IntroductionComprehensive information about the genome analysis and its prognostic values of NSCLC patients in Chinese population are still needed.PatientsA total of 117 Chinese patients with NSCLC were enrolled in this study. Tumor tissues or blood were collected and sequenced by targeted next-generation sequencing of 556 cancer related genes. The associations between clinical outcomes and clinical characteristics, TMB, mutated genes, treatment therapies were analyzed using Kaplan-Meier methods and further evaluated using multivariable Cox proportional hazards regression model.ResultsA total of 899 mutations were identified by targeted NGS. The most frequently mutations includedEGFR(47%),TP53(46%),KRAS(18%),LRP1B(12%) andSPTA1(10%). Patients with mutantTP53,PREX2,ARID1A,PTPRTandPIK3CGhad lower median overall survival (OS) than those patients with wild-type (P= 0.0056,P< 0.001,P< 0.0001,P< 0.0001 andP= 0.036, respectively). Using a multivariate Cox regression model,PREX2(P< 0.001),ARID1A(P< 0.001) andPIK3CG(P= 0.04) were independent prognostic factors in NSCLC. In the patients received chemotherapy, squamous patients had a significantly longer median OS than adenocarcinoma patients (P= 0.011). In the patients received targeted therapy, adenocarcinoma patients had a significantly longer survival period than squamous patients (P= 0.01).ConclusionsOur study provided comprehensive genomic alterations in a cohort of Chinese NSCLC. We also identified new prognostic biomarkers, which could provide potential clues for targeted therapies.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13000-023-01349-1.