Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer
DNA damage-repair machinery participates in maintaining genomic integrity and affects tumorigenesis. Molecular signatures based on DNA damage-repair-related genes (DRGs) capable of comprehensively indicating the prognosis, tumor immunometabolic profile and therapeutic responsiveness of breast cancer...
| 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 Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1127982/full |
| _version_ | 1797861053558685696 |
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| author | Chunzhen Li Shu Yu Jie Chen Qianshan Hou Siyi Wang Cheng Qian Shulei Yin |
| author_facet | Chunzhen Li Shu Yu Jie Chen Qianshan Hou Siyi Wang Cheng Qian Shulei Yin |
| author_sort | Chunzhen Li |
| collection | DOAJ |
| description | DNA damage-repair machinery participates in maintaining genomic integrity and affects tumorigenesis. Molecular signatures based on DNA damage-repair-related genes (DRGs) capable of comprehensively indicating the prognosis, tumor immunometabolic profile and therapeutic responsiveness of breast cancer (BRCA) patients are still lacking. Integrating public datasets and bioinformatics algorithms, we developed a robust prognostic signature based on 27 DRGs. Multiple patient cohorts identified significant differences in various types of survival between high- and low-risk patients stratified by the signature. The signature correlated well with clinicopathological factors and could serve as an independent prognostic indicator for BRCA patients. Furthermore, low-risk tumors were characterized by more infiltrated CD8+ T cells, follicular helper T cells, M1 macrophages, activated NK cells and resting dendritic cells, and fewer M0 and M2 macrophages. The favorable immune infiltration patterns of low-risk tumors were also accompanied by specific metabolic profiles, decreased DNA replication, and enhanced antitumor immunity. Low-risk patients may respond better to immunotherapy, and experience improved outcomes with conventional chemotherapy or targeted medicine. Real-world immunotherapy and chemotherapy cohorts verified the predictive results. Additionally, four small molecule compounds promising to target high-risk tumors were predicted. In vitro experiments confirmed the high expression of GNPNAT1 and MORF4L2 in BRCA tissues and their association with immune cells, and the knockdown of these two DRGs suppressed the proliferation of human BRCA cells. In summary, this DNA damage-repair-related signature performed well in predicting patient prognosis, immunometabolic profiles and therapeutic sensitivity, hopefully contributing to precision medicine and new target discovery of BRCA. |
| first_indexed | 2024-04-09T21:56:56Z |
| format | Article |
| id | doaj.art-f2a3e2b1878e4fc7be90290cf7f9b088 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T21:56:56Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-f2a3e2b1878e4fc7be90290cf7f9b0882023-03-24T05:15:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-03-011410.3389/fimmu.2023.11279821127982Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancerChunzhen LiShu YuJie ChenQianshan HouSiyi WangCheng QianShulei YinDNA damage-repair machinery participates in maintaining genomic integrity and affects tumorigenesis. Molecular signatures based on DNA damage-repair-related genes (DRGs) capable of comprehensively indicating the prognosis, tumor immunometabolic profile and therapeutic responsiveness of breast cancer (BRCA) patients are still lacking. Integrating public datasets and bioinformatics algorithms, we developed a robust prognostic signature based on 27 DRGs. Multiple patient cohorts identified significant differences in various types of survival between high- and low-risk patients stratified by the signature. The signature correlated well with clinicopathological factors and could serve as an independent prognostic indicator for BRCA patients. Furthermore, low-risk tumors were characterized by more infiltrated CD8+ T cells, follicular helper T cells, M1 macrophages, activated NK cells and resting dendritic cells, and fewer M0 and M2 macrophages. The favorable immune infiltration patterns of low-risk tumors were also accompanied by specific metabolic profiles, decreased DNA replication, and enhanced antitumor immunity. Low-risk patients may respond better to immunotherapy, and experience improved outcomes with conventional chemotherapy or targeted medicine. Real-world immunotherapy and chemotherapy cohorts verified the predictive results. Additionally, four small molecule compounds promising to target high-risk tumors were predicted. In vitro experiments confirmed the high expression of GNPNAT1 and MORF4L2 in BRCA tissues and their association with immune cells, and the knockdown of these two DRGs suppressed the proliferation of human BRCA cells. In summary, this DNA damage-repair-related signature performed well in predicting patient prognosis, immunometabolic profiles and therapeutic sensitivity, hopefully contributing to precision medicine and new target discovery of BRCA.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1127982/fullDNA damageDNA repairprognostic signatureimmune microenvironmentmetabolic statusbreast cancer |
| spellingShingle | Chunzhen Li Shu Yu Jie Chen Qianshan Hou Siyi Wang Cheng Qian Shulei Yin Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer Frontiers in Immunology DNA damage DNA repair prognostic signature immune microenvironment metabolic status breast cancer |
| title | Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer |
| title_full | Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer |
| title_fullStr | Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer |
| title_full_unstemmed | Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer |
| title_short | Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer |
| title_sort | risk stratification based on dna damage repair related signature reflects the microenvironmental feature metabolic status and therapeutic response of breast cancer |
| topic | DNA damage DNA repair prognostic signature immune microenvironment metabolic status breast cancer |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1127982/full |
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