甲状腺癌的治疗效果与分化程度密切相关，申请者对自己中心的23159例甲状腺癌的回顾性分析发现甲状腺乳头状癌（PTC）与分化差甲状腺癌/未分化甲状腺癌（PDTC/ATC）存在共存现象，且共存病例的5年CSS（cause sepecific survival）是64%，而同期经典PTC的5年CSS是98%（Int J Endocrinol 2018）。前期研究显示BRAF V600E突变和TERT promoter突变与PTC向PDTC/ATC的演进相关，但缺乏直接的实验证据和干预措施。本研究将应用自主构建的条件性过表达定点敲入mTert小鼠模型，与TPOCreER小鼠、BRAF V600E敲入小鼠杂交产生转基因小鼠模型，结合细胞系和肿瘤组织系统研究TERT活化的机制和促进BRAF突变PTC向PDTC/ATC转变的机制和干预措施，研究也将提高对TERT突变相关肿瘤的演进机制和药物治疗策略的认识

The prognosis of thyroid cancer is associated with the differentiation status. The retrospective analysis of 23159 thyroid cancer in the Fudan University Shanghai Cancer Center has identified the cases with co-occurrence of papillary thyroid carcinoma (PTC) and poorly differentiated thyroid cancer/ anaplastic thyroid cancer (PDTC/ATC). The 5 year cause specific survival (CSS) of cases with co-occurrence is 64%, while the 5 year CSS of classical PTC is 98% (Int J Endocrinol2018). The previous research showed the relationship between the BRAF V600E mutation and TERT promoter mutation with the progression from PTC to PDTC/ATC, while the direct experimental evidence and clinical available treatment were insufficient. The mTert conditional site specific knock-in mice model was constructed by us. The thyroid specific mice models were created by hybridization of TPOCreER mice, BRAF V600E knock-in mice and mTert overexpression mice. The mechanism of TERT activation and the role of TERT in the progression of PTC to PDTC/ATC were studied by using the mice model, cell line and cancer tissues. This research will also improve the knowledge of the progression and drug treatment method of cancers with TERT promoter mutation.