Schematic overview of the approach.

<p>Methylation matrix of continuous beta values is transformed into a discrete profile by comparing with the methylation profiles of normal samples by discretization (1 denotes hypermethylation, −1 denotes hypomethylation and 0 denotes no differential methylation). Identification of driver alteration required following three conditions. Firstly, for each locus, if its gene expression was significantly down- or up-regulated in hyper- or hypomethylated cancer samples comparing with the cancer samples which had no differential methylation at this locus (T-test, FDR<0.05), it is retained for follow analysis. We showed the hypermethylated locus (labeled with yellow) as an example. Secondly, the methylation alterations which influence the expression of significantly more downstream genes were selected (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061214#s2" target="_blank">Methods</a>). Thirdly, downstream genes of a driver methylation alteration should be enriched in at least one of the cancer-associated pathways.