Investigating the genetic causal relationship between breast cancer and endometrial cancer: A two-sample Mendelian randomization study

Observational studies have consistently shown a correlation between breast cancer (BC) and endometrial cancer (EC). Despite these findings, the causal relationship between these cancers has not been clearly defined. This research employed a bidirectional two-sample Mendelian randomization to explore the genetic causality between BC and EC. Genetic instruments for BC were derived from the Breast Cancer Association Consortium genome-wide association studies summary statistics, while for EC, data were sourced from the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. The primary analytical method was inverse-variance weighted. Additional analyses, such as MR-Egger and weighted median, were conducted to validate the robustness of our findings from multiple perspectives. The MR-Egger intercept test was conducted to examine potential pleiotropy, whereas Cochrane Q test was implemented to assess heterogeneity. A leave-one-out analysis was conducted to assess the sensitivity of the observed association. Our analysis identified a bidirectional genetic causal relationship between estrogen receptor-positive breast cancer (ER+BC) and EC. Inverse-variance weighted analysis indicated an odds ratio of 1.0686 (95% confidence interval: 1.0029-1.1386, P = .0403) from ER+BC to EC and an odds ratio of 1.0692 (95% confidence interval: 1.0183-1.1225, P = .0071) from EC to ER+BC. No significant horizontal pleiotropy was detected. This study confirms a bidirectional genetic link between ER+BC and EC, suggesting shared genetic etiologies and possibly linked pathophysiological pathways. Understanding the genetic interplay between ER+BC and EC can enhance strategies for the precise prevention and screening of these prevalent cancers, potentially leading to improved clinical outcomes and management of secondary primary malignancies.