National Key Laboratory of Medical Immunology and Institute of Immunology, Naval Medical University, Shanghai, China.
Front Immunol. 2023 Mar 24;14:1127982. doi: 10.3389/fimmu.2023.1127982. eCollection 2023.
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. 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.
DNA 损伤修复机制参与维持基因组完整性，并影响肿瘤发生。基于能够全面反映乳腺癌（BRCA）患者预后、肿瘤免疫代谢特征和治疗反应的 DNA 损伤修复相关基因（DRGs）的分子特征仍然缺乏。通过整合公共数据集和生物信息学算法，我们开发了一个基于 27 个 DRGs 的稳健预后特征。多个患者队列确定了根据该特征分层的高风险和低风险患者在各种类型生存中的显著差异。该特征与临床病理因素密切相关，可作为 BRCA 患者的独立预后指标。此外，低风险肿瘤的特征是浸润更多的 CD8 T 细胞、滤泡辅助 T 细胞、M1 巨噬细胞、活化 NK 细胞和静止树突状细胞，而 M0 和 M2 巨噬细胞较少。低风险肿瘤有利的免疫浸润模式也伴随着特定的代谢特征，减少 DNA 复制，并增强抗肿瘤免疫。低风险患者可能对免疫治疗反应更好，并通过常规化疗或靶向药物治疗获得更好的结果。真实世界的免疫治疗和化疗队列验证了预测结果。此外，还预测了四种有希望针对高风险肿瘤的小分子化合物。实验证实 GNPNAT1 和 MORF4L2 在 BRCA 组织中高表达，并与免疫细胞相关，这两种 DRGs 的敲低抑制了人 BRCA 细胞的增殖。总之，这个与 DNA 损伤修复相关的特征在预测患者预后、免疫代谢特征和治疗敏感性方面表现良好，有望为 BRCA 的精准医学和新靶标发现做出贡献。
