中国人甲状腺癌中TERT启动子的突变

项目名称： 中国人甲状腺癌中TERT启动子的突变

项目编号： No.81472579

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 邢明照

作者单位： 同济大学

项目金额： 80万元

中文摘要： 甲状腺癌是最常见的内分泌恶性肿瘤，目前在其诊断治疗及预后方面在世界各国，包括中国，均尚存困难之处。阐明甲状腺癌发生的分子机制，对建立基于分子的治疗策略十分重要。我们去年首次在甲状腺癌中发现了端粒反转录酶（TERT）基因启动子区突变，并提示其与高侵袭性甲状腺癌及BRAF V600E有相关性。这一发现开辟了一个新的甲状腺癌研究领域，有着重要的基础和临床意义。我们设想，在日益多发的中国人甲状腺癌中，TERT启动子突变是一个重要的分子事件，特别是在与BRAF V600E突变共存时可能与预后极差的甲状腺癌相关，具有特殊的帮助判断甲状腺癌病人预后的价值，并是甲状腺癌靶向治疗的新的有效的分子靶子。故此我们拟用包括各类甲状腺肿瘤的大样本中国人甲状腺癌对其深入研究，尤其是对TERT启动子突变与BRAF突变的关系及其对甲状腺肿瘤的生物行为和临床意义，在分子，细胞，动物模型，及病人标本等层次作深入的探索。

中文关键词： 甲状腺癌；TERT启动子突变；分子机制；靶向治疗；临床转化；中国人

英文摘要： Thyroid cancer is the most common endocrine malignancy currently with major diagnostic, prognostic, and therapeutic challenges in many countries in the world, including China. This is a challenging issue particularly in China, where, with a large population base, the incidence of this cancer has dramatically risen in recent years. A key to effectively tackling thyroid cancer in China would be to better understand the molecular mechanisms of thyroid cancer, based on which novel molecular-oriented management strategies can be developed. We were the first to make a landmark discovery of TERT promoter mutations in thyroid cancer. We have recently completed a novel study on TERT promoter mutations in Chinese thyroid cancer patients at several institutions in China, including the Shanghai Tenth People's Hospital (manuscript in press, J Clin Endocrinol Metab 2014; impact factor 6.43). Our preliminary data suggest that TERT promoter mutations are associated with aggressive types of thyroid cancer and often co-exist with the BRAF V600E mutation. Much remains unknown, however, about the mechanisms and clinical significance of these genetic patterns in thyroid cancer. Here, we hypothesize that TERT promoter mutations are an important genetic event in the tumorigenesis of thyroid cancer in the Chinese population, particularly when they co-exist with other major genetic alterations, such as BRAF V600E mutation, and coexistence of such genetic alterations represents a novel mechanism in thyroid tumorigenesis. We further hypothesize that co-existence of the TERT promoter and BRAF V600E mutations may promote progression and aggressiveness of thyroid cancer and therefore has a unique prognostic value in Chinese thyroid cancer patients. As such, therapeutically targeting both TERT and the co-existing oncogene BRAF V600E may be a novel effective molecular-targeted therapeutic strategy for thyroid cancer. To test these hypotheses, we will use a large expanded cohort of thyroid tumors of various histological types from Chinese patients to extensively explore TERT promoter mutations and their relationship with BRAF V600E mutation and tumor aggressiveness. We will test the prognostic and diagnostic values of TERT promoter mutations, alone or in combination with BRAF V600E mutation in Chinese thyroid cancer patients. We will also use cell lines and animal models as in vitro and in vivo systems, respectively, to functionally test the role of TERT promoter mutations alone or in combination with BRAF V600E to establish their role in thyroid tumorigenesis. This is a highly significant and innovative proposal and its successful completion may have a significant impact on understanding the molecular mechanisms of thyroid cancer and development of novel diagnostic, prognostic and therapeutic strategies for thyroid cancer patients in China.

英文关键词： Thyroid cancer;TERT promoter mutation;molecular mechanism;targeted therapy;clinical translation;chinese