Yu Yongfeng, Yao Fei, Wang Jin, Huang Zhan, Hu Tao, Zhu Changbin, Lu Shun
Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, Huaihai West Road, Shanghai, 200030, China.
Department of Medicine, Xiawei Medical Laboratory Co., Ltd, Shanghai, China.
BMC Pulm Med. 2025 Jul 3;25(1):316. doi: 10.1186/s12890-025-03774-y.
EGFR mutations have been classified into four functional subgroups (Classical-like, P-loop and αC-helical compressing (PACC), T790M-like, and exon 20 loop insertions) based on their influence on EGFR protein structure, as well as response to various types of EGFR-tyrosine kinase inhibitors (TKIs). However, the differences in molecular phenotypes and clinical outcomes for patients carrying these different forms of EGFR mutations are not fully understood. Here we sought to investigate the distribution of different EGFR structural types in Chinese NSCLC patients and the biological characteristics of each subgroup.
2992 EGFR mutant NSCLC patients with available next-generation sequencing result were collected for mutation analysis. 118 patients with targeted RNA sequencing data were further analyzed to compare transcriptome differences across mutation subgroups.
Across the entire cohort, 80.82% of patients were Classical-like, 5.92% were PACC, 10.76% were T790M-like, and 2.51% were Ex20ins. TP53 was the most common co-occurring mutation across the four subgroups, occurring in 60% of the T790M-like subgroup. Interestingly, the Ex20ins group exhibited a notable proportion of genomic alterations related to DNA repair processes. Additionally, both the Ex20ins and T790M subgroups demonstrated higher tumor mutational burden (TMB) scores. Furthermore, for the first time, we observed transcriptomic heterogeneity within these four subgroups. Classical-like group displayed enrichment of immune-related pathways, including PD1 signaling, CD28 family, and TCR signaling. Notably, the L858R group showed significant enrichment in immune activation signatures, including effector memory CD8 T cells, natural killer cells, and MHC I/II. This suggests a potentially robust immune response in that group. In contrast, the T790M-like subgroups showed lower anti-tumor immune signatures but were marked by a significant enrichment in tumor proliferation signatures.
In this study, we have employed a structure-based classification approach for EGFR mutants to comprehensively characterize the mutational landscape and heterogeneous biological traits at the transcriptional and functional levels in Chinese patients with NSCLC.
基于对EGFR蛋白结构的影响以及对各种类型EGFR酪氨酸激酶抑制剂（TKIs）的反应，EGFR突变已被分为四个功能亚组（经典样、P环和αC螺旋压缩（PACC）、T790M样和外显子20环插入）。然而，携带这些不同形式EGFR突变的患者在分子表型和临床结果方面的差异尚未完全了解。在此，我们旨在研究中国非小细胞肺癌（NSCLC）患者中不同EGFR结构类型的分布以及每个亚组的生物学特征。
收集2992例有可用下一代测序结果的EGFR突变NSCLC患者进行突变分析。对118例有靶向RNA测序数据的患者进行进一步分析，以比较不同突变亚组之间的转录组差异。
在整个队列中，80.82%的患者为经典样突变，5.92%为PACC，10.76%为T790M样，2.51%为外显子20插入（Ex20ins）。TP53是四个亚组中最常见的共发突变，在60%的T790M样亚组中出现。有趣的是，Ex20ins组显示出与DNA修复过程相关的基因组改变比例显著。此外，Ex20ins和T790M亚组均显示出较高的肿瘤突变负荷（TMB）评分。此外，我们首次观察到这四个亚组内的转录组异质性。经典样组显示免疫相关途径富集，包括PD1信号通路、CD28家族和TCR信号通路。值得注意的是，L858R组在免疫激活特征方面显著富集，包括效应记忆CD8 T细胞、自然杀伤细胞和MHC I/II。这表明该组可能有强大的免疫反应。相比之下，T790M样亚组显示出较低的抗肿瘤免疫特征，但以肿瘤增殖特征显著富集为标志。
在本研究中，我们采用基于结构的分类方法对EGFR突变进行分类，以全面表征中国NSCLC患者在转录和功能水平上的突变格局和异质生物学特征。
