肺癌脑膜转移的预后极恶劣，不经治疗的中位生存期仅1-3月，经治后中位生存期3-11月，治疗策略棘手，探索其发生机制迫在眉睫。我们前期研究发现脑膜转移更常见于EGFR突变肺腺癌患者（9.4%），进一步的探索脑膜转移的潜在演变过程，发现脑脊液可反映脑膜转移的独特基因谱，包括TP53 杂合性缺失（LOH）、RB1突变等；且TP53及RB1可引起肺腺癌靶向耐药及参与一系列细胞通路。TP53 LOH及RB1突变是否在脑膜转移中发挥关键作用，尚未报道。居于前期研究，本课题拟构建细胞株及动物模型，荧光显影技术评估脑膜转移模型成瘤情况，二代测序、IHC、FISH等技术探索EGFR、TP53、RB1基因的量化差异及下游信号通路的不同活化程度；并将综合二代测序结果建立脑膜转移的临床数据预后模型；探索及明确TP53及RB1基因在脑膜转移的发生与耐药机制，将为克服靶向耐药、临床研究提供实验室数据。

Leptomeningeal metastases (LM) are a devastating complication associated with poor survival of only 1-3months without any treatments and 3-11 months in those after active therapies, and optimal therapeutic approaches remain a big challenge, it is urgent to fully understand its mechanisms. In our previous studies, LM were much more frequent in NSCLC patients harboring EGFR mutations(9.4%).And further studies exploring the evolution of LM, we figured out that CSF could reveal the unique genetic profiles of LM, especially loss of heterozygosity (LOH) of TP53 and RB1 mutation; moreover, TP53 and RB1 could cause acquired resistance to EGFR-TKIs therapies, and activate in a series of pathways. However, it has not been reported that the role of TP53 LOH and RB1 mutations in LM. Based on the findings of our previous researches, this study plans to build up cell lines and animal models of LM, and perform NGS, IHC and FISH to explore the genetic profiles of EGFR, TP53 , RB1 and their downstream signaling pathways. Furthermore, the prognosis clinical model of LM will be established based on the results of NGS. We hope to fully explore and clarify the roles of TP53 and RB1 gene in LM, and find out the mechanisms of LM, and hope to provide important preclinical data for overcoming drug-resistance of LM.