The best studied genes that undergo the silencing change have an abnormal DNA change at the gene start sites involving increased addition of methyl groups to the DNA base cytosine (DNA hypermethylation).

I suspect that the paper has been cited frequently because of the expanding interest in epigenetic gene silencing in cancer and the interdigitation of this area with the study of chromatin modulation of gene expression. This interest is also fueled by the fact that it marries two vibrant areas of current basic research, one in the biology of cancer and the other in studies of gene expression and transcription. In addition, all of this has a true translational outlet with respect to possibilities for cancer prevention and therapy and for molecular strategies for cancer detection. Thus, a wide audience may have been attracted to the review.

The review covers discoveries made in both authors’ labs and by many others in the field of cancer epigenetics and chromatin modulation of gene expression. If two broad areas of discovery were to be designated, they might be: a) the documentation over the past several years that heritable silencing of transcription represents a true alternative to coding region mutations for disruption of tumor suppressor gene function; and b) realizing that an understanding of the basic mechanisms underlying such loss of gene function is rooted in studying the process from the perspective of the latest findings for the role of histone modifications in modulation of gene expression.

The discovery that critical genes can be reversibly silenced in all types of human cancer has spurred a wide interest in trying to understand how this silencing comes to take place during the progression of tumors, what molecular components determine the silencing, and how all of these parameters can be utililized for cancer treatment and prevention purposes. The best studied genes that undergo the silencing change have an abnormal DNA change at the gene start sites involving increased addition of methyl groups to the DNA base cytosine (DNA hypermethylation). The molecular causes for the abnormal DNA methylation of genes in cancer are now being tied to modifications of the histone proteins which form a core around which DNA is wound. These modifications have been recognized to be a guide for determining whether genes are expressed or not and most recently to be determinants of where DNA methylation takes place in the genome. In addition, DNA methylation may work to tightly silence genes through helping to alter key histone modification states. The hypermethylated genes in cancer are excellent models to study all of these events. In turn, inhibiting the histone modifications that are now known to accompany abnormal silencing of cancer genes represents a real hope for development of new strategies for cancer prevention and treatment. Also, sensitive assays for the DNA hypermethylation at cancer gene start sites are showing great promise as a molecular marker strategy for early cancer detection, assessment of cancer risk, and monitoring prognosis.

We recognized, some 15 years ago, that gene start site hypermethylation in cancer cells might constitute a non-genetic mechanism for silencing tumor suppressor genes. We came upon this somewhat accidentally while trying to determine molecular parameters which specify for the expression of neuroendocrine genes in human cancer. In studying DNA methylation as one possible such determinant, we found this change at the start site of a gene in a region that Adrian Bird and others had just designated as normally being free, for virtually all mammalian genes, of methylation in normal cells. We were thus excited to follow our finding and it took some 10 years more, in work with my long-time colleague and collaborator James Herman, to specifically assign the DNA hypermethylation, and its consequences, to a bona fide tumor suppressor gene in human cancer cells.

Stephen Bruce Baylin, M.D.
Professor of Medicine and Oncology
Chief of the Tumor Biology Division
Johns Hopkins Oncology Center
Associate Director for Research
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, MD, USA

Read comments by Peter A. Jones; co-author of this Fast Breaking Paper