Early-life tobacco exposure, genetic susceptibility and incident colorectal cancer risk in UK biobank: A prospective cohort analysis.
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BACKGROUND: Although tobacco exposure is an established risk factor for colorectal cancer (CRC), the specific impact of early-life exposure (from prenatal to adolescence) and its joints with genetic susceptibility remains uncertain. This population-based study aimed to investigate the joint effects of early-life tobacco exposure and polygenic risk on CRC. METHODS: Data from UK Biobank participants were analyzed to assess tobacco exposure during two periods: prenatal exposure (n = 429,847) and age of smoking initiation (n = 430,672). Using Cox proportional hazards models, the associations between early-life tobacco exposure and CRC incidence were explored. Additionally, we evaluated the mediating role of accelerated biological aging in the link between early-life tobacco exposure and CRC, and further integrated the polygenic risk score (PRS) to assess the joint effects of genetic on CRC risk. RESULTS: Early-life tobacco exposure exhibited age-at-initiation-dependent CRC risk associations. Smoking initiation in adolescence [hazard ratios (HR) = 1.13, 95 % confidence intervals (CI): 1.06-1.22], and adulthood (HR = 1.19, 95 % CI: 1.10-1.30) all significantly increased risk (P < 0.001), while in utero exposure and smoking initiation childhood (HR:1.06, 95 % CI: 0.94-1.19, P = 0.372) showed a suggestive but non-significant trend (HR:1.05, 95 % CI: 1.00-1.11, P = 0.066). In the joint analysis, high-PRS individuals with prenatal tobacco exposure had an elevated CRC risk compared to those with low PRS and no exposure (HR 1.28, 95 % CI: 1.16-1.42, P < 0.001). Furthermore, among high-PRS individuals, smoking initiation at any age (childhood, adolescence, or adulthood) increased CRC risk relative to never-smokers with low PRS. Mediation analysis indicated that accelerated biological aging may contribute to the association between smoking initiation at different ages and increased CRC risk. CONCLUSION: Early-life tobacco exposure elevated CRC risk, especially in genetically susceptible individuals. These findings underscored the importance of early tobacco prevention and enhanced screening for high genetic-risk populations.