De La Cruz Minyety Julianie, Shuboni-Mulligan Dorela D, Briceno Nicole, Young Demarrius, Gilbert Mark R, Celiku Orieta, Armstrong Terri S
Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Cancers (Basel). 2021 Jun 2;13(11):2756. doi: 10.3390/cancers13112756.
Circadian clock genes have been linked to clinical outcomes in cancer, including gliomas. However, these studies have not accounted for established markers that predict the prognosis, including mutations in Isocitrate Dehydrogenase (), which characterize the majority of lower-grade gliomas and secondary high-grade gliomas. To demonstrate the connection between circadian clock genes and glioma outcomes while accounting for the mutational status, we analyzed multiple publicly available gene expression datasets. The unsupervised clustering of 13 clock gene transcriptomic signatures from The Cancer Genome Atlas showed distinct molecular subtypes representing different disease states and showed the differential prognosis of these groups by a Kaplan-Meier analysis. Further analyses of these groups showed that a low period () gene expression was associated with the negative prognosis and enrichment of the immune signaling pathways. These findings prompted the exploration of the relationship between the microenvironment and clock genes in additional datasets. Circadian clock gene expression was found to be differentially expressed across the anatomical tumor location and cell type. Thus, the circadian clock expression is a potential predictive biomarker in glioma, and further mechanistic studies to elucidate the connections between the circadian clock and microenvironment are warranted.
昼夜节律时钟基因已与包括胶质瘤在内的癌症临床结局相关联。然而，这些研究并未考虑那些预测预后的既定标志物，包括异柠檬酸脱氢酶（IDH）的突变，该突变是大多数低级别胶质瘤和继发性高级别胶质瘤的特征。为了在考虑IDH突变状态的同时证明昼夜节律时钟基因与胶质瘤结局之间的联系，我们分析了多个公开可用的基因表达数据集。来自癌症基因组图谱的13个时钟基因转录组特征的无监督聚类显示出代表不同疾病状态的不同分子亚型，并通过Kaplan-Meier分析显示了这些组的不同预后。对这些组的进一步分析表明，低周期（Per）基因表达与不良预后和免疫信号通路的富集相关。这些发现促使我们在其他数据集中探索微环境与时钟基因之间的关系。发现昼夜节律时钟基因表达在解剖学肿瘤位置和细胞类型之间存在差异表达。因此，昼夜节律时钟表达是胶质瘤中一种潜在的预测生物标志物，有必要进行进一步的机制研究以阐明昼夜节律时钟与微环境之间的联系。
