Epigenetic analysis by integrating DNA methylation, miRNA and microarray data in glioblastoma, ovarian and non-small cell lung cancer

[[abstract]]Epigenetic regulation has been linked to the initiation and progression of cancer. Aberrant expression of microRNAs (miRNAs) is one such mechanism that can activate or silence oncogenes (OCG) and tumor suppressor genes (TSG) in cells. A growing number of studies suggest that miRNA expression can be regulated by methylation modification, thus triggering cancer development. However, there is no comprehensive in silico study concerning miRNA regulation by direct DNA methylation in cancer. This dissertation consists of three publications which constructed epigenetically regulated miRNA pathways. In the first study, this research integrated gene expression and methylation sites expression in glioblastoma (GBM) and ovarian cancer (OSC) with microRNA (miRNA), CpG island, target gene and cancer gene to establish epigenetic-regulated pathways in cancer formation. Next, the database “MethmiRbase”, a database of DNA methylation and miRNA expression in human cancer were set up. For a preliminary study, Non-small cell lung cancer (NSCLC) and ovarian cancer were selected. MethmiRbase made use of the meta-analysis (MA) method by using the Spearman correlation coefficient to identify significant anti-correlate DNA methylation and miRNA expression events (hypermethylation status with low expression miRNA or hypomethylation status with high expression miRNA) to construct epigenetic-mediated miRNA target gene pathways. Furthermore, our study proposed a systematic strategy to construct highly confident epigenetic-regulated miRNA pathways for OSC. The Spearman rank correlation coefficient (SRCC) was used to quantify the correlation between the CpG DNA methylation level and miRNA expression level. Meta-analysis was performed to reduce the effects of biological heterogeneity among different batches. miRNA-target interactions were also inferred by computing SRCC and meta-analysis to assess the correlation between miRNA expression and cancer-associated gene expression and the interactions were further validated by a query against the miRTarBase database. In the first publication, this study constructed several epigenetic-regulated miRNAs events which may potentially cause GBM and OSC. A web-based interface has been set up for the query at http://ppi.bioinfo.asia.edu.tw/ER_microRNA. In the second publication, this study presented MethmiRbase, a database that made use of meta-analysis to identify potential epigenetic-regulated miRNAs for three human cancers, i.e. lung adenocarcinoma, lung squamous carcinoma and ovarian cancers. This research also included experimentally verified cancer-associated miRNA target genes in MethmiRbase (http://ppi.bioinfo.asia.edu.tw/MethmiRbase). In the third publication, a total of 26 potential epigenetic-regulated miRNA genes that can target OCGs or TSGs in OSC were found to show biological relevance between DNA methylation and miRNA gene expression. The inclusion of direct DNA methylated miRNA events may offer another layer of explanation that along with genetics can give a better understanding of the carcinogenesis process. Keywords: Epigenetic, microRNA, DNA methylation, CpG islands, Ovarian cancer, Meta-analysis