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.

[1]  M. Golding,et al.  Reshaping the transcriptional frontier: Epigenetics and somatic cell nuclear transfer , 2014, Molecular reproduction and development.

[2]  J. Lebrun,et al.  MicroRNA-584 and the Protein Phosphatase and Actin Regulator 1 (PHACTR1), a New Signaling Route through Which Transforming Growth Factor-β Mediates the Migration and Actin Dynamics of Breast Cancer Cells* , 2013, The Journal of Biological Chemistry.

[3]  M. Ulaşlı,et al.  Gene expressions of TRP channels in glioblastoma multiforme and relation with survival , 2015, Tumor Biology.

[4]  D. Plas,et al.  TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. , 2014, Cancer cell.

[5]  J. Byrd,et al.  Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia. , 2012, Cancer research.

[6]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[7]  A. Riggs,et al.  Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay , 2007, Proceedings of the National Academy of Sciences.

[8]  R. Dahiya,et al.  Tumour suppressor microRNA-584 directly targets oncogene Rock-1 and decreases invasion ability in human clear cell renal cell carcinoma , 2010, British Journal of Cancer.

[9]  Toshima Z. Parris,et al.  Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas , 2014, Oncogenesis.

[10]  H. Deng,et al.  Relationship between miRNA‐338‐3p expression and progression and prognosis of human colorectal carcinoma , 2014, Chinese medical journal.

[11]  G. Lang,et al.  Genome-wide CpG island methylation analyses in non-small cell lung cancer patients. , 2013, Carcinogenesis.

[12]  Li‐yan Li,et al.  MicroRNA-584 functions as a tumor suppressor and targets PTTG1IP in glioma. , 2014, International journal of clinical and experimental pathology.

[13]  Hiromu Suzuki,et al.  DNA methylation and microRNA dysregulation in cancer , 2012, Molecular oncology.

[14]  J. Glennon,et al.  A Potential Regulatory Role for Intronic microRNA-338-3p for Its Host Gene Encoding Apoptosis-Associated Tyrosine Kinase , 2012, PloS one.

[15]  Alkes L. Price,et al.  Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals , 2011, PLoS genetics.

[16]  Peter Langfelder,et al.  Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects , 2012, BMC Genomics.

[17]  G. Melino,et al.  How the TP53 Family Proteins TP63 and TP73 Contribute to Tumorigenesis: Regulators and Effectors , 2014, Human mutation.

[18]  Jia Yu,et al.  DNA Methylation mediated down-regulating of MicroRNA-33b and its role in gastric cancer , 2016, Scientific Reports.

[19]  T. Murata,et al.  Characterization of phosphodiesterase 2A in human malignant melanoma PMP cells , 2013, Oncology reports.

[20]  Neal P. Kawas,et al.  Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis. , 2014, Human molecular genetics.

[21]  Tanja Kunej,et al.  Genome-Wide and Species-Wide In Silico Screening for Intragenic MicroRNAs in Human, Mouse and Chicken , 2013, PloS one.

[22]  D. Takai,et al.  Histone methylation-mediated silencing of miR-139 enhances invasion of non-small-cell lung cancer , 2015, Cancer medicine.

[23]  Yi Wen Kong,et al.  How do microRNAs regulate gene expression? , 2008, Biochemical Society transactions.

[24]  B. Boman,et al.  HOX genes and their role in the development of human cancers , 2014, Journal of Molecular Medicine.

[25]  C. Sander,et al.  Analysis of microRNA-target interactions across diverse cancer types , 2013, Nature Structural &Molecular Biology.

[26]  A. Bradley,et al.  Identification of mammalian microRNA host genes and transcription units. , 2004, Genome research.

[27]  Keith D Robertson,et al.  DNA methylation: superior or subordinate in the epigenetic hierarchy? , 2011, Genes & cancer.

[28]  Jianwen Liu,et al.  Post‐transcriptional regulation of the tumor suppressor miR‐139‐5p and a network of miR‐139‐5p‐mediated mRNA interactions in colorectal cancer , 2014, The FEBS journal.

[29]  Martha R. Stampfer,et al.  miRNA Gene Promoters Are Frequent Targets of Aberrant DNA Methylation in Human Breast Cancer , 2013, PloS one.

[30]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.