KRAS和TP53共突变对肺腺癌生物学行为的影响

Impact of KRAS/TP53 co-mutations on biological behaviors of lung adenocarcinoma

目的研究TP53共突变状态对KRAS突变肺腺癌转移倾向、基因组特征及对免疫检查点抑制剂应答等的影响。方法从cBioPortal数据库中下载肺腺癌转移、基因组、免疫治疗相关研究数据,使用R语言筛选出KRAS突变病例并根据TP53突变状态进行分组,使用SPSS统计分析以比较合并野生型TP53或突变型TP53两组患者远处转移倾向、基因组特征、及对免疫检查点抑制剂应答情况的差异。结果研究共纳入KRAS突变肺腺癌2304例,包括1456例TP53野生型和848例TP53突变型。远处转移分析发现,合并TP53共突变显著增加了KRAS突变肺腺癌远处转移发生率(84.6%vs 76.3%,P<0.001)、远处转移病灶个数(3.5 vs 3.0,P=0.009)、远处转移器官的个数(2.9 vs 2.4,P=0.001)。其中,骨(38.7%vs 31.8%,P=0.008)、胸膜(32.5%vs 27.3%,P=0.041)、中枢神经系统(28.2%vs 21.1%,P=0.003)、肝(18.1%vs 13.9%,P=0.040)、远处淋巴结(17.4%vs 13.3%,P=0.034)、肾上腺(15.2%vs 10.2%,P=0.006)、腹内(7.1%vs 4.1%,P=0.013)、胆道(6.9%vs 3.5%,P=0.004)的转移风险大大增加。基因组分析发现,TP53共突变显著增加KRAS突变肺腺癌肿瘤突变负荷、基因组改变分数,以及KRAS突变等位基因的频率。TP53共突变常合并细胞周期相关基因改变(31.9%vs 21.0%,P=0.001);而KRAS单突变则常合并NRF2(33.6%vs 18.1%,P<0.001)及PI3K(45.6%vs 30.9%,P<0.001)通路基因改变。对免疫检查点抑制剂应答的分析发现,合并TP53共突变显著延长了患者的中位无进展生存期(5.0个月vs 2.5个月,P=0.012)。进一步对PD-L1表达进行分析,发现共突变患者PD-L1表达≥1%(78.0%vs 42.0%,P<0.001)或≥50%(54.0%vs 23.2%,P=0.001)的比例显著高于KRAS单突变者。结论TP53共突变显著增加KRAS突变肺腺癌远处转移发生率,显著增加其肿瘤基因组的突变负荷,增加其免疫检查点抑制剂治疗获益。

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 2304 cases of KRAS-mutant lung adenocarcinoma were included,including 1456 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.