Mendelian Randomization Integrating GWAS and eQTL Data Reveals DAAM1, a Potential Immune-Related Biomarker for Breast...

The immune response plays a critical role in determining the prognosis of breast cancer (BC) patients. However, the underlying molecular mechanisms linking immune regulation to BC progression remain uncleared. This study aims to identify and functionally validate key immune-related genes that mechanistically impact on BC prognosis.

We used the Mendelian randomization (MR) integrating genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) data to prioritize candidate genes with a potential causal role in BC-related immune traits. This study was designed to establish a robust genetic rationale for candidate selection, minimizing false positives. Subsequent analyses focused on DAAM1, genes highlighted by the MR analysis, to explore their clinical relevance and biological functions. We validated their expression and association with immune infiltration levels using LASSO regression and patient tissue samples. Functional roles of DAAM1 were further investigated through in vitro assays based on cell proliferation, adhesion, invasion, and migration. The underlying mechanism was illustrated via Western blotting.

Our integrated MR analysis identified DAAM1 as a top candidate with a genetically supported link to BC immune traits. DAAM1 expression was significantly elevated in BC tissues and inversely correlated with immune infiltration levels, suggesting a role in modulating the tumor immune microenvironment. Functional experiments demonstrated that DAAM1 knockdown effectively suppressed BC cell proliferation, adhesion, invasion, and migration. Mechanistically, Western blot analysis revealed that DAAM1 promotes these malignant phenotypes potentially through activating the epithelial-mesenchymal transition (EMT) pathway.

This study identified DAAM1 as a key immune-related prognostic biomarker in breast cancer, whose upregulation contributes to tumor progression and metastasis via EMT pathway. Our findings, elaborated in a causal inference framework, provide a mechanistic basis for DAAM1's role in BC and underscore its potential as a therapeutic target.