In Utero and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk, and Cancer Incidence in Adulthood: A Prospective Cohort Study

To evaluate the association of early-life tobacco smoke exposure, especially interacting with cancer genetic variants, with adult cancer. We examined the associations of in utero tobacco smoke exposure, age of smoking initiation, and their interaction with genetic risk levels with cancer incidence in 393,081 participants from the UK Biobank. Information on tobacco exposure was obtained by self-reported questionnaires. A cancer polygenic risk score was constructed by weighting and integrating 702 genome-wide association studies–identified risk variants. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for overall cancer and organ-specific cancer incidence. During 11.8 years of follow-up, 23,450 (5.97%) and 23,413 (6.03%) incident cancers were included in the analyses of in utero exposure and age of smoking initiation, respectively. The HR (95% CI) for incident cancer in participants with in utero exposure to tobacco smoke was 1.04 (1.01-1.07) for overall cancer, 1.59 (1.44-1.75) for respiratory cancer, and 1.09 (1.03-1.17) for gastrointestinal cancer. The relative risk of incident cancer increased with earlier smoking initiation (Ptrend<.001), with the HR (95% CI) of 1.44 (1.36-1.51) for overall cancer, 13.28 (11.39-15.48) for respiratory cancer, and 1.72 (1.54-1.91) for gastrointestinal cancer in smokers with initiation in childhood compared with never smokers. Importantly, a positive additive interaction between age of smoking initiation and genetic risk was observed for overall cancer (Padditive=.04) and respiratory cancer (Padditive=.003) incidence. In utero exposure and earlier smoking initiation are associated with overall and organ-specific cancer, and age of smoking initiation interaction with genetic risk is associated with respiratory cancer.