
    2013
  • 资助金额:
    $ 36.49万
  • 项目类别:
Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer
甲状腺癌 PI3K/Akt 通路中的分子事件
  • 批准号:
    8074952
  • 财政年份:
    2009
  • 资助金额:
    $ 36.49万
  • 项目类别:
Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer
甲状腺癌 PI3K/Akt 通路中的分子事件
  • 批准号:
    8474705
  • 财政年份:
    2009
  • 资助金额:
    $ 36.49万
  • 项目类别:
Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer
甲状腺癌 PI3K/Akt 通路中的分子事件
  • 批准号:
    8264949
  • 财政年份:
    2009
  • 资助金额:
    $ 36.49万
  • 项目类别:
Molecular Events in the PI3K/Akt Pathway in Thyroid Cancer
甲状腺癌 PI3K/Akt 通路中的分子事件
  • 批准号:
    7728577
  • 财政年份:
    2009
  • 资助金额:
    $ 36.49万
  • 项目类别:
Genetic & Epigenetic Events in Papillary Thyroid Cancer
遗传
  • 批准号:
    7840386
  • 财政年份:
    2006
  • 资助金额:
    $ 36.49万
  • 项目类别:
Genetic and Epigenetic Alterations in Thyroid Tumors
甲状腺肿瘤的遗传和表观遗传改变
  • 批准号:
    7432579
  • 财政年份:
    2006
  • 资助金额:
    $ 36.49万
  • 项目类别:
Genetic and Epigenetic Alterations in Thyroid Tumors
甲状腺肿瘤的遗传和表观遗传改变
  • 批准号:
    7244434
  • 财政年份:
    2006
  • 资助金额:
    $ 36.49万
  • 项目类别:
Genetic & Epigenetic Events in Papillary Thyroid Cancer
遗传
  • 批准号:
    7034799
  • 财政年份:
    2006
  • 资助金额:
    $ 36.49万
  • 项目类别:

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