The Johns Hopkins Comprehensive Cancer Center; Johns Hopkins University
An epigenetic process, associated with aberrant methylation of normally unmethylated promoter region CpG islands, is an important alternative to coding region mutations for silencing tumor suppressor genes in cancer. There is a growing list of such genes and currently this includes the tumor suppressor genes Rb, VHL, p16, hMLH1, and E-cadherin ( E-cad ). Other important genes which also undergo this change include: p15, DAP-kinase, O6-MGMT, GST-Pi, and TIMP-3. Several aspects of the transcriptional silencing of the above genes illustrate how the associated gene silencing events constitute a heritable process which much resembles that for imprinted genes. This fact will be illustrated by studies of the p16 gene in a line of colon cancer, HCT 116, in which one copy of the gene is mutated in the coding region, and expressed, while the wild type copy is hypermethylated and transcriptionally silenced. To illustrate how the hypermethylation process fully participates in the loss of critical gene function, and that this process is reversible, studies of the hMLH1 gene in colorectal and endometrial carcinoma will be discussed. Also, the occurrence of promoter region hypermethylation as a heterogeneous allelic event which can be spontaneously altered during tumor progression will be presented. Finally, the importance of interactions between chromatin formation and methylation for maintaining the silencing of genes in cancer, and possibly causing the abnormal methylation patterns, will be illustrated. We will suggest that promoter hypermethylation methylation and histone deacetylase activity work together as layers of epigenetic control to stabilize loss of key gene functions in cancer cells. Also, the possibility that some targets for aberrant methylation arise in tumor progression as part of a process of "chromatin instability" will be entertained and it will be proposed that this process underlies the phenotype of mismatch repair deficiency that characterizes 10 to 15% of sporadic colorectal carcinomas.