MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer
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 gene...
Ausführliche Beschreibung
Autor*in: |
Lei Sun [verfasserIn] Man Li [verfasserIn] Ling Deng [verfasserIn] Yuchun Niu [verfasserIn] Yichun Tang [verfasserIn] Yu Wang [verfasserIn] Linlang Guo [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
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2021 |
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Übergeordnetes Werk: |
In: Frontiers in Pharmacology - Frontiers Media S.A., 2010, 12(2021) |
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Übergeordnetes Werk: |
volume:12 ; year:2021 |
Links: |
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DOI / URN: |
10.3389/fphar.2021.625593 |
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Katalog-ID: |
DOAJ016566521 |
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520 | |a 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. | ||
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10.3389/fphar.2021.625593 doi (DE-627)DOAJ016566521 (DE-599)DOAJc938984359264c67b5deabc1a2ecd8ed DE-627 ger DE-627 rakwb eng RM1-950 Lei Sun verfasserin aut MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. MGA mutation non-squamous non-small cell lung cancer biomarker immune checkpoint inhibitors Therapeutics. Pharmacology Man Li verfasserin aut Ling Deng verfasserin aut Yuchun Niu verfasserin aut Yichun Tang verfasserin aut Yu Wang verfasserin aut Linlang Guo verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2021) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2021 https://doi.org/10.3389/fphar.2021.625593 kostenfrei https://doaj.org/article/c938984359264c67b5deabc1a2ecd8ed kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.625593/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021 |
spelling |
10.3389/fphar.2021.625593 doi (DE-627)DOAJ016566521 (DE-599)DOAJc938984359264c67b5deabc1a2ecd8ed DE-627 ger DE-627 rakwb eng RM1-950 Lei Sun verfasserin aut MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. MGA mutation non-squamous non-small cell lung cancer biomarker immune checkpoint inhibitors Therapeutics. Pharmacology Man Li verfasserin aut Ling Deng verfasserin aut Yuchun Niu verfasserin aut Yichun Tang verfasserin aut Yu Wang verfasserin aut Linlang Guo verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2021) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2021 https://doi.org/10.3389/fphar.2021.625593 kostenfrei https://doaj.org/article/c938984359264c67b5deabc1a2ecd8ed kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.625593/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021 |
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10.3389/fphar.2021.625593 doi (DE-627)DOAJ016566521 (DE-599)DOAJc938984359264c67b5deabc1a2ecd8ed DE-627 ger DE-627 rakwb eng RM1-950 Lei Sun verfasserin aut MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. MGA mutation non-squamous non-small cell lung cancer biomarker immune checkpoint inhibitors Therapeutics. Pharmacology Man Li verfasserin aut Ling Deng verfasserin aut Yuchun Niu verfasserin aut Yichun Tang verfasserin aut Yu Wang verfasserin aut Linlang Guo verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2021) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2021 https://doi.org/10.3389/fphar.2021.625593 kostenfrei https://doaj.org/article/c938984359264c67b5deabc1a2ecd8ed kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.625593/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021 |
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10.3389/fphar.2021.625593 doi (DE-627)DOAJ016566521 (DE-599)DOAJc938984359264c67b5deabc1a2ecd8ed DE-627 ger DE-627 rakwb eng RM1-950 Lei Sun verfasserin aut MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. MGA mutation non-squamous non-small cell lung cancer biomarker immune checkpoint inhibitors Therapeutics. Pharmacology Man Li verfasserin aut Ling Deng verfasserin aut Yuchun Niu verfasserin aut Yichun Tang verfasserin aut Yu Wang verfasserin aut Linlang Guo verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2021) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2021 https://doi.org/10.3389/fphar.2021.625593 kostenfrei https://doaj.org/article/c938984359264c67b5deabc1a2ecd8ed kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.625593/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021 |
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10.3389/fphar.2021.625593 doi (DE-627)DOAJ016566521 (DE-599)DOAJc938984359264c67b5deabc1a2ecd8ed DE-627 ger DE-627 rakwb eng RM1-950 Lei Sun verfasserin aut MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. MGA mutation non-squamous non-small cell lung cancer biomarker immune checkpoint inhibitors Therapeutics. Pharmacology Man Li verfasserin aut Ling Deng verfasserin aut Yuchun Niu verfasserin aut Yichun Tang verfasserin aut Yu Wang verfasserin aut Linlang Guo verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2021) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2021 https://doi.org/10.3389/fphar.2021.625593 kostenfrei https://doaj.org/article/c938984359264c67b5deabc1a2ecd8ed kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.625593/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2021 |
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MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer |
abstract |
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. |
abstractGer |
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. |
abstract_unstemmed |
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. |
collection_details |
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title_short |
MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer |
url |
https://doi.org/10.3389/fphar.2021.625593 https://doaj.org/article/c938984359264c67b5deabc1a2ecd8ed https://www.frontiersin.org/articles/10.3389/fphar.2021.625593/full https://doaj.org/toc/1663-9812 |
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Man Li Ling Deng Yuchun Niu Yichun Tang Yu Wang Linlang Guo |
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Man Li Ling Deng Yuchun Niu Yichun Tang Yu Wang Linlang Guo |
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up_date |
2024-07-03T21:47:38.962Z |
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