中国人甲状腺癌中TERT启动子的突变

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.

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。

甲状腺癌目前在诊断治疗及预后方面均存困难之处。比如，广为用应的超声检查就急需提高准确性，以分子结合超声检查有望对其实现。甲癌也需新的分子治疗靶点。这些都需以分子为基础的临床转化研究来实现。本课题探讨BRAFV600E和TERT突变在中国人甲癌中相关的分子变化在临床方面的应用，比如看其是否可以辅助B超对甲癌的精确诊断及危险分级。为证实BRAFV600E在甲状腺癌方面的诊断预后价值，我们首先完成并发表了大样本甲癌BRAFV600E的Meta分析，显示BRAFV600E阳性的甲癌，特别是最常见的微小甲癌（PTMC）表现出侵袭性临床特征，证明了BRAFV600E在甲癌风险分级中的价值，为能探索BRAF和TERT结合临床特点，特别是超声，指导甲癌诊断和危险预后提供了重要的前提。基于此目的，我们也开展B超ARFI弹性成像在甲癌的临床诊断中的研究，结果显示ARFI对甲状腺良恶性结节的鉴别诊断具有高度敏感性和特异性，提高了诊断恶性甲状腺结节的特异性，并且证明甲状腺乳头状癌合并常规使用超声，应变弹性成像和声辐射力脉冲（ARFI）弹性成像，比常规的超声显著提高了颈部中央区淋巴结转移的预测效果。基于这些结果，我们发表了5篇重要的文章，对下一步与BRAF和TERT结合的研究，进而建立分子结合超声的崭新的甲癌诊断和危险评估的手段，完成了必要的一步。在探索新的靶点治疗方面，我们探讨了小檗碱对甲癌细胞的影响，发现小檗碱可诱导甲癌细胞凋亡及细胞周期停滞和迁移，我们证明其机制是通过引起经典 MAP 激酶和PI3K信号通路进行的，为建立甲癌的新的治疗方法提供了新路子。另外，我们已收集了716例甲癌患者的临床和超声信息，有了甲癌BRAFV600E/TERT的检测结果。我们将继续扩大样本，检测基因背景，最终建立一个适合中国甲癌病人的分子基础与超声特点相结合的超精确的甲癌诊断和风险评估系统。