Aberrant Methylation of Gene Promoters in Cancer—Concepts, Misconcepts, and Promise

Extract

In this issue of the Journal, Tang et al. (1) report that the presence of abnormal methylation in the 5` region of the death-associated protein (DAP) gene in tumor DNA predicts shorter survival in patients who had undergone surgery for non-small-cell lung cancer (NSCLC). This change in methylation is an example of an epigenetic process that is attracting increasing attention, both because of its potential significance to our basic understanding of cancer and because of its possible use for improved cancer diagnosis and treatment. However, the study by Tang et al. also raises many of the questions that constitute an ongoing vigorous, but constructive, debate as to the true biologic significance of these postreplicative DNA changes (2).

“CpG islands” surround the transcription start regions of almost half of the genes in the human genome and are normally unmethylated. Hypermethylation of CpG islands in cancers is associated with transcriptional silencing of the genes in which this change occurs. “Association” is the operative word here because central to this debate is whether methylation initiates, or is even essential for, gene silencing. However, the main point of the study by Tang et al. involves CpG methylation as a molecular marker that may be independent of its functional implications. Indeed, as the authors imply, promoter hypermethylation is emerging as one of the most promising molecular strategies for early detection of cancer, independent of its role in tumor development.