CRS: a circadian rhythm score model for predicting prognosis and treatment response in cancer patients

Abstract

Background: Circadian rhythm regulates complex physiological activities in organisms. A strong link between circadian dysfunction and cancer has been identified. However, the factors of dysregulation and functional significance of circadian rhythm genes in cancer have received little attention.

Methods: In 18 cancer types from The Cancer Genome Atlas (TCGA), the differential expression and genetic variation of 48 circadian rhythm genes (CRGs) were examined. The circadian rhythm score (CRS) model was created using the ssGSEA method, and patients were divided into high and low groups based on the CRS. The Kaplan-Meier curve was created to assess the patient survival rate. Cibersort and estimate methods were used to identify the infiltration characteristics of immune cells between different CRS subgroups. Gene Expression Omnibus (GEO) dataset is used as verification queue and model stability evaluation queue. The CRS model's ability to predict chemotherapy and immunotherapy was assessed. Wilcoxon rank-sum test was used to compare the differences of CRS among different patients. We use CRS to identify potential "clock-drugs" by the connective map method.

Results: Transcriptomic and genomic analyses of 48 CRGs revealed that most core clock genes are up-regulated, while clock control genes are down-regulated. Furthermore, we show that copy number variation may affect CRGs aberrations. Based on CRS, patients can be classified into two groups with significant differences in survival and immune cell infiltration. Further studies showed that patients with low CRS were more sensitive to chemotherapy and immunotherapy. Additionally, we identified 10 compounds (e.g. flubendazole, MLN-4924, ingenol) that are positively associated with CRS, and have the potential to modulate circadian rhythms.

Conclusions: CRS can be utilized as a clinical indicator to predict patient prognosis and responsiveness to therapy, and identify potential "clock-drugs".

Keywords: Chemotherapy; Circadian rhythm gene; Clock-drugs; Immune cell infiltration; Immunotherapy; Prognosis.