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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...

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Autores principales: Li, Chunzhen, Yu, Shu, Chen, Jie, Hou, Qianshan, Wang, Siyi, Qian, Cheng, Yin, Shulei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080010/
https://www.ncbi.nlm.nih.gov/pubmed/37033959
http://dx.doi.org/10.3389/fimmu.2023.1127982
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author Li, Chunzhen
Yu, Shu
Chen, Jie
Hou, Qianshan
Wang, Siyi
Qian, Cheng
Yin, Shulei
author_facet Li, Chunzhen
Yu, Shu
Chen, Jie
Hou, Qianshan
Wang, Siyi
Qian, Cheng
Yin, Shulei
author_sort Li, Chunzhen
collection PubMed
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.
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spelling pubmed-100800102023-04-08 Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of breast cancer Li, Chunzhen Yu, Shu Chen, Jie Hou, Qianshan Wang, Siyi Qian, Cheng Yin, Shulei Front Immunol Immunology 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. Frontiers Media S.A. 2023-03-24 /pmc/articles/PMC10080010/ /pubmed/37033959 http://dx.doi.org/10.3389/fimmu.2023.1127982 Text en Copyright © 2023 Li, Yu, Chen, Hou, Wang, Qian and Yin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Li, Chunzhen
Yu, Shu
Chen, Jie
Hou, Qianshan
Wang, Siyi
Qian, Cheng
Yin, Shulei
Risk stratification based on DNA damage-repair-related signature reflects the microenvironmental feature, metabolic status and therapeutic response of 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 Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080010/
https://www.ncbi.nlm.nih.gov/pubmed/37033959
http://dx.doi.org/10.3389/fimmu.2023.1127982
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