Development and Validation of a Novel Circadian Rhythm-Related Signature to Predict the Prognosis of the Patients with Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most important causes of cancer-related deaths and remains a major public health challenge worldwide. Considering the extensive heterogeneity of HCC, more accurate prognostic models are imperative. The circadian genes regulate the daily oscillations of key biological processes, such as nutrient metabolism in the liver. Circadian rhythm disruption has recently been recognized as an independent risk factor for cancer. In this study, The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were compared and 248 differentially expressed genes (DEGs) of the circadian rhythm were identified. HCC was classified into two subtypes based on these DEGs. The prognostic value of each circadian rhythm-associated gene (CRG) for survival was assessed by constructing a multigene signature from TCGA cohort. A 6-gene signature was created by applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, and all patients in TCGA cohort were divided into high- and low-risk groups according to their risk scores. The survival rate of patients with HCC in the low-risk group was significantly higher than that in the high-risk group ( $p<0.001$ ). The patients with HCC in the Gene Expression Omnibus (GEO) cohort were also divided into two risk subgroups using the risk score of TCGA cohort, and the overall survival time (OS) was prolonged in the low-risk group ( $p=0.012$ ). Based on the clinical characteristics, the risk score was an independent predictor of OS in the patients with HCC. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that multiple metabolic pathways, cell cycle, etc., were enhanced in the high-risk group. Using the metabolic pathway single-sample gene set enrichment analysis (ssGSEA), it was found that the metabolic pathways in the high- and low-risk groups between TCGA and GEO cohorts were altered essentially in the same way. In conclusion, the circadian genes play an important role in HCC metabolic rearrangements and can be further used to predict the prognosis the patients with HCC.