In 2015, scientists made a surprising discovery about physiologically normal human skin: More than 25 percent of cells carried genetic mutations known to cause cancer and the average number of mutations per cell was similar to the burden observed in many tumors.1 This research demonstrated that while genetic mutations are critical drivers of cancer development, other factors also play key roles. Indeed, scientists are increasingly finding that epigenetic factors, which do not change the genetic code but can drastically alter gene expression, are important for cancer risk and resilience as well.
To explore how epigenetic modifications acquired during development affected cancer risk, Ilaria Panzeri, an epigeneticist at the Van Andel Institute, took advantage of a unique mouse model. Mice with a mutation in one copy of the gene Trim28—an important regulator of developmental epigenetic processes—can be identical in terms of genetics and environmental exposures but nevertheless have distinct epigenetic profiles as neonates. A previous study by Panzeri’s mentor at the Van Andel Institute, Andrew Pospisilik, determined that these distinct neonatal profiles produced important physiological differences in adulthood—some of the mice developed typically while others developed elevated body mass (denoted as light and heavy morphs).2
In a new study, published in Nature Cancer, Panzeri demonstrated that these mice also had significantly different cancer risk profiles later in life: At 70 weeks, nearly 90 percent of the heavy morphs were still alive, while the light morphs developed multiple kinds of cancers and less than half survived until the end of the experiment.3
Researchers analyzed DNA methylation profiles ten days after the mice were born, well before any phenotypic differences were apparent. They observed more than one thousand differentially-methylated loci in the mice that would go on to develop into the light, high cancer-risk morph compared to the heavy, lower-risk morph. Importantly, said Panzeri, “Many of the [regions] that are differentially methylated are actually oncogenes. Heavy animals have higher methylation at oncogenes; light animals have hypomethylated oncogenes.” Panzeri noted that hypomethylation could increase cancer risk by changing gene expression or by altering genome stability.4
Joseph Wiemels, a University of California, San Francisco epidemiologist who studies genetic and epigenetic influence on cancer risk in humans, said that animal experiments like this one are important for determining causality and eliminating the heterogeneity of genetic and environmental impacts that necessarily exist in human studies. “It’s great science and has what looks like profound implications for human physiology,” he said. “And I think it gives people like me a challenge—to find these [different epigenetic states] in humans and see if we can perhaps influence them and reduce cancer risk.”