Prognostic value of a circadian rhythm-related gene signature in breast cancer patients: A retrospective cohort study

By 2020, breast cancer (BRCA) surpassed lung cancer as the most prevalent cancer globally, exhibiting high morbidity and mortality. Given the emerging role of circadian rhythm in cancer progression, this study aimed to develop a prognostic signature based on circadian rhythm-related genes (CRRGs) to predict BRCA patient survival. Gene expression profiles and clinical data were sourced from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and the Molecular Signatures Database (MSigDB). A multigene signature was constructed using LASSO-penalized Cox regression. Patients were stratified into high- and low-risk groups based on median risk scores. Pathway activity was assessed via gene set variation analysis (GSVA). Prognostic performance was evaluated using ROC curves, Kaplan-Meier (K-M) analysis, and multivariate Cox regression. A 20-CRRG prognostic signature was identified, effectively stratifying patients into distinct risk groups (K-M *P* < .05). ROC analysis demonstrated high predictive accuracy (AUC > 0.7). Functional enrichment linked these CRRGs to circadian regulation, nuclear components, and DNA binding. Further refinement revealed a 9-gene subset (ADRB1, BHLHE41, BTG1, EGR3, NONO, NR1H3, NTRK3, OPN4, PIGF) with superior 5-year survival prediction (AUC 0.82) compared to 1- and 3-year outcomes. The CRRG-based signature, particularly the 9-gene subset, robustly predicts BRCA patient survival, offering potential clinical utility for long-term prognosis. These findings underscore the role of circadian rhythms in BRCA progression and highlight novel biomarkers for risk stratification.