Abstract
INTRODUCTION: Cancer and depression frequently co-occur, leading to a poor prognosis. Circadian rhythm disruption is a contributing factor, yet its precise role in the development of this comorbidity remains to be illustrated.
OBJECTIVES: This study aimed to investigate the associations of evening chronotype with cancer-depression comorbidity, and further to explore the potential shared biological pathways.
METHODS: Using prospective UK Biobank data (N = 299,155), we examined the relationship between evening chronotype and the risk of cancer-depression comorbidity across different transition pathways (baseline to comorbidity, cancer to comorbidity, depression to comorbidity). Mendelian randomization (MR) and polygenic risk scores (PRS) were applied for causal inference and genetic stratification. Summary-data-based MR (SMR), colocalization, and immune cell infiltration analysis were integrated to investigate shared circadian clock-related genes (CRGs) and pathways.
RESULTS: Evening chronotype significantly increased the risk of developing comorbidity from a healthy baseline for overall cancer, colorectal cancer, and breast cancer (fully adjusted HRs = 1.30, 1.55, and 1.43, respectively), as well as the risk of developing depression after a cancer diagnosis (HRs = 1.29, 1.50, and 1.34, respectively). Subgroup analyses identified females, smokers, and those with lower income as priority groups for circadian intervention. Genetic analyses found individuals with both an evening chronotype and a low morning chronotype PRS as the highest risk subgroup. Five key CRGs (GAL, ALAS1, SUCNR1, PTK2, DDIT3) showed consistent risk effects on both cancer and depression, implicating shared neuroendocrine and metabolic pathways. GAL and SUCNR1/PTK2 were significantly associated with mast cell and CD8 + T cell infiltration, indicating a pathway from circadian disruption to comorbidity through neuro-endocrine-immune dysregulation.
CONCLUSION: Evening chronotype is an independent and potential risk factor for cancer-depression comorbidity, particularly for breast and colorectal cancers. Assessment of chronotype in cancer patients and targeted circadian interventions may offer novel strategies for preventing comorbid depression.