Background: The circadian clock governs a large variety of fundamentally important physiological processes in all
three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction
underpinning many disease pathologies including human neoplasms. Yet, detailed pan-cancer evidence supporting
this notion has been limited.
Methods: In an integrated approach uniting genomic, transcriptomic and clinical data of 21 cancer types
(n=18,484), we interrogated copy number and transcript profles of 32 circadian clock genes to identify putative lossof-function (ClockLoss) and gain-of-function (ClockGain) players. Kaplan–Meier, Cox regression and receiver operating
characteristic analyses were employed to evaluate the prognostic signifcance of both gene sets.
Results: ClockLoss and ClockGain were associated with tumour-suppressing and tumour-promoting roles respectively. Downregulation of ClockLoss genes resulted in signifcantly higher mortality rates in fve cancer cohorts
(n=2914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach
(P=0.0007). In contrast, patients with high expression of oncogenic ClockGain genes had poorer survival outcomes
(n=2784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas
(P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of
tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous
oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may infuence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated
by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive ClockLoss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing
a novel framework for investigating the hypoxia-clock signalling axis.
Conclusions: Loss of timekeeping fdelity promotes tumour progression and infuences clinical outcomes. ClockLoss
and ClockGain may ofer novel druggable targets for improving patient prognosis. Both gene sets can be used for
patient stratifcation in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and
hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination
with frst-line treatments
