Background: MicroRNAs (miRNAs) are non-uniformly distributed in genomes and ~30\% of the miRNAs in the human genome are clustered. In this study we have focused on the imprinted miRNA cluster miR-379/miR-656 on 14q32.31 (hereafter C14) to test their coordinated function. We have analyzed expression profile of >1000 human miRNAs in >1400 samples representing seven different human tissue types obtained from cancer patients along with matched and unmatched controls.Results: We found 68\% of the miRNAs in this cluster to be significantly downregulated in glioblastoma multiforme (GBM), 61\% downregulated in kidney renal clear cell carcinoma (KIRC), 46\% in breast invasive carcinoma (BRCA) and 14\% in ovarian serous cystadenocarcinoma (OV). On a genome-wide scale C14 miRNAs accounted for 12-30\% of the total downregulated miRNAs in different cancers. Pathway enrichment for the predicted targets of C14 miRNA was significant for cancer pathways, especially Glioma (p< 3.77x10-6, FDR<0.005). The observed downregulation was confirmed in GBM patients by real-time PCR, where 79\% of C14 miRNAs (34/43) showed downregulation. In GBM samples, hypermethylation at C14 locus (p<0.003) and downregulation of MEF2, a crucial transcription factor for the cluster was observed which likely contribute to the observed downregulation of the entire miRNA cluster.Conclusion: We provide compelling evidence that the entire C14 miRNA cluster is a tumor suppressor locus involved in multiple cancers, especially in GBM, and points toward a general mechanism of coordinated function for clustered miRNAs.Reviewers: Reviewed by: Prof. Gregory J Goodall and Dr. Alexander Max Burroughs. © 2013 Laddha et al.; licensee BioMed Central Ltd.