<i>In Utero</i> and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk, and Lung Cancer Incidence and Mortality in Adulthood

Abstract

<b>Rationale:</b> The individual effects of early-life tobacco smoke exposure and its interactions with genetic factors on lung cancer in adulthood remain unclear. <b>Objectives:</b> To investigate the associations of early-life tobacco exposures as well as their interactions with polygenic risk scores (PRSs) with lung cancer incidence and mortality. <b>Methods:</b> A total of 432,831 participants from the UK Biobank study were included. We estimated the associations of <i>in utero</i> exposure to tobacco smoke, the age of smoking initiation and their interactions with PRSs with lung cancer incidence and mortality in adulthood using Cox proportional hazard models. <b>Measurements and Main Results:</b> Lung cancer incidence (hazard ratio [HR]: 1.59, 95% confidence interval [CI], 1.44-1.76) increased among participants with <i>in utero</i> tobacco exposure. Multivariable-adjusted HRs (with 95% CIs) of lung cancer incidence for smoking initiation in adulthood, adolescence, and childhood (versus never-smokers) were 6.10 (5.25-7.09), 9.56 (8.31-11.00), and 15.15 (12.90-17.79) (<i>P</i>_trend < 0.001). Similar findings were observed in lung cancer mortality. Participants with high PRSs and <i>in utero</i> tobacco exposure (versus low PRSs participants without <i>in utero</i> exposure) had an HR of 2.35 for lung cancer incidence (95% CI, 1.97-2.80, <i>P</i>_interaction = 0.089) and 2.43 for mortality (95% CI, 2.05-2.88, <i>P</i>_interaction = 0.032). High PRSs with smoking initiation in childhood (versus never-smokers with low PRSs) had HRs of 18.71 for incidence (95% CI, 14.21-24.63, <i>P</i>_interaction = 0.004) and 19.74 for mortality (95% CI, 14.98-26.01, <i>P</i>_interaction = 0.033). <b>Conclusions:</b> <i>In utero</i> and childhood/adolescence exposure to tobacco smoke and its interaction with genetic factors may substantially increase the risks of lung cancer incidence and mortality in adulthood.