Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers

Circadian clock genes were dysregulated in cancer especially at expression level; expressions of core clock genes were downregulated by higher DNA methylation in tumor; The expression signature of core clock genes was correlated with virus infection; The expression signature of core clock genes was correlated with immunephenotypes; Core clock genes and expression signature were related with cancer survival.

Abstract

It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects. In this study, we systematically analyzed the aberrances of circadian clock genes across cancers based on data from The Cancer Genome Atlas (TCGA). These data showed that the frequencies of mutations and copy number alterations in core clock genes (PER1/2/3, CLOCK, CRY1/2, and ARNTL) were low, but that the expression levels of core clock genes were downregulated by the higher levels of DNA methylation in most tumors. The circadian clock index (CCI) was established through a principal component analysis, and this measure well represents the overall expression of the core clock genes. In fact, the CCI was significantly lower in hepatocellular carcinoma with HBV infection than in other cancers. Furthermore, pathways such as the MAPK, JAK‐STAT, and immune‐related signaling pathways were enriched in tumors with high CCI values. Interestingly, the CCI was generally positively related to the immunophenoscores and immunophenotypes of tumors. Additionally, the expression levels of core clock genes and the CCI were also generally positively related to survival across cancers. Taken together, the results of this study provide a comprehensive analysis of circadian clock aberrances in cancer, and the results should aid further investigations of the molecular mechanisms of cancer and the development of therapeutic strategies.

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