Integrative Analysis of miR-SNP–Associated Alterations in miRNA Expression and Regulatory Networks in Breast Cancer: A Systematic Review

Abstract

Genetic variants located within mature miRNA-coding regions (miR-SNPs) have been implicated in breast cancer susceptibility; however, their regulatory effects on mature miRNA expression and downstream function remain incompletely characterized and inconsistently reported. In this study, we performed an integrative analysis of 3 miR-SNPs (rs11614913, rs2910164 and rs3746444) by combining evidence from population-based studies, TCGA transcriptomic data, and in silico analyses. A systematic literature search identified eligible population-based and cell-based studies examining rs11614913 (miR-196a), rs2910164 (miR-146a), or rs3746444 (miR-499a) in relation to mature miRNA expression. Meta-analyses were conducted under codominant, dominant, recessive, and over-dominant genetic models using standardized mean difference (SMD, Hedges’ g) to accommodate heterogeneous expression metrics. Expression patterns of mature miRNAs were further examined using TCGA-BRCA miRNA-sequencing data, while miRNA–target interaction networks and binding energy changes (ΔG) were analyzed in silico to explore potential regulatory alterations. Population-based meta-analyses revealed genetic model-dependent associations, including a moderate association between rs11614913 and miR-196a-5p expression under the homozygote model (SMD = 0.49, 95% CI: 0.19 - 0.78, p = 0.001) and a small but significant association between rs2910164 and miR-146a-5p expression under the dominant model (SMD = 0.41, 95% CI: 0.13 - 0.69, p = 0.004), whereas evidence for rs3746444 was limited to single-study data. Cell-based experiments demonstrated strand-specific effects, with rs11614913 preferentially affecting miR-196a-5p expression and rs2910164 primarily influencing miR-146a-3p levels, highlighting context-dependent regulatory patterns. TCGA analyses showed significant upregulation of miR-146a-3p and miR-499a-3p in breast cancer tissues, while both miR-196a strands were upregulated; however, genotype-specific associations could not be assessed. In silico predictions suggested that these miR-SNPs may alter miRNA–target interaction networks involving cancer-related pathways. Collectively, this study provides preliminary and exploratory evidence that miR-SNPs are associated with strand- and genetic model–dependent variation in miRNA expression. Given the limited number of eligible studies and the lack of genotype-resolved tumor data, these findings should be interpreted with caution and are intended to provide a structured framework for future functional and clinical investigations.

HIGHLIGHTS

• An integrative analysis was performed to evaluate the regulatory relevance of 3 miR-SNPs (rs11614913, rs2910164, rs3746444) in breast cancer.
• Population-based meta-analyses identified genetic model–dependent associations between miR-SNPs and mature miRNA expression.
• Cell-based studies demonstrated context-dependent and strand-specific regulatory effects of miR-SNPs.
• TCGA miRNA-seq data revealed arm-specific dysregulation in breast cancer, including predominant upregulation of miR-146a-3p, miR-499a-3p, and both miR-196a strands.
• This study provides exploratory evidence and a structured framework for future functional and clinical investigations of miR-SNP–mediated regulation.

GRAPHICAL ABSTRACT