Genome-wide association analysis identified inflammatory mechanisms mediating the effects of lipid metabolism on endometrial carcinoma in situ.

BACKGROUND

While lipids and inflammation are recognized as key modulators of tumor progression, their causal interplay in endometrial carcinoma in situ (ECIS)-the precursor of endometrial cancer-remains mechanistically undefined. Despite broad associations between lipid metabolism and cancer, the specific pathways driving ECIS initiation through inflammatory mediators are unknown.

METHOD: We pioneer an integrative Mendelian randomization (MR) framework combining multivariable MR, Bayesian weighted MR (BWMR), and sensitivity analyses to address pleiotropy. This approach was systematically applied to 179 lipids and 91 inflammatory factors. Methodological novelty further includes mediation analysis quantifying inflammatory factors' role in lipid-ECIS pathways.

RESULTS

First evidence reveals a phosphatidylcholine (O-18:0_16:1)-TNFSF12-ECIS axis: TNFSF12 mediates 4.894 % of phosphatidylcholine's effect (OR: 2.925; beta: 1.073; 95 % CI: 1.752-4.884; p = 4.032E-05), attenuating the direct lipid-ECIS association. This represents the inaugural demonstration of an inflammation-mediated lipid pathway in ECIS pathogenesis.

CONCLUSION

As the first MR study decoding lipid-ECIS causality, we establish the following.