Aberrant Methylation of the Imprinted C19MC and MIR371-3 Clusters in Patients with Non-Small Cell Lung Cancer

SIMPLE SUMMARY: Aberrations in DNA methylation profiles may alter the expression of key miRNAs in non-small cell lung cancer. In this study, we focus on the analysis of the imprinted C19MC and MIR371-3 miRNA clusters due to their oncogenic role. We identified the DNA methylation status and discovered its deregulated target genes in this disease. Additionally, we found five downstream target genes that were correlated with worse overall survival in non-small cell lung cancer. We conclude that C19MC and MIR371-3 are key players in lung cancer because their polycistronic epigenetic regulation leads to differential tumor expression, affecting downstream targets with prognostic value. ABSTRACT: Epigenetic mechanisms have emerged as an important contributor to tumor development through the modulation of gene expression. Our objective was to identify the methylation profile of the imprinted C19MC and MIR371-3 clusters in patients with non-small cell lung cancer (NSCLC) and to find their potential target genes, as well as to study their prognostic role. DNA methylation status was analyzed in a NSCLC patient cohort (n = 47) and compared with a control cohort including COPD patients and non-COPD subjects (n = 23) using the Illumina Infinium Human Methylation 450 BeadChip. Hypomethylation of miRNAs located on chromosome 19q13.42 was found to be specific for tumor tissue. We then identified the target mRNA–miRNA regulatory network for the components of the C19MC and MIR371-3 clusters using the miRTargetLink 2.0 Human tool. The correlations of miRNA-target mRNA expression from primary lung tumors were analyzed using the CancerMIRNome tool. From those negative correlations identified, we found that a lower expression of 5 of the target genes (FOXF2, KLF13, MICA, TCEAL1 and TGFBR2) was significantly associated with poor overall survival. Taken together, this study demonstrates that the imprinted C19MC and MIR371-3 miRNA clusters undergo polycistronic epigenetic regulation leading to deregulation of important and common target genes with potential prognostic value in lung cancer.