Altered methylation patterns in cancer cell genomes: cause or consequence?

CpG islands are associated with at least half of all cellular genes and are normally methylation-free. Dense methylation of cytosine residues within islands causes strong and heritable transcriptional silencing. Such silencing normally occurs almost solely at genes subject to genomic imprinting or to X chromosome inactivation. Aberrant methylation of CpG islands associated with tumor suppressor genes has been proposed to contribute to carcinogenesis. However, questions of mechanisms underlying the cancer changes and the precise consequences for tumorigenesis exist in the field, and must continue to be addressed before the importance of abnormalities in genomic methylation patterns in carcinogenesis can be fully understood. In this article, two workers in DNA methylation, one concentrating on cancer biology and the other on developmental biology, address recurrent questions about cancer epigenetics from different perspectives. The goal is to highlight important controversies in the field which can be productive targets of ongoing and future research.