肺癌中枢神经系统（CNS）转移治疗手段有限、疗效有限、预后极差。携带EGFR突变接受靶向治疗的患者，CNS转移是靶向治疗失败的主要原因之一，且机制未明。目前研究发现主干基因在肺癌原发灶及脑转移灶中高度一致，而存在差异的基因意义不明，发生率低下，无法解释CNS转移机制。本研究对EGFR突变接受靶向治疗的肺癌患者的脑转移灶及肺原发灶同时进行基因检测及甲基化组检测，探索CNS转移的可能机制。前期我们从两种病灶的甲基化差异特征分析中发现，在脑转移灶中NTRK1甲基化表达显著增强，可能通过激活PIK3CA促进了肺癌的CNS转移，且NTRK1甲基化的异常高表达与甲基转移酶KMT2D密切相关。本项目将在此基础上进一步明确NTRK1甲基化对CNS转移的促进作用，阐明与PIK3CA的相关性，并深入研究KMT2D对NTRK1的表达调控及分子机制，探索抑制NTRK1甲基化达到延缓或预防肺癌CNS转移的可能性。

The treatment of central nervous system metastasis in lung cancer is limited, the curative effect is limited, and the prognosis is very poor. Even in patients with EGFR-sensitive mutations receiving EGFR-TKI targeted therapy, central nervous system metastasis is one of the main manifestations of failure in EGFR-TKI therapy, and the mechanism is unclear. At present, it has been found that the main driver genes are highly consistent in the primary lung and brain metastatic foci of lung cancer, but the differences in gene variation are unknown and the incidence is low, which cannot be used as a reasonable mechanism of brain metastasis. Therefore, in the study of brain metastasis mechanism, we need to consider more dimensions to explore. In order to explore the potential mechanisms of central nervous system metastasis from the point of view of methylation, the matched brain metastasis and primary lung cancer foci of patients with EGFR mutation treated with EGFR-TKI were detected at the same time by gene detection and methylated group detection. In the previous study, we found that the expression of NTRK1 methylation was significantly increased in brain metastatic tumors from the analysis of methylation differences between the two lesions, which may promote the brain metastasis of lung cancer by activating PIK3CA signaling pathway. Moreover, the abnormal high expression of NTRK1 methylation is closely related to methyltransferase KMT2D. This project will further clarify the role of NTRK1 methylation in promoting brain metastasis and the role of PIK3CA in this process, and further study the expression regulation and molecular mechanism of KMT2D on NTRK1. Finally, to explore the possibility of inhibiting NTRK1 methylation to delay or prevent brain metastasis from lung cancer.