CRS：一种用于预测癌症患者预后和治疗反应的生物钟节律评分模型。
CRS: a circadian rhythm score model for predicting prognosis and treatment response in cancer patients.
机构信息
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.
Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, China.
出版信息
J Transl Med. 2023 Mar 9;21(1):185. doi: 10.1186/s12967-023-04013-w.
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".
背景
昼夜节律调节着生物体复杂的生理活动。昼夜节律功能障碍与癌症之间存在很强的关联。然而，昼夜节律基因失调的因素及其在癌症中的功能意义尚未得到关注。
方法
在癌症基因组图谱（TCGA）的 18 种癌症类型中，检测了 48 个昼夜节律基因（CRG）的差异表达和遗传变异。使用 ssGSEA 方法创建昼夜节律评分（CRS）模型，并根据 CRS 将患者分为高组和低组。创建 Kaplan-Meier 曲线评估患者的生存率。使用 Cibersort 和 estimate 方法在不同 CRS 亚组之间识别免疫细胞的浸润特征。使用基因表达综合数据库（GEO）数据集作为验证队列和模型稳定性评估队列。评估 CRS 模型预测化疗和免疫治疗的能力。Wilcoxon 秩和检验用于比较不同患者的 CRS 差异。我们使用 CRS 通过连接图方法识别潜在的“时钟药物”。
结果
对 48 个 CRG 的转录组和基因组分析表明，大多数核心时钟基因上调，而时钟控制基因下调。此外，我们表明拷贝数变异可能会影响 CRG 异常。基于 CRS，患者可以分为两组，两组之间的生存率和免疫细胞浸润存在显著差异。进一步的研究表明，低 CRS 患者对化疗和免疫治疗更敏感。此外，我们还确定了 10 种与 CRS 呈正相关且具有调节昼夜节律潜力的化合物（如氟苯达唑、MLN-4924、ingenol）。
结论
CRS 可用作临床指标，预测患者预后和对治疗的反应，并识别潜在的“时钟药物”。
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