Impact of maternal and offspring smoking and breastfeeding on oesophageal cancer in adult offspring

Abstract

Numerous risk factors for oesophageal cancer are linked to lifestyle habits, but the role of early-life factors in its incidence and mortality is unclear. Using UK Biobank data, we explore the association among breastfeeding, maternal smoking, smoking in offspring, and oesophageal cancer risk in adult offspring via multivariable Cox regression. Here, we show that being breastfed, compared with not being breastfed, is associated with a lower risk of oesophageal cancer incidence (HR: 0.83, 95% CI: 0.70-0.98) and mortality (HR: 0.74, 95% CI: 0.61-0.89) in adult offspring. Additionally, it is associated with a reduced impact of smoking in offspring on oesophageal cancer incidence (HR: 0.79, 95% CI: 0.64-0.96) and mortality (HR: 0.73, 95% CI: 0.59-0.91). We subsequently construct a polygenic risk score for oesophageal cancer to explore the influence of genetic factors. Our findings emphasize the importance of breastfeeding, and smoking cessation to prevent oesophageal cancer.

Fig. 1. Detailed process diagram.

502,406 UK Biobank participants were first included. 148 with oesophageal cancer were excluded, leaving 502,258. More exclusions for missing data created subsets: maternal smoking (n = 432,622), offspring smoking (n = 499,313), breastfeeding (n = 383,533), genotyping (n = 487,019). The flowchart details exclusions and retained participants. Source data are provided as a Source Data file.

Fig. 2. Association of maternal smoking, smoking status of offspring and breastfeeding with oesophageal cancer incidence and mortality.

HR Hazard Ratio, 95%CI 95% confidence intervals, Ref reference. Adjusted for age; sex (Female/Male); race (White, Mixed, Asian or Asian British, Black or Black British, Chinese, Other ethnic group); Townsend Deprivation index; smoke (Yes/No/Missing); drink (Never/Previous/Current/Missing); body mass index (<25 kg/m², 25 to 29.9 kg/m², ≥30 kg/m²); physical activity; family of cancer history (Yes/No); income (<£18,000, £18,000 to £30,999, £31,000 to £51,999, £52,000 to £100,000, >£100,000, or missing); insomnia (Never/ Sometimes/ Usually/ Missing). Data are presented as hazard ratios with 95% confidence intervals; Each point shows the point estimate of HR from Cox regression. Bars show 95%CI; HR and 95%CI were estimated by Cox regression (two-sided Wald test). Source data are provided as a Source Data file.

Fig. 3. Association of maternal smoking and smoking status of offspring with oesophageal cancer incidence and mortality.

HR Hazard Ratio, 95%CI 95% confidence intervals, Ref reference, FDR false discovery rate. Adjusted for age; sex (Female/Male); race (White, Mixed, Asian or Asian British, Black or Black British, Chinese, Other ethnic group); Townsend Deprivation index; drink (Never/Previous/Current/Missing); body mass index (<25 kg/m², 25 to 29.9 kg/m², ≥30 kg/m²); physical activity; family of cancer history (Yes/No); income (less than £18,000, £18,000 to £30,999, £31,000 to £51,999, £52,000 to £100,000, >£100,000, or missing); insomnia (Never/Sometimes/Usually/ Missing). Data are presented as hazard ratios with 95% confidence intervals; Each point shows the point estimate of HR from Cox regression. Bars show 95%CI; HR and 95%CI were estimated by Cox regression (two-sided Wald test). Source data are provided as a Source Data file.

Fig. 4. Association of maternal smoking and breastfeeding with oesophageal cancer incidence and mortality.

HR Hazard Ratio, 95%CI 95% confidence intervals, Ref reference, FDR false discovery rate. Adjusted for age; sex (Female/Male); race (White, Mixed, Asian or Asian British, Black or Black British, Chinese, Other ethnic group); Townsend Deprivation index; smoke (Yes/No/Missing); drink (Never/Previous/Current/Missing); body mass index (<25 kg/m², 25 to 29.9 kg/m², ≥30 kg/m²); physical activity; family of cancer history (Yes/No); income (less than £18,000, £18,000 to £30,999, £31,000 to £51,999, £52,000 to £100,000, greater than £100,000, or missing); insomnia (Never/Sometimes/Usually/Missing). Data are presented as hazard ratios with 95% confidence intervals; Each point shows the point estimate of HR from Cox regression. Bars show 95%CI; HR and 95%CI were estimated by Cox regression (two-sided Wald test). Source data are provided as a Source Data file.

