多发性内分泌腺瘤病2型(MEN2)是最为重要的遗传性内分泌疾病之一，已知的病因是RET基因突变，但对其多器官肿瘤本身的调控却了解甚少，且表型的异质性提示MEN2中存在RET外的重要调控机制。我们前期用二代测序技术对MEN2的配对肿瘤进行了外显子组测序，发现翻译起始因子EIF4G1在MEN2多个肿瘤中不同方式的变异；并证实EIF4G1促进肿瘤细胞增殖和RET磷酸化，激活MAPK及AKT通路。本研究拟在此基础上，在临床、细胞及动物三个层面系统分析EIF4G1对MEN2相关肿瘤发生发展的影响；进一步建立MEN2与mTOR可能的联系，并运用高通量测序分析mRNA翻译谱寻找MEN2中直接受EIF4G1调控翻译的下游分子或途径；最后分析EIF4G1变异的遗传特征及临床相关性。最终阐明EIF4G1介导的真核翻译过程对MEN2的影响与分子机制，揭示除RET之外的分子事件，为MEN2的治疗提供新的可能途径。

Multiple endocrine neoplasia type 2 (MEN2) is one of the most important hereditary endocrine diseases. RET proto-oncogene mutations play a critical role in MEN2 tumoriogenesis. However, the frequency of non-RET genetic events, their impacts and molecular mechanisms remain to be discovered. We performed next-generation-sequencing of the exome in paired MEN2 tumors, namely medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid. We found recurrent alterations (SNV and CNV) of EIF4G1, eukaryotic translation initiation factor 4 gamma, in multiple MEN2 tumors. Over 60% of MEN2 tumors showed positive EIF4G1 immunostaining. Furthermore, we confirmed the oncogenic roles of mutant EIF4G1 in MEN2 tumor cells (TT, MZ-CRC1 and PC12 cell lines) by showing its upregulation of cell proliferation as well as phosphorylation of RET, MAPK and AKT. Based upon these findings, the current study is designed to investigate the roles of EIF4G1 in MEN2 tumorigenesis clinically, in vitro and in vivo. We also aim to establish the possible correlation between MEN2 and mTOR, apply high-resolution transcriptome-scale ribosome profiling to reveal the translation target of EIF4G1 in MEN2 tumors. Finally, our study will reveal the type and frequency of its genetic variations in MEN2 and control population, as well as the correlation of these variations with MEN2 phenotype. Our study will provide important information of how eukaryotic translation initiation factor impact MEN2 tumorigenesis, eventually leading to the discovery of novel therapy.