理解甲状腺良性结节发生的分子机制对于进一步提高良恶性甲状腺结节的术前诊断有重要意义，但目前对于良性甲状腺结节发生的分子机制了解很少。腺瘤样甲状腺结节是最为常见的良性甲状腺结节。课题组前期通过对腺瘤样结节进行全外显子组测序，发现腺瘤样结节存在高频EZH1基因Q571R突变，扩大样本证实其发生频率高达9.3%，提示EZH1基因Q571R突变在良性甲状腺结节的发生过程中发挥重要作用。本课题拟进一步通过细胞模型与小鼠模型评估EZH1基因Q571R突变对于甲状腺滤泡上皮细胞在分化、甲状腺激素的合成与分泌、对于TSH的反应以及肿瘤学行为的影响，以及上述过程的分子机制，进而评估EZH1基因Q571R突变检测对于不能明确良恶性的甲状腺结节的诊断价值。本研究将为深入理解甲状腺良性结节的形成机制提供科学证据，并为甲状腺癌的分子诊断增加阴性标记物，降低良性甲状腺结节的手术比例。

Understand the molecular mechanism of benign thyroid nodule is very important to improve the accuracy of diagnosing malignant thyroid nodule before surgery. However, the genomic alterations for benign thyroid nodule, especially adenomatoid nodule, one of the most common type of hyperplasia lesion, are ill-studied. To systematically investigate the genetic characteristics of benign thyroid nodules we performed whole exome sequencing and/or transcriptome sequencing on adenomatoid nodules and found recurrent point mutations of EZH1Q571R. In an enlarged sample size we confirmed the frequency of EZH1Q571R mutation is 9.3%, suggesting a causal role of EZH1Q571R mutation in the formation of adenomatoid nodule. This project is designed to illustrate the of EZH1Q571R hotspot mutation in the formation of benign thyroid nodule. This includes whether and how it effects the differentiation of thyroid follicle, the synthesis and secretion of thyroid hormone, the response to TSH regulation, and the tumorigenesis related activities. Whether adding this mutation in the current molecular test panel should improve the current diagnosis accuracy will also be evaluated. This project will provide evidence for understanding the molecular basis of benign thyroid nodule and offer a modified molecular test panel to improve the accuracy of the current molecular testing for thyroid cancer.