A novel circadian cycle-related gene signature for prognosis prediction of patients with breast cancer

Abstract

The extensive and intricate relationships between circadian rhythm and cancer have been reported in numerous studies. However, in breast cancer (BC), the potential role of circadian clock-related genes (CCRGs) in prognosis prediction has not been fully clarified. The transcriptome data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. A CCRGs-based risk signature was established by differential expression analysis, univariate, Lasso and multivariate Cox regression analyses. we conducted a gene set enrichment analysis (GSEA) between groups. A nomogram integrating independent clinical factors and risk score was generated and evaluated by calibration curves and decision curve analysis (DCA). Differentially expression analysis revealed 80 differentially expressed CCRGs, and 27 of them were significantly associated with the overall survival (OS) of BC. BC can be classified into 4 molecular subtypes with significant differences in prognosis based on the 27 CCRGs. Three prognostic CCRGs, including desmocollin 1 (DSC1), LEF1, and protocadherin 9 (PCDH9), were identified to be independent risk factors of BC prognosis and were used to construct a risk score model. BC patients were divided into high- and low-risk groups, and there were significant differences in prognosis between the 2 groups both in the training and validation cohorts. It was found that patients in different groups of race, status, or T stage had significant levels of risk score. Furthermore, patients of different risk levels exhibit varying degrees of sensitivity to vinorelbine, lapatinib, metformin, and vinblastine. GSEA showed that in the high-risk group, immune response-related activities were dramatically repressed whereas cilium-related processes were significantly stimulated. Cox regression analysis demonstrated that age, N stage, radiotherapy and the risk score were independent prognostic risk factors of BC, and a nomogram was established based on these variables. The nomogram exerted a favorable concordance index (0.798) as well as calibration performance, which strongly supports the clinical application of the nomogram. Our study indicated the disruption of the expression of CCRGs in BC and built a favorable prognostic risk model based on 3 independent prognostic CCRGs. These genes may be applied as candidate molecular targets for the diagnosis and therapy of BC.