A Pan-Cancer Analysis of microRNA Tissue Specificity and Its Association with Dysregulation

MicroRNAs are frequently dysregulated in cancer, yet how their tissue specificity is remodeled during malignant transformation remains poorly characterized. Here, we systematically quantified the tissue specificity of miRNAs across normal (GTEx) and cancer (TCGA) tissues using the Tau index as the primary metric and the Gini index for independent validation. Our analysis revealed a negative association between tissue specificity in healthy tissues and changes in specificity during malignant transformation, indicating that miRNAs with higher tissue specificity in normal tissues tend to undergo greater loss of specificity in cancer. To robustly define dysregulation, we combined two independent analyses: a binomial test over per-project differential expression across 17 matched normal tissues within the TCGA cohort, and a TCGA–GTEx pan-tissue comparison of mean expression. The change in specificity (ΔTau) separated up- from downregulated miRNAs, showing moderate agreement with the binomial signal and a strong correlation with the expression-based contrast. Finally, we identified six miRNAs that lose tissue specificity upon transformation while remaining consistently upregulated (miR-519a-5p, miR-512-3p, miR-522-3p, miR-105-5p, miR-935, miR-1269a). Functional analysis of their experimentally validated and predicted targets showed significant enrichment for converging on core oncogenic programs. Collectively, integrating specificity dynamics with dysregulation evidence pinpoints candidate miRNAs with coordinated, cancer-relevant regulatory roles and highlights those with favorable tissue-specificity profiles that may warrant further investigation as potential therapeutic candidates.