TERT Promoter Mutations in Thyroid Cancer

描述（由申请人提供）：乳头状甲状腺癌（PTC）和滤泡性甲状腺癌（FTC）是最常见的甲状腺恶性肿瘤，其中的一个亚群可能变得具有侵袭性和不可治愈，给预后和治疗带来重大挑战。我们小组在甲状腺癌中TERT启动子突变的发现获得了获奖的里程碑式发现（Liu X et al.）。内源性相关癌症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.）。中华内分泌杂志2014；Xing等。临床肿瘤学杂志，2014)。然而，在这个令人兴奋的新研究领域的早期阶段，关于TERT启动子突变还有很多未知之处；它们在甲状腺癌中的病理作用和临床意义尚未完全明确，分子机制也有待阐明。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发挥重要作用，特别是当与激活PTC中的MAP激酶途径和FTC中的PI3K途径的经典驱动基因改变合作时，后者被TERT启动子中的共同多态性rs2853669 T>C进一步修饰；这有两个重要的临床意义，1)TERT启动子突变与经典遗传改变的共存，取决于rs2853669的状态，可能与PTC和FTC的预后特别差有关，因此具有独特的预后价值；2)在治疗上同时靶向TERT和携带共存基因改变的信号通路可能特别有效。

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.