Andrew Feinberg, a professor of molecular medicine at Johns Hopkins University, has been having a real chicken-or-the-egg problem in his studies with cancer epigenetics. “One of the puzzling things [in the field] has been how to know what occurs first — whether an epigenetic change arises before the tumor arises or after,” he says.
To get to the bottom of the mystery, Feinberg and his team decided to study epigenetic changes that are present in normal cells and see how it compares to a disorder involving such a change. They homed in on a particular epigenetic change — loss of imprinting — and designed experiments to see how it affected the insulin-like growth factor II, or IGF2, gene often connected with colorectal cancer. “We made a mouse model to test the hypothesis that loss of imprinting really does increase tumor risk,” Feinberg says. The team combined a mouse with loss of imprinting of the gene “with a mouse that’s prone to developing intestinal tumors,” he says. “Basically the mice had both loss of imprinting and a mutation in the APC gene.” As it turns out, mice that had the loss of imprinting had double the likelihood of developing tumors as the other mice.
That study has raised plenty of other questions for Feinberg, who has been studying epigenetic changes for years. “One of the questions that we’re really interested in is which genes are really mediating this,” he says. “We’re … interested in understanding the IGF2 signaling pathway and which particular downstream effects are responsible for this phenotype.”
Feinberg isn’t the only one intrigued by these results. “From the epidemiological community there’s actually a lot of interest” in this kind of work, he says.
— Meredith Salisbury