MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer.
MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer.
复制标题
DOI：
10.3389/fphar.2021.625593
复制
发表时间：
2021
影响因子：
5.6
通讯作者：
Guo L
中科院分区：
文献类型：
--
作者：
Sun L;Li M;Deng L;Niu Y;Tang Y;Wang Y;Guo L
背景：免疫检查点抑制剂改变了晚期非小细胞肺癌的治疗前景。然而，只有一小部分患者从ICI中获益。因此，迫切需要发现预测性生物标志物。有证据表明，癌细胞中的遗传畸变可以调节肿瘤免疫环境。因此，我们探讨了非鳞状NSCLC中致癌基因突变与ICI疗效之间的关系。 研究方法：我们整理了来自发现队列的四项独立研究的314例接受ICI的非鳞状NSCLC患者的基因组和临床数据。对于外部验证，使用了来自ICI治疗队列的305例患者和来自两个非ICI治疗队列的1，027例患者。研究了致癌突变与免疫治疗结果之间的关系。多元考克斯回归模型用于调整混杂因素。在The Cancer Genome Atlas肺腺癌队列中对肿瘤抗原性和抗肿瘤免疫进行了进一步研究。 结果如下：在发现队列中，根据肿瘤学知识库数据库，共确定并研究了82种癌基因/肿瘤抑制基因，频率大于3%。在这些基因中，MGA突变在具有持久临床益处的患者中富集（p = 0.001，错误发现率q < 0.05）。MGA突变患者的客观缓解率也显著更高（2.63倍，p < 0.001，FDR q < 0.05）。在MGA突变患者中发现了更长的无进展生存期（HR，0.41; 95%CI，0.23-0.73; p = 0.003），并且在控制肿瘤突变负荷（TMB）、程序性细胞死亡配体-1表达和治疗方案后，这种相关性仍然显著。在验证队列中，发现携带MGA突变的患者的总生存期显着改善（HR，0.39; 95%CI，0.17-0.88; p = 0.02）。此外，在非ICI治疗队列中未检测到生存差异。我们还证实了MGA突变与较高的TMB、升高的新抗原负荷和DNA损伤修复缺陷相关。基因集富集分析显示，关于激活的免疫应答的基因集在MGA突变的肿瘤中富集。 结论：我们的工作提供了证据表明，MGA突变可以作为一种新的预测非鳞状NSCLC ICI反应的生物标志物，值得进一步的临床和临床前验证。
Background: Immune checkpoint inhibitors have changed the treatment landscape for advanced non-small cell lung cancer. However, only a small proportion of patients experience clinical benefit from ICIs. Thus, the discovery of predictive biomarkers is urgently warranted. Evidence have shown that genetic aberrations in cancer cells can modulate the tumor immune milieu. We therefore explored the association between oncogenic mutations and efficacy to ICIs in non-squamous NSCLC. Methods: We curated genomic and clinical data of 314 non-squamous NSCLC patients receiving ICIs from four independent studies for the discovery cohort. For external validation, 305 patients from an ICI-treated cohort and 1,027 patients from two non-ICI-treated cohorts were used. Relations between oncogenic mutations and outcomes of immunotherapy were examined. Multivariate Cox regression models were applied to adjust confounding factors. Further investigation on tumor antigenicity and antitumor immunity was performed in The Cancer Genome Atlas lung adenocarcinoma cohort. Results: A total of 82 oncogenes/tumor suppressor genes according to the Oncology Knowledge base database with a frequency greater than 3% were identified and investigated in the discovery cohort. Within these genes, MGA mutations were enriched in patients with durable clinical benefit (p = 0.001, false discovery rate q < 0.05). The objective response rate was also significantly higher in patients with MGA mutation (2.63-fold, p < 0.001, FDR q < 0.05). Longer progression-free survival was found in MGA-mutated patients (HR, 0.41; 95% CI, 0.23–0.73; p = 0.003), and the association remained significant after controlling for tumor mutational burden (TMB), programmed cell death ligand-1 expression, and treatment regimens. In the validation cohort, significant improvement in overall survival was found in patients harboring MGA mutation (HR, 0.39; 95% CI, 0.17–0.88; p = 0.02). Furthermore, the survival difference was not detected in non-ICI-treated cohorts. We also demonstrated that MGA mutation correlate with higher TMB, elevated neoantigen load and DNA damage repair deficiency. Gene set enrichment analysis revealed that gene sets regarding activated immune responses were enriched in MGA-mutated tumors. Conclusion: Our work provides evidence that MGA mutation can be used as a novel predictive biomarker for ICI response in non-squamous NSCLC and merits further clinical and preclinical validation.
登录
查看更多内容
影响因子：
4.2
作者：
Gessani S;Conti L;Del Cornò M;Belardelli F
通讯作者：
Belardelli F
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
30.5
作者：
Dunn, GP;Bruce, AT;Schreiber, RD
通讯作者：
Schreiber, RD
影响因子：
30.8
作者：
Miao D;Margolis CA;Vokes NI;Liu D;Taylor-Weiner A;Wankowicz SM;Adeegbe D;Keliher D;Schilling B;Tracy A;Manos M;Chau NG;Hanna GJ;Polak P;Rodig SJ;Signoretti S;Sholl LM;Engelman JA;Getz G;Jänne PA;Haddad RI;Choueiri TK;Barbie DA;Haq R;Awad MM;Schadendorf D;Hodi FS;Bellmunt J;Wong KK;Hammerman P;Van Allen EM
通讯作者：
Van Allen EM
DOI：
10.1084/jem.20101158
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diamond MS;Kinder M;Matsushita H;Mashayekhi M;Dunn GP;Archambault JM;Lee H;Arthur CD;White JM;Kalinke U;Murphy KM;Schreiber RD
通讯作者：
Schreiber RD