Mouse study shows that epigenetic alterations can cause tumors
Changing a gene’s activity can cause cancer, even though the DNA itself hasn’t mutated, a new study demonstrates.
The finding is some of the first direct evidence that epigenetic changes can cause cancer. Epigenetic modifications are chemical tags tacked onto DNA or associated proteins. Such tags alter gene activity without changing the information in genes.
Scientists have long suspected that epigenetic modifications contribute to cancer. “The problem is, all of the studies we’ve done so far have been correlative,” says cancer epigeneticist Lanlan Shen, of Baylor College of Medicine in Houston, who led the new study. Those studies showed that epigenetic tagging is different in cancer cells than in healthy cells. However, the research couldn’t establish whether the epigenetic changes spurred the cancer’s growth or were one of its consequences.
Shen and her colleagues went after hard evidence that cancer could result from changing an epigenetic mark known as DNA methylation. In DNA methylation, enzymes attach a chemical tag called a methyl group to the DNA building block cytosine. Such a tag can shut down a nearby gene.
Shen’s team genetically engineered mice to carry a bit of DNA that acts as a methylation magnet. They placed this bit of DNA in front of a gene named p16. That gene’s protein is a tumor suppressor; that is, it normally stops cells from growing out of control.
As the mice carrying the methylation magnet aged, their p16 genes carried a higher and higher amount of DNA methylation. As a result, the gene’s activity plummeted. More than a quarter of middle aged and elderly mice — those between 35 and 100 weeks of age — that had the DNA methylation attractor developed tumors, including lung cancer, lymphoma and sarcomas, researchers report July 25 in the Journal of Clinical Investigation. None of the normal mice in the study got cancer in that time.
“It’s very clever what they did,” says Peter Jones, a cancer epigeneticist at the Van Andel Research Institute in Grand Rapids, Mich. The work confirms that epigenetic modifications can fuel cancer, he says. “We’ve believed it for years, but it’s important to show it in an experimental system.”
The study also strongly suggests, but is not yet definitive proof, that epigenetics alone can cause cancer, says Stephen Baylin, a cancer biologist at Johns Hopkins University School of Medicine. The mice may have harbored DNA mutations elsewhere in the genome that could have produced the tumors. But he adds, “These are very important clues that epigenetic changes are important in cancer.”
D.-H. Yu et al. Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice. Journal of Clinical Investigation. Published online July 25, 2014. doi:10.1172/JCI76507.