PT  - JOURNAL ARTICLE
AU  - Jarrod Shilts
AU  - Guanhua Chen
AU  - Jacob J. Hughey
TI  - Widespread dysregulation of the circadian clock in human cancer
AID  - 10.1101/130765
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 130765
4099  - http://biorxiv.org/content/early/2017/06/09/130765.short
4100  - http://biorxiv.org/content/early/2017/06/09/130765.full
AB  - The mammalian circadian clock is a critical regulator of metabolism and cell division. Although multiple lines of evidence indicate that systemic disruption of the circadian clock can promote cancer, whether the clock is disrupted in primary human tumors is unknown. Here we used transcriptome data from mice to define a signature of the mammalian circadian clock based on the co-expression of 12 genes that form the core clock or are directly controlled by the clock. Our approach can be applied to samples that are not labeled with time of day and were not acquired over the entire circadian (24-h) cycle. We validated the clock signature in circadian transcriptome data from humans, then developed a metric we call the delta clock correlation distance (ΔCCD) to describe the extent to which the signature is perturbed in samples from one condition relative to another. We calculated the ΔCCD comparing human tumor and non-tumor samples from The Cancer Genome Atlas and eight independent datasets, discovering widespread dysregulation of clock gene co-expression in tumor samples. Subsequent analysis of gene expression in clock gene knockouts in mice suggested that clock dysregulation in human cancer is not caused solely by loss of activity of clock genes. Our findings suggest that dysregulation of the circadian clock is a common mechanism by which human cancers achieve unrestrained growth and division. In addition, our approach opens the door to using publicly available transcriptome data to quantify clock disruption in a multitude of human phenotypes. Our method is available as a web application at https://jakejh.shinyapps.io/deltaccd.