Causal associations between fibroblast growth factors and breast cancer: Evidence from 2-sample Mendelian randomization analysis

Previous studies have suggested a potential association between fibroblast growth factors (FGFs) and breast cancer (BC), but the evidence for the relationship between specific FGFs with BC is limited and controversial. To explore the interactions between 13 FGFs and 3 fibroblast growth factor receptors (FGFRs) with BC and its subtypes (ER+ and ER-), we conducted a Mendelian randomization (MR) analysis based on genome-wide association study summary statistics of European ancestry. Several techniques were used to ensure the stability of the causal effect, such as inverse-variance weighting, weighted median, MR-Egger regression, and Mendelian Randomization Pleiotropy Residual Sum and Outlier. Heterogeneity was assessed by calculating the Cochran's Q value. The inverse-variance weighting analysis showed that for overall BC, FGF20 showed a genetically protective effect (odds ratio [OR] 0.996, 95% CI: 0.993-1.000, P = .027), FGF4 can genetically promote the risk of BC (OR 1.004, 95% CI: 1.001-1.007, P = .013). FGF1 (OR 1.055, 95% CI: 1.005-1.107, P = .029) and FGF7 (OR 1.068, 95% CI: 1.007-1.133, P = .028) were consistently associated with increased risk of ER+ BC, however FGF20 (OR 0.959, 95% CI: 0.920-0.999, P = .046) decreased the risk of ER+ BC. FGF23 (OR 1.077, 95% CI: 1.003-1.158, P = .042) promote the risk of ER- BC. In the reverse MR study, ER+ BC tended to exhibit elevated levels of FGF7 (OR 1.072, 95% CI: 1.004-1.144, P = .037) and decreased levels of FGFR2 (OR 0.930, 95% CI: 0.872-0.992, P = .027). Our study results indicate that only specific types of FGFs and FGFRs may have a causal relationship with BC. Th research provides a new perspective on the mechanisms of action of different types of FGFs and FGFRs in BC, and offers potential genetic support for personalized medicine and precision therapy.