Association between out-seed miRNA variants targeting WNT/NOTCH signaling and breast cancer risk in Vietnamese women

Abstract Background Breast cancer susceptibility is shaped by regulatory variation that may act in a subtype-dependent manner, yet miRNA polymorphisms, particularly those in the out-seed region that can modulate non-canonical target pairing, remain underexplored in Vietnamese populations. Methods A pathway-informed case–control study was conducted with 50 breast cancer patients and 50 non-cancer controls to evaluate 23 single-nucleotide polymorphisms located in miRNA out-seed regions. These SNPs were predicted in-silico to target key genes within the WNT/β-catenin and NOTCH signaling networks. SNPs were genotyped using a custom-targeted panel NGS approach. Associations with breast cancer risk were assessed using logistic regression with codominant, dominant, recessive, over-dominant, and log-additive models, reporting both unadjusted and age-adjusted odds ratios, along with 95% confidence intervals. Results Three SNPs showed nominal associations with breast cancer or breast cancer subtypes: rs10061133 (hsa-miR-449b-5p; predicted target DLL1), rs404337 (hsa-miR-8084; predicted target NOTCH1), and rs2986407 (hsa-miR-1343-5p; predicted target CSNK1A1). In the overall analysis, rs10061133 was associated with breast cancer risk before age adjustment (dominant model OR = 2.47, p = 0.026; over-dominant model OR = 2.25, p = 0.044), although this effect was attenuated after age adjustment. In exploratory subtype analyses, rs10061133 remained significant after age adjustment in HER2-positive, Ki-67-positive, and HR+HER2 + cases. rs404337 showed over-dominant associations in ER-negative, PR-negative, and HER2-positive subgroups, whereas rs2986407 was associated with PR-negative breast cancer only after age adjustment. Conclusions These findings suggest that miRNA out-seed variants, rs10061133, rs404337, and rs2986407, predicted to regulate WNT/NOTCH pathway nodes may contribute to breast cancer susceptibility in a subtype-dependent manner. However, replication in a larger population and functional validation of allele-specific miRNA–target interactions are warranted.