NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer
BackgroundPatients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear.MethodsA total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue...
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.920253/full |
| _version_ | 1811291631845900288 |
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| author | Xiao-yang Gong Hai-bin Chen Li-qing Zhang Dong-sheng Chen Wang Li Dong-hui Chen Jin Xu Han Zhou Le-le Zhao Yun-jie Song Ming-zhe Xiao Wang-long Deng Chuang Qi Xue-rong Wang Xi Chen |
| author_facet | Xiao-yang Gong Hai-bin Chen Li-qing Zhang Dong-sheng Chen Wang Li Dong-hui Chen Jin Xu Han Zhou Le-le Zhao Yun-jie Song Ming-zhe Xiao Wang-long Deng Chuang Qi Xue-rong Wang Xi Chen |
| author_sort | Xiao-yang Gong |
| collection | DOAJ |
| description | BackgroundPatients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear.MethodsA total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively.ResultsTo the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 (TP53, 78.5%), FAT atypical cadherin 1 (FAT1, 26%), LDL receptor related protein 1B (LRP1B, 19%), cyclin dependent kinase inhibitor 2A (CDKN2A, 17%), tet methylcytosine dioxygenase 2 (TET2, 17%), notch receptor 1 (NOTCH1, 12%) and neuregulin 1 (NRG1, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1-mutant patients.ConclusionsGenomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort. |
| first_indexed | 2024-04-13T04:32:33Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T04:32:33Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-6ba630dd5c504c1ea8ba532fa07f7aac2022-12-22T03:02:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.920253920253NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancerXiao-yang Gong0Hai-bin Chen1Li-qing Zhang2Dong-sheng Chen3Wang Li4Dong-hui Chen5Jin Xu6Han Zhou7Le-le Zhao8Yun-jie Song9Ming-zhe Xiao10Wang-long Deng11Chuang Qi12Xue-rong Wang13Xi Chen14Department of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaJiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, ChinaDepartment of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaJiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, ChinaJiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, ChinaJiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, ChinaJiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, ChinaJiangsu Simcere Diagnostics Co., Ltd, The State Key Laboratory of Translational Medicine and Innovative Drug Development, Nanjing, ChinaDepartment of Pharmacology, Nanjing Medical University, Nanjing, ChinaDepartment of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaBackgroundPatients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear.MethodsA total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively.ResultsTo the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 (TP53, 78.5%), FAT atypical cadherin 1 (FAT1, 26%), LDL receptor related protein 1B (LRP1B, 19%), cyclin dependent kinase inhibitor 2A (CDKN2A, 17%), tet methylcytosine dioxygenase 2 (TET2, 17%), notch receptor 1 (NOTCH1, 12%) and neuregulin 1 (NRG1, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1-mutant patients.ConclusionsGenomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort.https://www.frontiersin.org/articles/10.3389/fimmu.2022.920253/fullT1-2N0 laryngeal cancerrelapsetumor mutation burdenNOTCH1 mutationtumor immunitymolecular alterations |
| spellingShingle | Xiao-yang Gong Hai-bin Chen Li-qing Zhang Dong-sheng Chen Wang Li Dong-hui Chen Jin Xu Han Zhou Le-le Zhao Yun-jie Song Ming-zhe Xiao Wang-long Deng Chuang Qi Xue-rong Wang Xi Chen NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer Frontiers in Immunology T1-2N0 laryngeal cancer relapse tumor mutation burden NOTCH1 mutation tumor immunity molecular alterations |
| title | NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer |
| title_full | NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer |
| title_fullStr | NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer |
| title_full_unstemmed | NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer |
| title_short | NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer |
| title_sort | notch1 mutation associates with impaired immune response and decreased relapse free survival in patients with resected t1 2n0 laryngeal cancer |
| topic | T1-2N0 laryngeal cancer relapse tumor mutation burden NOTCH1 mutation tumor immunity molecular alterations |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.920253/full |
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