Diagnostic and prognostic potential clustered miRNAs in bladder cancer

At specific genomic loci, miRNAs are in clusters and their association with copy number variations (CNVs) may exhibit abnormal expression in several cancers. Hence, the current study aims to understand the expression of miRNA clusters residing within CNVs and the regulation of their target genes in bladder cancer. To achieve this, we used extensive bioinformatics resources and performed an integrated analysis of recurrent CNVs, clustered miRNA expression, gene expression, and drug–gene interaction datasets. The study identified nine upregulated miRNA clusters that are residing on CNV gain regions and three miRNA clusters (hsa-mir-200c/mir-141, hsa-mir-216a/mir-217, and hsa-mir-15b/mir-16-2) are correlated with patient survival. These clustered miRNAs targeted 89 genes that were downregulated in bladder cancer. Moreover, network and gene enrichment analysis displayed 10 hub genes (CCND2, ETS1, FGF2, FN1, JAK2, JUN, KDR, NOTCH1, PTEN, and ZEB1) which have significant potential for diagnosis and prognosis of bladder cancer patients. Interestingly, hsa-mir-200c/mir-141 and hsa-mir-15b/mir-16-2 cluster candidates showed significant differences in their expression in stage-specific manner during cancer progression. Downregulation of NOTCH1 by hsa-mir-200c/mir-141 may also sensitize tumors to methotrexate thus suggesting potential chemotherapeutic options for bladder cancer subjects. To overcome some computational challenges and reduce the complexity in multistep big data analysis, we developed an automated pipeline called CmiRClustFinder v1.0 (https://github.com/msls-bioinfo/CmiRClustFinder_v1.0), which can perform integrated data analysis of 35 TCGA cancer types.