前期我们发现并定义了家族性甲状腺非髓样癌（familial non-medullary cancer, FNMTC）的一个亚型--MEK5胚系变异型FNMTC，其发病机制尚不清楚。揭示其遗传和发病机制，有助于该亚型肿瘤治疗靶点的发现和发病的防控。基于预实验我们猜测：MEK5变异可导致细胞应激防御调控的自噬机制障碍而失去抑癌保护功能，在叠加MAPK信号通路激活后，促成恶性肿瘤的发生。本项目拟利用大规模临床样本为支撑，扩建FNMTC临床队列的同时准确定义该亚型的占比、胚系变异热点以及临床病理特征；阐明围绕“MEK5变异-自噬障碍-MAPK信号通路激活-恶性肿瘤发生”的分子机制。本项目的科学意义在于阐明其从正常甲状腺滤泡细胞到肿瘤形成过程中重要的细胞-分子事件，从而可围绕其发病机制，探索和论证该类型患者潜在治疗靶点和防控靶点，为预防和控制甲状腺非髓样癌高发提供新的思路和理论依据。

Previously, we defined a new sub-type of familial non-medullary cancer (FNMTC) named “MEK5 germline mutated FNMTC” and the oncogenesis mechanism is still known. Elucidating its heredity and pathogenesis helps for discovering its therapeutic targets as well as disease prevention and control. Based on the preliminary data, we suppose that MEK5 germline mutation can inhibit follicular cell autophagy formation result in loss of tumor repression. After accumulation of enough mutations e.g. activation of MAPK signaling, malignant tumor cell formed. This project which largely dependent on our FNMTC cohort, is aimed to precisely define the percentage of MEK5 germline mutated FNMTC in total FNMTC, the clinical pathological characteristics, and the molecular events promoting normal follicular cells to cancer cells along MEK5 mutation/autophagy inhibition/MAPK signaling activation. The scientific significance of this project is to uncover the mechanism of tumor genesis for MEK5 germline mutated FNMTC, which may contribute to discovering therapeutic and prevention targets for this subtype of disease and providing new strategies for NMTC prevention and control.