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 (). 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 (). 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.

中文翻译：

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开发和验证一种新的昼夜节律相关特征以预测肝细胞癌患者的预后

肝细胞癌 (HCC) 是癌症相关死亡的最重要原因之一，并且仍然是全球主要的公共卫生挑战。考虑到 HCC 的广泛异质性，更准确的预后模型势在必行。昼夜节律基因调节关键生物过程的日常波动，例如肝脏中的营养代谢。昼夜节律紊乱最近被认为是癌症的独立危险因素。在这项研究中，比较了癌症基因组图谱 (TCGA) 和基因型组织表达 (GTEx)，并确定了 248 个昼夜节律的差异表达基因 (DEG)。基于这些 DEG 将 HCC 分为两个亚型。通过构建来自 TCGA 队列的多基因特征来评估每个昼夜节律相关基因 (CRG) 对生存的预后价值。通过应用最小绝对收缩和选择算子 (LASSO) Cox 回归方法创建 6 基因特征，并根据风险评分将 TCGA 队列中的所有患者分为高风险组和低风险组。低危组HCC患者的生存率明显高于高危组（）。基因表达综合（GEO）队列中的HCC患者也使用TCGA队列的风险评分分为两个风险亚组，低风险组的总生存时间（OS）延长。）。根据临床特征，风险评分是 HCC 患者 OS 的独立预测因子。基因本体论 (GO) 和京都基因与基因组百科全书 (KEGG) 分析表明，高危组的多种代谢途径、细胞周期等均得到增强。使用代谢途径单样本基因集富集分析 (ssGSEA)，发现 TCGA 和 GEO 队列之间的高风险和低风险组的代谢途径基本上以相同的方式改变。总之，昼夜节律基因在HCC代谢重排中起重要作用，可进一步用于预测HCC患者的预后。