Investigating the relationship between birthweight and breast cancer from a non-linear and mediation perspective

Abstract Purpose: Epidemiological studies have shown a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations also emerged. We here attempted to re-explore the association between them in the UK Biobank cohort.Methods: Relying on large-scale data available from the UK Biobank cohort (5,760 cancer cases and 162,778 controls), we evaluated the causal linear mediation between birthweight and breast cancer, with age of menarche and age at menopause as two potential mediators under the traditional mediation analysis framework. The non-linear relationship between birthweight and breast cancer was also investigated by including the square of birthweight or discretized birthweight categories (4.0). Furthermore, we performed a stratification analysis in terms of the menopause status.Results: We revealed that birthweight can indirectly influence breast cancer risk in adulthood via the path of age of menarche or age at menopause, and found statistical evidence supporting the existence of suggestive non-linear association between birthweight and breast cancer (β=0.062 and P=0.004 for the square of birthweight) although failing to discover a linear relationship (P=0.230). We also demonstrated that such non-linear association seemed more pronounced and robust for premenopausal women compared to postmenopausal ones (27.5% vs. 19.5% increase in breast cancer risk).Conclusions: This study provides an in-depth insight into the observed relationship between birthweight and breast cancer and reveals that non-linear impact and causal mediation commonly drive the connection between the two traits.