And in another example of turning conventional wisdom on its head, researchers from Scotland report that aberrant DNA hypermethylation of CpG island (CGI) promoters does not contribute to cancer development via silencing. Generally, those genes are already repressed before cancer even starts.
Researchers have noticed for a long time that many genes’ CGI promoters are hypermethylated in cancer versus normal tissue, and it often happens at tumor suppressor genes. But even after lots of studies, it’s still unclear how happens and whether this hypermethylation is really the primary event that silences those genes.
One nail in the coffin for the theory comes from this U.K. team’s previous work. Last year, they showed that genes with hypermethylated promoters in breast cancer cells already were repressed in their original cell lineages. And when they got rid of the methylation, most of the genes didn’t re-activate.
In the current study, the team expands these findings, showing that this is also the case for 1154 tumors from seven different human tissues. Here’s a little of what they found:
- They found that 1009 genes were susceptible to hypermethylation in at least one cancer type.
- Almost half of these were hypermethylated only in some cancer types, which hints at some degree of tissue specificity.
- Genes with hypermethylated CGI promoters had hallmarks of tissue-specificity, such as GO terms like “Organ Development” or their mRNAs have tissue-specific expression patterns.
- A gene’s expression (or lack of expression) in normal tissues predicted whether the gene’s promoter was hypermethylated in cancer tissues.
The researchers conclude that “the major contribution of general CGI promoter hypermethylation to cancer cannot be the silencing of tumor suppressor genes because it affects genes that are already repressed in pre-cancerous tissue.”
Get the full story at Genome Biology October 2012.