嘧啶代谢是癌症的标志,并将很快成为癌症治疗的重要组成部分。在肿瘤微环境中,细胞在细胞内和细胞外重新编程嘧啶代谢,从而促进肿瘤发生。嘧啶代谢中的代谢物对促进癌症进展和调节免疫系统反应具有显著影响。在临床前研究和实际临床应用中,嘧啶代谢的关键目标是通过药物对肿瘤发挥有希望的治疗作用。然而,乳腺癌(BC)中的嘧啶代谢仍在很大程度上不足。在这项研究中,检索到163个可靠的嘧啶代谢相关基因(PMGs),并测定其体细胞突变和表达水平。此外,通过使用癌症基因组图谱(TCGA)和乳腺癌国际联合会(METABRIC)的分子分类学数据库,使用单变量Cox回归分析确定与总生存期(OS)相关的12个PMG。随后,通过对TCGA-BRCA数据集中的12个PMG进行LASSOCox危害回归分析,我们使用八个OS相关的PMG开发了预后列线图,然后在METABRIC中验证了这一点,GSE96058、GSE20685、GSE42568和GSE86166数据。此外,我们验证了嘧啶代谢指数(PMI)与患者生存概率之间的关系,基本临床参数,包括TNM阶段和PAM50亚型。接下来,我们验证了最优模型的预测能力,包括签名,PAM50亚型,和年龄,使用ROC分析和校准曲线,并使用决策曲线分析将其与其他单一临床因素的获益预测能力进行比较。最后,我们研究了嘧啶代谢对免疫检查点的潜在影响,肿瘤浸润免疫细胞,和细胞因子水平,并确定嘧啶代谢在BC免疫治疗中的潜在意义。总之,我们的研究结果表明,嘧啶代谢在BC中具有潜在的预后意义,并且可以为具有不同预后和更精确的免疫治疗的患者提供新的治疗方法.
Pyrimidine metabolism is a hallmark of cancer and will soon become an essential part of cancer therapy. In the tumor microenvironment, cells reprogram pyrimidine metabolism intrinsically and extracellularly, thereby promoting tumorigenesis. Metabolites in pyrimidine metabolism have a significant impact on promoting cancer advancement and modulating immune system responses. In preclinical studies and practical clinical applications, critical targets in pyrimidine metabolism are acted upon by drugs to exert promising therapeutic effects on tumors. However, the pyrimidine metabolism in breast cancer (BC) is still largely underexplored. In this study, 163 credible pyrimidine metabolism-related genes (PMGs) were retrieved, and their somatic mutations and expression levels were determined. In addition, by using The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, 12 PMGs related to the overall survival (OS) were determined using the univariate Cox regression analysis. Subsequently, by performing the LASSO Cox hazards regression analysis in the 12 PMGs in TCGA-BRCA dataset, we developed a prognosis nomogram using eight OS-related PMGs and then verified the same in the METABRIC, GSE96058, GSE20685, GSE42568 and GSE86166 data. Moreover, we validated relationships between the pyrimidine metabolism index (PMI) and the survival probability of patients, essential clinical parameters, including the TNM stage and the PAM50 subtypes. Next, we verified the predictive capability of the optimum model, including the signature, the PAM50 subtype, and age, using ROC analysis and calibration curve, and compared it with other single clinical factors for the predictive power of benefit using decision curve analysis. Finally, we investigated the potential effects of pyrimidine metabolism on immune checkpoints, tumor-infiltrating immune cells, and cytokine levels and determined the potential implications of pyrimidine metabolism in BC immunotherapy. In conclusion, our findings suggest that pyrimidine metabolism has underlying prognostic significance in BC and can facilitate a new management approach for patients with different prognoses and more precise immunotherapy.