Genetic evidence for causal roles of circulating proteins on breast cancer susceptibility

Circulating proteins represent promising candidates for understanding breast cancer (BC) etiology. This study employed a two-sample Mendelian randomization framework to investigate the potential causal relationships between genetically predicted levels of circulating proteins and BC risk. By integrating large-scale protein quantitative trait loci (pQTL) data from two major cohorts (DeCODE and UK Biobank) with BC genetic association data from three independent sources (FinnGen, BCAC), the analysis identified four proteins—intestinal alkaline phosphatase (ALPI), coiled-coil domain containing 134 (CCDC134), cadherin 1 (CDH1), and ST3 beta-galactoside alpha-2,3-sialyltransferase 2 (ST3GAL2)—with levels associated with a significantly reduced risk of BC. Colocalization analysis further supported a shared causal variant for ALPI. These proteins exhibited distinct associations with BC molecular subtypes. The findings highlight specific circulating proteins as potential mediators of BC risk. This work suggests avenues for exploring the biological mechanisms of BC and may inform future strategies for risk assessment.