Objective To investigate the impact of KRAS/TP53 co-mutations on the biological behaviors of lung adenocarcinoma.Methods Research data related to metastasis,genomics,and immunotherapy of lung adenocarcinoma were obtained from the cBioPortal database.Lung adenocarcinoma cases with KRAS mutations were screened out and divided into KRAS mutation and KRAS/TP53 co-mutation group using R software.The distant metastasis propensity,genomic characteristics,and response to immune checkpoint inhibitors were compared between KRAS mutation and KRAS/TP53 co-mutation groups with SPSS statistical analysis.Results A total of 2 304 cases of KRAS-mutant lung adenocarcinoma were included,including 1 456 cases with wild-type TP53(KRAS mutation group)and 848 cases with mutant TP53(KRAS/TP53 co-mutation group).The incidence of distant metastasis(84.6％vs 76.3％,P＜0.001),the number of distant metastatic lesions(3.5 vs 3.0,P=0.009),and the number of distant metastatic organs(2.9 vs 2.4,P=0.001)in KRAS/TP53 co-mutation group were significantly increased,compared to KRAS mutation group.The risks of metastasis to bone(38.7％vs 31.8％,P=0.008),pleura(32.5％vs 27.3％,P=0.041),central nervous system(28.2％vs 21.1％,P=0.003),liver(18.1％vs 13.9％,P=0.040),distant lymph nodes(17.4％vs 13.3％,P=0.034),adrenal gland(15.2％vs 10.2％,P=0.006),intra-abdominal region(7.1％vs 4.1％,P=0.013),and bile duct(6.9％vs 3.5％,P=0.004)were significantly increased in KRAS/TP53 co-mutation group.Genomic analysis found that TP53 co-mutation significantly increased tumor mutational burden,the fraction of genome altered,and the frequency of KRAS mutant allele in KRAS-mutant lung adenocarcinoma.The alterations in cell cycle-related genes frequently occurred in KRAS/TP53 co-mutation group(31.9％vs 21.0％,P=0.001),while the alterations in NRF2(33.6％vs 18.1％,P＜0.001)and PI3K(45.6％vs 30.9％,P＜0.001)pathway genes frequently occurred in KRAS single mutation lung adenocarcinoma.Immune checkpoint inhibitor therapy significantly prolonged the median progression-free survival of patients(5.0 months vs 2.5 months,P=0.012)in KRAS/TP53 co-mutation group.Further analysis showed that the proportion of patients with PD-L1 expression≥1％(78.0％vs 42.0％,P＜0.001)and≥50％(54.0％vs 23.2％,P=0.001)in KRAS/TP53 co-mutation group was significantly higher than those with KRAS single mutation.Conclusion TP53 co-mutation significantly increases the incidence of distant metastasis in KRAS-mutant lung adenocarcinoma,significantly increases its tumor genomic mutation burden,and enhances the benefits of immune checkpoint inhibitor therapy.
万方数据
维普
