Abstract:

Previous studies have suggested a potential interplay between the lipidome and immune cell dynamics in the development of estrogen receptor–positive (ER+) breast cancer (BC); however, the causal contribution of specific lipid species and their potential mediation through immune cells remain poorly defined. To address this gap, the present study leveraged large-scale genome-wide association study (GWAS) data covering 179 lipid species. Two-sample Mendelian randomization (TSMR) was employed as the primary analytical framework to systematically evaluate the causal effects of diverse molecular lipid subtypes on ER+BC risk, as well as on short-term (5-year) and long-term (15-year) survival outcomes. The robustness of the primary causal estimates was further examined using Bayesian weighted Mendelian randomization (BWMR), alongside comprehensive sensitivity analyses, including formal assessments of heterogeneity and horizontal pleiotropy. Our analyses revealed that several lipid classes, most notably diacylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and triacylglycerol, exerted significant causal effects on both ER+BC susceptibility and patient survival. In addition, 29 immune cell phenotypes were identified as being associated with prognosis, among which five emerged as potential key mediators linking lipid metabolism to ER+BC survival. Collectively, these findings provided robust genetic evidence supporting a causal role of the lipidome in the pathogenesis and progression of ER+BC, with this effect appearing to be partially mediated by specific immune cell populations.

Key words: ER+BC, Lipidome, Immune cell, Mendelian randomization