Association of Circadian Syndrome with Incident Risk of 23 Site-Specific Cancers: A Large-Scale Prospective Study in the UK Biobank.

Circadian disruption and metabolic dysfunction are linked to chronic disease, but whether circadian syndrome, which combines metabolic, sleep, and mood traits, relates to overall and site-specific cancer risk remains unclear. We prospectively studied 367,832 cancer-free participants in the UK Biobank, of whom 82,547 (22.4%) had circadian syndrome, defined by at least 4 of 7 features: abdominal obesity, high triglycerides, low levels of high-density lipoprotein cholesterol, high blood pressure, impaired glucose regulation, short sleep, and depression. Associations with overall cancer and 23 site-specific cancers were evaluated using Cox proportional-hazards and competing-risk models, with additional dose-response, biomarker, and population-burden analyses. During follow-up, 47,695 participants developed cancer. Circadian syndrome was associated with a higher incidence of overall cancer (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.10 to 1.14). The strongest positive associations were observed for endometrial cancer (HR, 1.88; 95% CI, 1.71 to 2.08), liver cancer (HR, 1.67; 95% CI, 1.47 to 1.89), and kidney cancer (HR, 1.55; 95% CI, 1.41 to 1.70). Findings remained similar after accounting for death from other causes and across sensitivity analyses, whereas inverse associations for prostate and brain cancers were exploratory. Sex-hormone-binding globulin statistically accounted for 51.0% of the endometrial cancer association, and C-reactive protein accounted for 26.4% of the overall cancer association. The highest population-attributable fractions were estimated for endometrial (13.5%) and liver cancers (13.4%). Circadian syndrome may help identify populations at increased cancer risk and inform prevention strategies integrating circadian and metabolic health.