Unlike most genes, the copy of IGF2 that should be silent depends only on which parent it came from, a situation called genomic imprinting. For IGF2, the copy inherited from the mother is always supposed to be turned off.
In the mice and in some people, however, cells lack the epigenetic "marks" that sit on the DNA and keep the maternally inherited copy turned off. As a result, cells make a double dose of the IGF2 protein and are said to have "loss of imprinting" of IGF2.
Although Feinberg and others have already noted an association between loss of imprinting of IGF2 and colon cancer in people, the current experiments were designed to find out whether the loss of imprinting is involved in cancer's development or just in its progression.
"Most researchers, including me, expect epigenetic differences to influence progression -- whether a tumor would grow slowly or quickly, or whether it would spread," says Feinberg. "But, in this case, our results show that loss of imprinting of IGF2 contributes to colon cancer's development in the mice. It doesn't cause tumors directly, but it creates an environment which is ripe for cancer to start."
Because precursor cells in the colon's lining had been identified as a likely starting point for tumors, Feinberg and his team tossed a cancer-causing genetic mutation into the mix. The IGF2 mice were crossed with mice carrying a mutation in a gene called APC, which had been tied to colon cancer by researchers studying families with excessive growths, or polyps, in the colon.
Mice with extra IGF2 and the APC mutation developed twice the number of tumors as mice with the mutation but whose IGF2 levels were normal. The tumors grew at the same rate in both sets of mice, suggesting that more tumors get started in the mice with extra IGF2, notes Feinberg.