Night shift work and lung cancer risk: a prospective cohort study with mediator analysis from the UK Biobank

STUDY OBJECTIVES: This study investigated the association between night shift work and lung cancer risk using data from the UK Biobank cohort of 278 650 participants, while exploring potential biological mediators and gene-environment interactions. METHODS: Cox proportional hazards models assessed relationships between current night shift status, lifetime duration, and frequency of night shifts with lung cancer incidence. Mediation analyses examined physical measurements, lifestyle habits, blood immune cell parameters, and plasma proteins as potential mediating pathways. Polygenic risk scores evaluated genetic predisposition interactions. RESULTS: During a median follow-up of 10.64 years, 1524 incident lung cancer cases were identified. A significant dose-response relationship was observed between increasing categories of current night shift work and lung cancer risk (Shift but never/rarely night shifts HR 1.18, 95% CI = 1.00 to 1.39, p = .047; Some night shifts HR 1.28, 95% CI = 1.06 to 1.55, p = .010; Some night shifts HR 1.19, 95% CI = 0.90 to 1.57, p = .220; p for trend = .004). Smoking plays a significant mediating role in this association. Mediation analysis also identified prostasin (PRSS8), alkaline phosphatase (ALPP), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as key mediators, collectively explaining over 25 per cent of the total effect. CONCLUSIONS: This study suggests that night shift work, particularly when combined with smoking, is associated with an increased risk of lung cancer. The identification of potential mediators such as prostasin, ALPP and CEACAM5 provides insights into the underlying biological mechanisms. Future research should validate these findings and explore targeted prevention strategies for high-risk populations.