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".

Elucidation of clinical implications Arising from circadian rhythm and insights into the tumor immune landscape in breast cancer

“…BC is a highly heterogeneous disease, with multiple genetic, environmental, and lifestyle factors involved in its pathogenesis, the precise mechanisms of which have not been completely defined [ 60 ]. Increasing evidence suggests that circadian rhythms regulate physiological processes like cell cycle, metabolism, and immune function, thereby influencing BC risk, progression, and prognosis [ [61] , [62] , [63] , [64] ]. Therefore, we investigated the risk, prognosis, and immunological microenvironment of BC from the perspective of CRGs.…”

Circadian rhythm-associated lncRNA RP11-414H17.5 as a key therapeutic target in osteosarcoma affects the tumor immune microenvironment and enhances malignancy

“…Many scholars have previously explored the effects of circadian rhythm-associated genes on different tumors. Brooks et al [ 54 ] found that circadian rhythm-related lncRNA ADIRF-AS1 drove clear cell renal carcinoma progression through targeting PBAF; Zhang et al [ 55 ] constructed a model of circadian rhythm-associated lncRNAs that stably predicted the prognosis of hepatocellular carcinoma with a significant impact to the immune infiltration status of the tumor; Liu et al [ 56 ] constructed a circadian rhythm-associated gene risk model to predict survivals in patients with melanoma, non-small-cell lung cancer, and glioma, and could differentiate the immune cell infiltration status in these patients. This research is the first to construct a circadian rhythm-associated lncRNAs prognostic prediction model for the precise prediction of prognosis in osteosarcoma patients.…”