Model: Variation in tumor hypermethylation profiles reflects gene expression in normal tissue. (a) Genes repressed in a tissue-specific manner are prone to hypermethylation in tumors derived from that tissue. (b) Possible mechanisms that result in the hypermethylation of repressed CGI promoters in cancer. CGI promoter hypermethylation could result from either the loss of a mechanism maintaining CGIs in a hypomethylated state (for example,TET enzymes) or a gain of de novo methyltransferase activity at the CGI (whether targeted by transcription factors or through an increase in levels of the proteins in the cell). CGI, CpG island.