Causal effects of breast cancer risk factors across hormone receptor breast cancer subtypes: A two-sample Mendelian randomization study

Abstract

AbstractBackgroundIt is unclear if established breast cancer risk factors exert similar causal effects across hormone receptor breast cancer subtypes. We estimated and compared causal estimates of height, body mass index (BMI), type 2 diabetes, age at menarche, age at menopause, breast density, alcohol consumption, regular smoking, and physical activity across these subtypes.MethodsWe used a two-sample Mendelian randomization approach and selected genetic instrumental variables from large-scale risk factor GWAS. Publicly available summary-level data for the following subtypes were included: luminal A-like; luminal B/HER2-negative-like; luminal B-like; HER2-enriched-like; triple negative. We employed multiple methods to evaluate the strength of causal evidence for each risk factor-subtype association.ResultsCollectively, our analyses indicated that increased height and decreased BMI are probable causal risk factors for all five subtypes. For the other risk factors, the strength of evidence for causal effects differed across subtypes. Heterogeneity in the magnitude of causal effect estimates for age at menopause and breast density was explained by null findings for triple negative tumours. Regular smoking was the sole risk factor for which there was no evidence for a causal effect on any subtype.ConclusionsThis study suggests that established breast cancer risk factors differ across hormone receptor subtypes.