Widespread dysregulation of the circadian clock in human cancer

Jarrod Shilts, Guanhua Chen, Jacob J. Hughey

bioRxiv

Abstract

The mammalian circadian clock is a critical regulator of metabolism and cell division. Although systemic disruption of the circadian clock can promote cancer, whether the clock is disrupted within human tumors is unknown. Here we investigated clock dysregulation in a range of solid human cancers. Our approach, which is based on the co-expression of 12 clock genes, can be applied to samples that are not labeled with time of day and were not acquired over the entire circadian (24-h) cycle. Using publicly available data, we defined a signature of clock gene co-expression from healthy mouse organs and validated the signature in healthy human tissues. We then created a metric, the delta clock correlation distance (ΔCCD), to quantify the extent to which the signature is perturbed in different conditions. By using the ΔCCD to compare human tumor and non-tumor samples from twenty datasets, we discovered widespread dysregulation of clock gene co-expression in tumors. Subsequent analysis of data from clock gene knockouts in mice suggested that clock dysregulation in human cancer is not caused solely by loss of activity of clock genes. Furthermore, by analyzing a large set of genes previously inferred to be rhythmic in healthy human lung, we observed systematic changes in patterns of circadian gene expression in lung tumors. Our findings suggest that clock dysregulation is a common means by which human cancers achieve unrestrained growth and division. Our approach opens the door to using publicly available transcriptome data to quantify clock disruption in a multitude of human phenotypes.