Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes
Abstract Background Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mut...
| Hlavní autoři: | , , , , , , , , , , , , |
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| Médium: | Článek |
| Jazyk: | English |
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BMC
2023-10-01
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| Edice: | Cancer Cell International |
| Témata: | |
| On-line přístup: | https://doi.org/10.1186/s12935-023-03056-9 |
| _version_ | 1827708180087439360 |
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| author | Kewei Wang Zixi Li Ying Xuan Yong Zhao Chao Deng Meidan Wang Chenjun Xie Fenglai Yuan Qingfeng Pang Wenjun Mao Dongyan Cai Zhangfeng Zhong Jie Mei |
| author_facet | Kewei Wang Zixi Li Ying Xuan Yong Zhao Chao Deng Meidan Wang Chenjun Xie Fenglai Yuan Qingfeng Pang Wenjun Mao Dongyan Cai Zhangfeng Zhong Jie Mei |
| author_sort | Kewei Wang |
| collection | DOAJ |
| description | Abstract Background Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mutation and Nrf2-activating mutation and responsiveness to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and other multiple cancers. Methods The study with the largest sample size (n = 49,533) explored the landscape of NFE2L2 mutations and their impact response/resistance to ICIs using public cohorts. In addition, the in-house WXPH cohort was used to validate the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Results In two pan-cancer cohorts, Nrf2-activating mutation was associated with higher TMB value compared to wild-type. We identified a significant association between Nrf2-activating mutation and shorter overall survival in pan-cancer patients and NSCLC patients but not in those undergoing ICIs treatment. Similar findings were obtained in cancer patients carrying the NFE2L2 mutation. Furthermore, in NSCLC and other cancer cohorts, patients with NFE2L2 mutation demonstrated more objective responses to ICIs than patients with wild type. Our in-house WXPH cohort further confirmed the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Lastly, decreased inflammatory signaling pathways and immune-depleted immunological microenvironments were enriched in Nrf2-activating mutation patients with NSCLC. Conclusions Our study found that patients with Nrf2-activating mutation had improved immunotherapy outcomes than patients with wild type in NSCLC and other tumor cohorts, implying that Nrf2-activating mutation defined a distinct subset of pan-cancers and might have implications as a biomarker for guiding ICI treatment, especially NSCLC. |
| first_indexed | 2024-03-10T17:00:04Z |
| format | Article |
| id | doaj.art-93c71c2729654feaa7752940d901b005 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-03-10T17:00:04Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-93c71c2729654feaa7752940d901b0052023-11-20T10:59:28ZengBMCCancer Cell International1475-28672023-10-0123111810.1186/s12935-023-03056-9Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomesKewei Wang0Zixi Li1Ying Xuan2Yong Zhao3Chao Deng4Meidan Wang5Chenjun Xie6Fenglai Yuan7Qingfeng Pang8Wenjun Mao9Dongyan Cai10Zhangfeng Zhong11Jie Mei12Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan UniversityDepartment of Physiopathology, Wuxi School of Medicine, Jiangnan UniversityDepartment of Thoracic Surgery, Affiliated Hospital of Jiangnan UniversityDepartment of Physiopathology, Wuxi School of Medicine, Jiangnan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan UniversityInstitute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan UniversityDepartment of Physiopathology, Wuxi School of Medicine, Jiangnan UniversityDepartment of Thoracic Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical UniversityDepartment of Oncology, Affiliated Hospital of Jiangnan UniversityMacao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauInstitute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan UniversityAbstract Background Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mutation and Nrf2-activating mutation and responsiveness to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and other multiple cancers. Methods The study with the largest sample size (n = 49,533) explored the landscape of NFE2L2 mutations and their impact response/resistance to ICIs using public cohorts. In addition, the in-house WXPH cohort was used to validate the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Results In two pan-cancer cohorts, Nrf2-activating mutation was associated with higher TMB value compared to wild-type. We identified a significant association between Nrf2-activating mutation and shorter overall survival in pan-cancer patients and NSCLC patients but not in those undergoing ICIs treatment. Similar findings were obtained in cancer patients carrying the NFE2L2 mutation. Furthermore, in NSCLC and other cancer cohorts, patients with NFE2L2 mutation demonstrated more objective responses to ICIs than patients with wild type. Our in-house WXPH cohort further confirmed the efficacy of immunotherapy in the NFE2L2 mutated patients with NSCLC. Lastly, decreased inflammatory signaling pathways and immune-depleted immunological microenvironments were enriched in Nrf2-activating mutation patients with NSCLC. Conclusions Our study found that patients with Nrf2-activating mutation had improved immunotherapy outcomes than patients with wild type in NSCLC and other tumor cohorts, implying that Nrf2-activating mutation defined a distinct subset of pan-cancers and might have implications as a biomarker for guiding ICI treatment, especially NSCLC.https://doi.org/10.1186/s12935-023-03056-9NFE2L2NSCLCBiomarkerNGSImmunotherapy |
| spellingShingle | Kewei Wang Zixi Li Ying Xuan Yong Zhao Chao Deng Meidan Wang Chenjun Xie Fenglai Yuan Qingfeng Pang Wenjun Mao Dongyan Cai Zhangfeng Zhong Jie Mei Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes Cancer Cell International NFE2L2 NSCLC Biomarker NGS Immunotherapy |
| title | Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes |
| title_full | Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes |
| title_fullStr | Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes |
| title_full_unstemmed | Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes |
| title_short | Pan-cancer analysis of NFE2L2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes |
| title_sort | pan cancer analysis of nfe2l2 mutations identifies a subset of lung cancers with distinct genomic and improved immunotherapy outcomes |
| topic | NFE2L2 NSCLC Biomarker NGS Immunotherapy |
| url | https://doi.org/10.1186/s12935-023-03056-9 |
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