Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers
BackgroundFBXW7 is recognized as a critical tumor suppressor gene and a component of the ubiquitin-proteasome system, mediating the degradation of multiple oncogenic proteins, including c-MYC, Cyclin E, c-Jun, Notch, p53. Around 16% of colorectal cancer (CRC) patients carried FBXW7 somatic mutations...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1154432/full |
| _version_ | 1797857631885328384 |
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| author | Yiping Liu Hanlin Chen Hua Bao Jinfeng Zhang Runda Wu Lingjun Zhu |
| author_facet | Yiping Liu Hanlin Chen Hua Bao Jinfeng Zhang Runda Wu Lingjun Zhu |
| author_sort | Yiping Liu |
| collection | DOAJ |
| description | BackgroundFBXW7 is recognized as a critical tumor suppressor gene and a component of the ubiquitin-proteasome system, mediating the degradation of multiple oncogenic proteins, including c-MYC, Cyclin E, c-Jun, Notch, p53. Around 16% of colorectal cancer (CRC) patients carried FBXW7 somatic mutations, while a comprehensive characterization of FBXW7 somatic mutations in CRC is still lacking.MethodsColorectal cancer patients with tumor samples and matching white blood cell samples in the past five years were screened and DNA sequenced. DNA sequencing data of MSK MetTropism cohort and RNA sequencing data of TCGA COAD cohort were analyzed.ResultsWe discovered that the FBXW7 mutations were associated with higher tumor mutation burden (TMB), higher microsatellite instability (MSI) score, and lower chromosomal instability (CIN) score. Patients with FBXW7 mutations showed better overall survival (HR: 0.67; 95%CI: 0.55-0.80, P < 0.001). However, patients with FBXW7 R465C mutation displayed worse overall survival in multi-variate cox analysis when compared with patients carrying other FBXW7 mutations (HR: 1.6; 95%CI: 1.13-3.1, P = 0.015), and with all other patients (HR: 1.87; 95%CI: 0.99-2.5, P = 0.053). Moreover, in MSI patients, the FBXW7 mutated group showed higher M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration rates, and significant enrichment of multiple immune-related gene sets, including interferon-gamma response, interferon-alpha response, IL6 JAK STAT3 signaling, p53 pathway.ConclusionThis analysis comprehensively identified FBXW7 alterations in colorectal cancer patients and uncovered the molecular, clinicopathological, and immune-related patterns of FBXW7-altered CRC patients. |
| first_indexed | 2024-04-09T20:59:50Z |
| format | Article |
| id | doaj.art-9234dce53ded4bc48253cea0cf787b5b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-09T20:59:50Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-9234dce53ded4bc48253cea0cf787b5b2023-03-29T10:48:03ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-03-011310.3389/fonc.2023.11544321154432Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancersYiping Liu0Hanlin Chen1Hua Bao2Jinfeng Zhang3Runda Wu4Lingjun Zhu5Department of Oncology, Xiangya Hospital, Central South University, Changsha, ChinaGeneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, ChinaGeneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, ChinaGeneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, ChinaDepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDepartment of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaBackgroundFBXW7 is recognized as a critical tumor suppressor gene and a component of the ubiquitin-proteasome system, mediating the degradation of multiple oncogenic proteins, including c-MYC, Cyclin E, c-Jun, Notch, p53. Around 16% of colorectal cancer (CRC) patients carried FBXW7 somatic mutations, while a comprehensive characterization of FBXW7 somatic mutations in CRC is still lacking.MethodsColorectal cancer patients with tumor samples and matching white blood cell samples in the past five years were screened and DNA sequenced. DNA sequencing data of MSK MetTropism cohort and RNA sequencing data of TCGA COAD cohort were analyzed.ResultsWe discovered that the FBXW7 mutations were associated with higher tumor mutation burden (TMB), higher microsatellite instability (MSI) score, and lower chromosomal instability (CIN) score. Patients with FBXW7 mutations showed better overall survival (HR: 0.67; 95%CI: 0.55-0.80, P < 0.001). However, patients with FBXW7 R465C mutation displayed worse overall survival in multi-variate cox analysis when compared with patients carrying other FBXW7 mutations (HR: 1.6; 95%CI: 1.13-3.1, P = 0.015), and with all other patients (HR: 1.87; 95%CI: 0.99-2.5, P = 0.053). Moreover, in MSI patients, the FBXW7 mutated group showed higher M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration rates, and significant enrichment of multiple immune-related gene sets, including interferon-gamma response, interferon-alpha response, IL6 JAK STAT3 signaling, p53 pathway.ConclusionThis analysis comprehensively identified FBXW7 alterations in colorectal cancer patients and uncovered the molecular, clinicopathological, and immune-related patterns of FBXW7-altered CRC patients.https://www.frontiersin.org/articles/10.3389/fonc.2023.1154432/fullFbxw7colorectal cancernext generation sequencing - NGSbiomarkerGSEA analysis |
| spellingShingle | Yiping Liu Hanlin Chen Hua Bao Jinfeng Zhang Runda Wu Lingjun Zhu Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers Frontiers in Oncology Fbxw7 colorectal cancer next generation sequencing - NGS biomarker GSEA analysis |
| title | Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers |
| title_full | Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers |
| title_fullStr | Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers |
| title_full_unstemmed | Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers |
| title_short | Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers |
| title_sort | comprehensive characterization of fbxw7 mutational and clinicopathological profiles in human colorectal cancers |
| topic | Fbxw7 colorectal cancer next generation sequencing - NGS biomarker GSEA analysis |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1154432/full |
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