Association of Circadian Clock Gene Expression with Glioma Tumor Microenvironment and Patient Survival

Abstract

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 (IDH), 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 IDH 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 (PER) 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.

Molecular markers related to patient outcome in patients with IDH-mutant astrocytomas grade 2 to 4: A systematic review

“…Upregulation of other genes, such as FREM2 [46], TXNDC12 [38], and the eIF3-complex [11] were only associated with poor prognosis in one cohort per gene, but were not significant in other cohorts. High expression of ADAR3 [44], PER1 [16] and WDFY3-AS2 [42] were associated with improved overall survival in grade 2 and 3 IDHmutant astrocytomas, and for PER1 and WDFY3-AS2 also in grade 4 IDH-mutant astrocytomas. The expression of TGM2 [3] and MPC1 [20] were not associated with overall survival.…”

Circadian Period 2 (Per2) downregulate inhibitor of differentiation 3 (Id3) expression via PTEN/AKT/Smad5 axis to inhibits glioma cell proliferation

“…A recent study reported a close association between higher PER expression and better overall survival for IDH-mutated or wild-type samples in TCGA, and PER expression was shown to be an independent prognostic factor in glioma according to a Cox proportional hazards analysis with the glioma microenvironment influencing PER expression. But the level of PER expression obtained from the average of PER1/2/3 expression reflected overall PER expression in the research rather than the level of subgenes [ 25 ]. Previous research indicated that Per2 is highly expressed in low-grade glioma and exhibits low expression in high-grade glioma in clinical samples [ 26 ].…”

Overview on Common Genes Involved in the Onset of Glioma and on the Role of Migraine as Risk Factor: Predictive Biomarkers or Therapeutic Targets?

“…A new study described an inverse correlation between the tumor suppressor activity of CLOCK and hypoxia [49], supporting the thesis that the suppression of CLOCK in tumor cells enhanced survival and reduced migration of the microglia [50]. Future works should increase the acknowledgement of clock genes in glioma research [51].…”