Identification of novel cuproptosis-related lncRNA signatures to predict the prognosis and immune microenvironment of breast cancer patients.

Background: Cuproptosis is a new modality of cell death regulation that is currently considered as a new cancer treatment strategy. Nevertheless, the prognostic predictive value of cuproptosis-related lncRNAs in breast cancer (BC) remains unknown. Using cuproptosis-related lncRNAs, this study aims to predict the immune microenvironment and prognosis of BC patients. and develop new therapeutic strategies that target the disease.

Methods: The Cancer Genome Atlas (TCGA) database provided the RNA-seq data along with the corresponding clinical and prognostic information. Univariate and multivariate Cox regression analyses were performed to acquire lncRNAs associated with cuproptosis to establish predictive features. The Kaplan-Meier method was used to calculate the overall survival rate (OS) in the high-risk and low-risk groups. High risk and low risk gene sets were enriched to explore functional discrepancies among risk teams. The mutation data were analyzed using the "MAFTools" r-package. The ties of predictive characteristics and immune status had been explored by single sample gene set enrichment analysis (ssGSEA). Last, the correlation between predictive features and treatment condition in patients with BC was analyzed. Based on prognostic risk models, we assessed associations between risk subgroups and immune scores and immune checkpoints. In addition, drug responses in at-risk populations were predicted.

Results: We identified a set of 11 Cuproptosis-Related lncRNAs (GORAB-AS1, AC 079922.2, AL 589765.4, AC 005696.4, Cytor, ZNF 197-AS1, AC 002398.1, AL 451085.3, YTH DF 3-AS1, AC 008771.1, LINC 02446), based on which to construct the risk model. In comparison to the high-risk group, the low-risk patients lived longer (p < 0.001). Moreover, cuproptosis-related lncRNA profiles can independently predict prognosis in BC patients. The AUC values for receiver operating characteristics (ROC) of 1-, 3-, and 5-year risk were 0.849, 0.779, and 0.794, respectively. Patients in the high-risk group had lower OS than those in the low-risk group when they were divided into groups based on various clinicopathological variables. The tumor burden mutations (TMB) correlation analysis showed that high TMB had a worse prognosis than low-TMB, and gene mutations were found to be different in high and low TMB groups, such as PIK3CA (36% versus 32%), SYNE1 (4% versus 6%). Gene enrichment analysis indicated that the differential genes were significantly concentrated in immune-related pathways. The predictive traits were significantly correlated with the immune status of BC patients, according to ssGSEA results. Finally, high-risk patients showed high sensitivity in anti-CD276 immunotherapy and conventional chemotherapeutic drugs such as imatinib, lapatinib, and pazopanib.

Conclusion: We successfully constructed of a cuproptosis-related lncRNA signature, which can independently predict the prognosis of BC patients and can be used to estimate OS and clinical treatment outcomes in BRCA patients. It will serve as a foundation for further research into the mechanism of cuproptosis-related lncRNAs in breast cancer, as well as for the development of new markers and therapeutic targets for the disease.