Fig. 5. Association of smoking status of offspring and breastfeeding with oesophageal cancer incidence and mortality.

HR Hazard Ratio, 95%CI 95% confidence intervals, Ref reference, FDR false discovery rate. Adjusted for age; sex (female/male); race (White, Mixed, Asian or Asian British, Black or Black British, Chinese, Other ethnic group); Townsend Deprivation index; smoke (Yes/No/Missing); drink (Never/Previous/Current/Missing); body mass index (<25 kg/m², 25–29.9 kg/m², ≥30 kg/m²); physical activity; family of cancer history (Yes/No); income (less than £18,000, £18,000 to £30,999, £31,000 to £51,999, £52,000 to £100,000, greater than £100,000, or missing); insomnia (Never/Sometimes/Usually/Missing). Data are presented as hazard ratios with 95% confidence intervals; Each point shows the point estimate of HR from Cox regression. Bars show 95%CI; HR and 95%CI were estimated by Cox regression (two-sided Wald test). Source data are provided as a Source Data file.

Fig. 6. Association of the interaction of maternal smoking, smoking status of offspring, and breastfeeding with offspring oesophageal cancer incidence and mortality.

HR Hazard Ratio, 95%CI 95% confidence intervals, Ref reference, FDR false discovery rate. Adjusted for age; sex (Female/Male); race (White, Mixed, Asian or Asian British, Black or Black British, Chinese, Other ethnic group); Townsend Deprivation index; drink (Never /Previous/Current/Missing); body mass index (<25 kg/m², 25 to 29.9 kg/m², ≥30 kg/m²); physical activity; family of cancer history (Yes/No); income (less than £18,000, £18,000 to £30,999, £31,000 to £51,999, £52,000 to £100,000, greater than £100,000, or missing); insomnia (Never/ Sometimes/ Usually/ Missing). Data are presented as hazard ratios with 95% confidence intervals; Each point shows the point estimate of HR from Cox regression. Bars show 95%CI; HR and 95%CI were estimated by Cox regression (two-sided Wald test). Source data are provided as a Source Data file.

Fig. 7. Prospective association of inflammatory markers with breastfeeding and oesophageal cancer incidence and mortality.

A Multivariable adjusted linear regression modeling of the relationship between breastfeeding and inflammatory marker levels. The significance of the regression coefficients was assessed using a t-test, and p-values were calculated to evaluate the statistical significance of the association. Neutrophil: P = 4.08 × 10⁻⁷⁷; Monocyte: P = 8.04 × 10⁻⁶; CRP: P = 7.44 × 10⁻¹⁵; Leukocyte: P = 8.20 × 10⁻³⁰; Monocyte percentage: P = 0.388; Neutrophil percentage: P = 3.94 × 10⁻⁹⁴; Lymphocyte: P = 9.96 × 10⁻⁵; Platelet: P = 1.65 × 10⁻²²; Lymphocyte percentage: P = 1.78 × 10⁻¹¹¹. B Association of nine inflammatory markers with oesophageal cancer incidence and mortality; Data on these inflammatory indicators were complete for the number of participants: n = 365,377 (leukocytes), n = 364,705 (lymphocytes, neutrophils, monocytes), n = 364,709 (lymphocyte%, monocyte%, neutrophil%), n = 365,378 (platelets), and n = 358,145 (CRP), respectively; Each point shows the point estimate of HR from Cox regression. Bars show 95%CI; HR and 95%CI were estimated by Cox regression (two-sided Wald test). C Exposure-response curves between indicators of inflammation and risk of oesophageal cancer incidence and mortality. The upper left curve represents the exposure-response curve between indicators of inflammation and the risk of death from oesophageal cancer. Bold lines represent HRs, while shaded areas indicate 95% CI; All p-values were calculated using two-sided Wald tests. D Six of the nine inflammatory markers significantly mediated the prospective association between breastfeeding and oesophageal cancer incidence and death. Mediation analysis was conducted using the mediation package in R. The significance of the mediating effects was assessed using 500 bootstrap iterations. NS: not significant. Source data are provided as a Source Data file.