Circadian Clock Genes Act as Diagnostic and Prognostic Biomarkers of Glioma: Clinic Implications for Chronotherapy

Abstract

Gliomas are the most common primary intracranial tumors and closely related to circadian clock. Due to the high mortality and morbidity of gliomas, exploring novel diagnostic and early prognostic markers is necessary. Circadian clock genes (CCGs) play important roles in regulating the daily oscillation of biological processes and the development of tumor. Therefore, we explored the influences that the oscillations of circadian clock genes (CCGs) on diagnosis and prognosis of gliomas using bioinformatics. In this work, we systematically analyzed the rhythmic expression of CCGs in brain and found that some CCGs had strong rhythmic expression; the expression levels were significantly different between day and night. Four CCGs (ARNTL, NPAS2, CRY2, and DBP) with rhythmic expression were not only identified as differentially expressed genes but also had significant independent prognostic ability in the overall survival of glioma patients and were highly correlated with glioma prognosis in COX analysis. Besides, we found that CCG-based predictive model demonstrated higher predictive accuracy than that of the traditional grade-based model; this new prediction model can greatly improve the accuracy of glioma prognosis. Importantly, based on the four CCGs’ circadian oscillations, we revealed that patients sampled at night had higher predictive ability. This may help detect glioma as early as possible, leading to early cancer intervention. In addition, we explored the mechanism of CCGs affecting the prognosis of glioma. CCGs regulated the cell cycle, DNA damage, Wnt, mTOR, and MAPK signaling pathways. In addition, it also affects prognosis through gene coexpression and immune infiltration. Importantly, ARNTL can rhythmically modulated the cellular sensitivity to clinic drugs, temozolomide. The optimal point of temozolomide administration should be when ARNTL expression is highest, that is, the effect is better at night. In summary, our study provided a basis for optimizing clinical dosing regimens and chronotherapy for glioma. The four key CCGs can serve as potential diagnostic and prognostic biomarkers for glioma patients, and ARNTL also has obvious advantages in the direction of glioma chronotherapy.

Molecular mechanisms of tumour development in glioblastoma: an emerging role for the circadian clock

“…622 glioma samples and 628 healthy controls: CLOCK SNP rs7698022 correlated with a poor prognosis in HGG 98 622 glioma samples and 628 healthy controls: higher expression of CLOCK in glioma 98 TCGA-LGG/HGG: high expression of CLOCK was associated with lower grade and longer OS 42 . TCGA-LGG/HGG: CLOCK expression significantly lower in HGG compared to LGG 22 TCGA glioma: high expression of CLOCK was associated with a longer OS 71 . PER1 U87-MG cells: Overexpression of IDHmut (R132H) decreased the expression of PER1 compared to overexpression of IDH WT 97 .…”

Circadian rhythm-related genes index: A predictor for HNSCC prognosis, immunotherapy efficacy, and chemosensitivity

“…Crosstalk between cancer cells and TME is closely related to tumor proliferation, invasion, and metastasis [27]. And while Tumor-infiltrating immune cells (TIICs) are one of the important components of TME, their composition, and distribution are inextricably linked to the process of tumor development.…”

“…There are also suggestions that dysregulation of circadian genes can contribute to inflammation and tumor progression through activation of p38, c-Myc, NF-kB, Bcl-XL, and protein kinase A (PKA) pathways (17,(22)(23)(24)(25). Considering the significant role of CRRGs in tumors, several biological clock genes have been considered as prognostic biomarkers for various cancers (26)(27)(28). Currently, the prognostic value of CRRGs in HNSCC and the role of the tumor immune microenvironment are unclear.…”

Exploring Chromatin Regulatory Factor Genes as Novel Biomarkers and Immunotherapy Targets through Multi-Omics Analysis in Kidney Renal Clear Cell Carcinoma to Uncover Tumor Heterogeneity

“…The tumor microenvironment (TME) intricately interacts with tumor cells, exerting an indirect impact on tumor proliferation, invasion, and metastasis [24]. In the tumor microenvironment (TME), the composition and distribution of tumor-in ltrating immune cells (TIICs) represent a pivotal element that bears substantial relevance to the processes of tumor development [25].…”