Background:We aim to address one question:do cancer vs.normal tissue cells execute their transcription regulation essentially the same or differently,and why?Methods:We utilized an integrated computational study of cancer epigenomes and transcriptomes of 10 cancer types,by using penalized linear regression models to evaluate the regulatory effects of DNA methylations on gene expressions.Results:Our main discoveries are:(i) 56 genes have their expressions consistently regulated by DNA methylation specifically in cancer,which enrich pathways associated with micro-environmental stresses and responses,particularly oxidative stress;(ii) the level of involvement by DNA methylation in transcription regulation increases as a cancer advances for majority of the cancer types examined;(iii) transcription regulation in cancer vs.control tissue cells are substantially different,with the former being largely done through direct DNA methylation and the latter mainly done via transcriptional factors;(iv) the altered DNA methylation landscapes in cancer vs.control are predominantly accomplished by DNMT1,TET3 and CBX2,which are predicted to be the result of persistent stresses present in the intracellular and micro-environments of cancer cells,which is consistent with the general understanding about epigenomic functions.Conclusions:Our integrative analyses discovered that a large class of genes is regulated via direct DNA methylation of the genes in cancer,comparing to TFs in normal cells.Such genes fall into a few stress and response pathways.As a cancer advances,the level of involvement by direct DNA methylation in transcription regulation increases for majority of the cancer types examined.