TNBC Molecular Subtypes and Risk Signatures Based on Copper Metabolism: Prognostic and Immunological Importance

Abstract

Abstract Background Cuproptosis is a copper-dependent cellular death mechanism linked to tumor progression, prognosis, and immune response. Yet, the precise impact of copper-related genes (CRGs) on the tumor microenvironment (TME) within triple-negative breast cancer (TNBC) remains enigmatic. Methods In total, we collected 222 samples of triple-negative breast cancer (TNBC) from The Cancer Genome Atlas database and three Gene Expression Omnibus datasets. The classification was carried out utilizing R software packages. Simultaneously, unsupervised clustering analysis using the ConsensusClusterPlus R package was applied to establish a consensus molecular subtyping of copper subtypes. We thoroughly investigated the relationships between the various subgroups and their clinical pathological characteristics, immune infiltration traits, as well as the mutation status of the tumor microenvironment (TME). Lastly, to enhance the clinical utility of the CRG_score, we developed a nomogram and a calibration curve to predict the probability of patient survival. Results A comprehensive set of 196 CRGs underwent meticulous analysis, leading to the identification of 14 genes that distinctly impact the survival outcomes of patients across all cohorts. Based on risk scores, patients were stratified into different groups. Pathway enrichment analysis revealed pronounced enrichment of immune-related pathways across all datasets. Intriguingly, our observations unveiled that the high-risk CRG group exhibited heightened expression of all immune checkpoints and genes associated with antitumor activities. Correspondingly, a substantial proportion of the mentioned immune genes, with the exception of CD274, HAVCR2, CXCL9, and TNF, showcased elevated expression within gene cluster A. Furthermore, a predictive nomogram was meticulously crafted, leveraging patient characteristics and risk scores, to prognosticate the outcomes of patients diagnosed with hepatocellular carcinoma (HCC). Conclusion In this study, we constructed a cuproptosis least absolute shrinkage and selection operator (LASSO) Cox regression model. It was revealed to be a potential independent prognostic indicator of HCC and high CRGs samples showed a poor prognosis. Interestingly, CRGs were correlated with TME characteristics as well as clinical treatment efficacy. Importantly, compared with the low-risk CRGs group, the high-risk CRGs group may benefit from immunotherapy treatment.