Analysis of Somatic Mutations and Immunotherapy Biomarkers in Chinese Patients With Non-Small Cell Lung Cancer During 2019-2024: A Retrospective Study.

Understanding genetic alterations in lung cancer remains challenging due to tumor heterogeneity and malignancy. This study aimed to investigate somatic variations and immune-related biomarkers in Chinese patients with NSCLC. This retrospective study involved Chinese patients with NSCLC from October 2019 to December 2024. A total of 554 pathological specimens were analyzed using targeted NGS panels. Fisher's exact test (two-sided, 95% confidence interval) was applied to assess statistical significance. The functional impact of certain mutations was validated in lung cancer cell lines. A total of 1302 genetic variations were identified. The most frequently altered genes included EGFR, TP53, KRAS, PIK3CA, STK11, ERBB2, BRAF, CTNNB1, MET, and PTEN. Enrichment analysis indicated that these genetic alterations were primarily concentrated in the EGFR, PI3K-AKT, microRNAs, P53, MAPK, ErbB, VEGF, JAK-STAT, and FoxO signaling pathways. Several co-occurring and mutually exclusive mutations were identified among the top altered genes. The co-mutation of PDGFRA and MET, or NRAS and PTEN in A549 cells, promoted cell proliferation and invasion compared with the control cells. Among patients receiving immunotherapy, the objective response rates were significantly higher in the TMB-high group than in the TMB-low group (62.5% vs. 34.2%), as well as in the heterozygous HLA-I group compared to the homogenous HLA-I group (51.6% vs. 25.9%). Analysis showed that TMB status was correlated with the tumor-infiltrating immune cells in the TCGA LUAD and LUSC datasets. TP53 mutations were more prevalent in males (p = 0.03) and associated with squamous cell carcinomas (p = 0.007), whereas EGFR mutations were more common in females (p < 0.001) and associated with lung adenocarcinomas (p = 0.029). Our findings suggest that a high TMB combined with a heterozygous HLA-I genotype serves as an effective biomarker for predicting the efficacy of immunotherapy in Chinese patients with NSCLC.