Co-localized genomic regulation of miRNA and mRNA via DNA methylation affects survival in multiple tumor types

Aberrant gene expression in cancer is due in part to irregular patterns of DNA methylation and miRNA target gene down regulation. Using data from The Cancer Genome Atlas (TGCA), we investigated co-localized mRNA, miRNA and DNA methylation data across 15 cancer types, focusing on cases where evidence for direct regulation was strong. Restricting attention to regions where miRNA markers co-localize within a corresponding mRNA transcript, we checked expression data from 2839 samples for 354 mRNAs, 389 miRNAs and 13,809 DNA methylation probes for correlations greater than an absolute 0.6. We identified 32 genes, 34 miRNAs and 143 DNA methylation site probes comprising 180 "triplet combinations" that together provide evidence of co-localized genomic regulation in cancer. The five triplet combinations showing the highest prevalence across tissue types were found in four genes, HOXC5, PDE2A, SH3TC2 and TP63. Of the total 32 genes, eight among two tumor types (Kidney Renal Clear Cell Carcinoma (KIRC, 4) and Low Grade Glioma (LGG, 4)) were significantly associated with survival time (p < 0.002). Together, the data presented in this paper provide evidence toward our primary hypothesis, that both genes and miRNAs strongly correlated with methylation level are more likely to be associated with cancer outcomes.