少数发展缓慢甚至惰性的肿瘤并不具有恶化及转移的风险，却被早期手术干预甚至辅以更加侵袭性的治疗。本项目研究者利用本中心积累了大量肺癌病例、保存有长期随访数据的优势，前期即筛选出相对罕见的惰性肺癌病例作为研究对象，发现其具备以下特征：EGFR驱动突变型为主；肿瘤效应T细胞数目和功能显著上调。随后通过全外显子测序我们在EGFR突变型惰性肺癌患者中发现了高频LNX4胚系突变（rs74955204），并且对LNX4的功能进行了初步的探索，根据前期结果我们提出LNX4可能通过调控EGFR信号及PD-L1泛素化导致肿瘤细胞的增殖及侵袭能力减弱，肺癌进展受限而呈惰性。本课题将继续扩大样本量验证rs74955204在早期EGFR突变型肺癌患者中的预后价值，通过体内外实验明确LNX4在惰性肺癌中发挥的功能和具体机制，有望发现肺癌惰性生长的重要机制和靶点，为肺癌的诊断和治疗提供新的理论支持。

A few lung tumors manifested as slow-growing or indolent course were noticed by CT screening, leading to overdiagnosis and even overtreatment. As a large number of lung cancer cases and their long-term follow-up data was accumulated in our center, we took this advantage to pick out indolent cases, which was relatively rare. Two main characters were identified as high frequency of EGFR driver mutation and enhanced effector T cells. Then, a high frequency of LNX4 germline mutation (rs74955204) was identified via whole-exome sequencing in patients with EGFR mutant indolent lung cancer, and the function of LNX4 were preliminarily explored. Therefore, we propose that LNX4 weaken the proliferation and invasion of tumor cells by regulating EGFR signaling and PD-L1 ubiquitination, resulting in indolent lung cancer progression. In this project, we plan to expand the sample size to confirm its potential prognostic value of rs74955204 in patients with early-stage EGFR mutant lung cancer, and to study the role and mechanism of LNX4 in regulation of EGFR signaling and PD-L1 ubiquitination in vitro and in vivo. We aim to verify the key role of LNX4 in slowing down the progression of lung cancer and to provide a new theoretical basis for the treatment of lung cancer.