Gene-set Analysis with CGI Information for Differential DNA Methylation Profiling

DNA methylation is a well-established epigenetic biomarker for many diseases. Studying the relationships among a group of genes and their methylations may help to unravel the etiology of diseases. Since CpG-islands (CGIs) play a crucial role in the regulation of transcription during methylation, including them in the analysis may provide further information in understanding the pathogenesis of cancers. Such CGI information, however, has usually been overlooked in existing gene-set analyses. Here we aimed to include both pathway information and CGI status to rank competing gene-sets and identify among them the genes most likely contributing to DNA methylation changes. To accomplish this, we devised a Bayesian model for matched case-control studies with parameters for CGI status and pathway associations, while incorporating intra-gene-set information. Three cancer studies with candidate pathways were analyzed to illustrate this approach. The strength of association for each candidate pathway and the influence of each gene were evaluated. Results show that, based on probabilities, the importance of pathways and genes can be determined. The findings confirm that some of these genes are cancer-related and may hold the potential to be targeted in drug development.