Abstract
Ferroptosis is a new form of regulated cell death (RCD), and its emergence has provided a new approach to the progression and drug resistance of breast cancer (BRCA). However, there is still a great gap in the study of ferroptosis-related genes in BRCA, especially luminal-type BRCA patients. We downloaded the mRNA expression profiles and corresponding clinical data of BRCA patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) databases. Then, we built a prognostic multigene signature with ferroptosis-related differentially expressed genes (DEGs) in the METABRIC cohort and validated it in the TCGA cohort. The predictive value of this signature was investigated in terms of the immune microenvironment and the probability of a response to immunotherapy and chemotherapy. The patients were divided into a high-risk group and a low-risk group according to the ferroptosis-associated gene signature, and the high-risk group had a worse overall survival (OS). The risk score based on the 10 ferroptosis-related gene-based signature was determined to be an independent prognostic predictor in both the METABRIC and TCGA cohorts (HR, 1.41, 95% CI, 1.14–1.76, P = 0.002; HR, 2.19, 95% CI, 1.13–4.26, P = 0.02). Gene set enrichment analysis indicated that the term “cytokine-cytokine receptor interaction” was enriched in the high-risk score subgroup. Moreover, the immune infiltration scores of most immune cells were significantly different between the two groups, the low-risk group was much more sensitive to immunotherapy, and six drugs might have potential therapeutic implications in the high-risk group. Finally, a nomogram incorporating a classifier based on the 10 ferroptosis-related genes, tumor stage, age and histologic grade was established. This nomogram showed favorable discriminative ability and could help guide clinical decision-making for luminal-type breast carcinoma.
Highlights
Ferroptosis is a new form of regulated cell death (RCD), and its emergence has provided a new approach to the progression and drug resistance of breast cancer (BRCA)
BRCA patients from the METABRIC cohort were included as a training set, and 754 patients from the The Cancer Genome Atlas (TCGA) cohort were enrolled as a testing set
Candidate prognostic ferroptosis‐related differentially expressed genes (DEGs) were identified in the METABRIC cohort
Summary
Ferroptosis is a new form of regulated cell death (RCD), and its emergence has provided a new approach to the progression and drug resistance of breast cancer (BRCA). A nomogram incorporating a classifier based on the 10 ferroptosis-related genes, tumor stage, age and histologic grade was established This nomogram showed favorable discriminative ability and could help guide clinical decision-making for luminal-type breast carcinoma. Prediction at the molecular level still relies heavily on ER, PR and HER2 These traditional factors alone are not sufficient for optimal treatment decisions, and several molecular assays based on multiple gene expression signatures have been developed to better predict the prognosis and treatment responses of BRCA patients. Finak et al.[17] identified a new 26-gene stroma-derived prognostic predictor (SDPP) associated with the clinical outcome of BRCA patients These 26 genes comprise CD48, TRBV5-4, and other genes that are closely related to the immune response. The exploration of BRCA-associated gene signatures is important for precise BRCA treatment
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