Epigenetics Alone Can Alter Cancer Susceptibility

By Deborah Borfitz

February 13, 2025 | Evidence is emerging that epigenetic differences prior to birth can signal the type of cancer that occurs decades later by dictating which mutated cells turn into a tumor. It is “underappreciated” that most otherwise healthy people are walking around with cancer-causing mutations that their body suppresses unless their built-in defense system mysteriously fails, according to J. Andrew Pospisilik, Ph.D., chair of the department of epigenetics at the Van Andel Institute, in Grand Rapids, Michigan. 

It is now becoming clear that epigenetic change alone—before there is any change in the DNA sequence—is enough to alter cancer susceptibility, he says, which should help launch a new field of cancer research. Pospisilik and his colleagues laid their stake in the ground with the discovery of two distinct epigenetic states linked to a higher or lower lifetime cancer risk, each with its own disease consequences, as reported recently in Nature Cancer (DOI: 10.1038/s43018-024-00900-3).  

Study findings suggest that people in the lower risk state who develop cancer are more likely to have a liquid tumor, while those in the higher risk state are more apt to have a solid tumor. The existence of epigenetic sub-forms that are deterministic for cancer outcomes has previously been demonstrated but only in “more bizarre organisms” like zebrafish and fruit flies that people have a harder time relating to the human condition, says Pospisilik. 

Here, the study subjects were mouse models of human disease. Mice and humans share 95% of the same genes that do the same thing, he says. “We really aren’t that far from mice. All mammals are more or less the same.” 

Importantly, for epigenetic learning purposes, these are unique Trim28 mouse models that enabled researchers to look at two different types of mice with one genetic background. Trim28 is a previously discovered epigenetic regulator, which Pospisilik and his team first leveraged to generate the model of intrinsic developmental heterogeneity a decade ago. 

Up to now, epigenetics has largely been thought of as a secondary process relevant only after a person has cancer that impacts a tumor’s aggressiveness and response to treatment, he says.  “Our study shows that the epigenetic differences beforehand can determine what kind of cancer you get.” 

‘Third Dimension’

All cancers are driven by oncogenic mutations, but the epigenetic differences in place prior to birth can set the tone for which cells might get those mutations and at what frequencies, says Pospisilik. More realistically, they determine “which cells once they get a mutation actually turn into a tumor.” That is why cancer is said to be “a bit like a game of chance.” 

In the newly published study, some of the genetically identical Trim28 mice—all born in environmentally controlled chambers and cages and fed the same food—showed a “clear disposition for cancer” marked by a molecular signature, he says. “So, it’s a different subset of regulatory processes.” 

This suggests a diagnostic test might be developed to identify high-risk individuals at birth so they can perhaps undergo more screening than other people, says Pospisilik. He looks forward to the day when everyone’s exact sub-form of disease is more perfectly treated with precision medicine with a better understanding of this “third dimension of who we are” beyond genetic and environmental differences. 

Right now, research funding for human precision medicine initiatives is being directed primarily to genetics-related studies even if it is somewhat common for epigenetics to push people into “alternate states” that result in disease. In a 2022 study published in Nature Metabolism (DOI: 10.1038/s42255-022-00629-2), Pospisilik and his colleagues found about quarter of genetically identical mice had phenotypically and molecularly distinct subtypes of obesity. 

That equates to somewhere between 10% and 25% of people, based on a validation study in a small human twin cohort, he says. “That’s a hand-wavy number... but this is not something that is exceedingly rare.”  

‘Two Versions of Ourselves’

Pospisilik says he was motivated to take up the study of epigenetics because of the “obvious lack of understanding of something we know to be exquisitely important.” He was also intrigued by the discovery of the unique mouse model years earlier by the pioneering Australian epigeneticist Emma Whitelaw. 

The mouse system emerged from her search for new epigenetic regulators, he says. “She found Trim28 as a new epigenetic regulator, but didn’t realize it was making two different types of mice.” 

It is analogous to soldier ants and workers ants, two totally different types of ants that have the exact same DNA, he explains. “A soldier ant has a big head, big jaws, and defends the colony.” A worker ant has a smaller body, mandibles, and a variety of jobs to do. 

With the mice he studies, says Pospisilik, taking away just one copy of Trim28 it produces two different types of mice—one that’s bigger and heavier, and behaves a bit differently than the other. “That concept threw me for a loop because it means you or me could have two versions of ourselves, one that is predisposed to some disease and the other that behaves differently, is shaped a bit differently, and is predisposed to other diseases.” 

Trim28 regulates genetic silencing and therefore affects other genes in the human genome. Typically, people have two copies of each gene, one inherited from each parent, but here one of them is deleted. “It is actually a very mild mutation to the animal,” he points out. “There is plenty of genes between us where I have twice as much of the gene output as you do, and vice versa, so this is a very normal context even though... this mutation was made in those mice intentionally.”  

Role of Dietary Exposures

Next steps for Pospisilik and his team are to start interrogating very specific cancer types using the Trim28 mouse model, he says, since the team found evidence of the two epigenetic states throughout tissues in the body. The goal is to learn to what extent they play a role in important diseases such as leukemia and cancers of the stomach and pancreas. “The problem with cancer biology is that it’s like 200 different diseases.” 

The expectation is that “some cancers will not care about what happened during development to epigenetics, but there are going to be other cancers where this is very relevant,” he says. As cancer researchers are all aware, individual tumors tend to be highly unpredictable. 

Pospisilik says he is hopeful the work in his lab will help jump-start a new field of cancer research. There is already growing appreciation that many chronic diseases of Western societies are “much more developmental than we previously thought,” he says. 

Data from his obesity study, for example, suggests that about half of cases started as a developmental disorder. “That alone tells you there is already two different types of disease, because children are programmed to run around and if they’re not hungry they don’t eat,” says Pospisilik.  

“We’ve known that if you eat unhealthily, it may not be good for long-term diabetes or obesity susceptibility, and now we can add cancer to that list,” he says. “We need to be healthy in the womb, and we need to be healthy as parents before we’re conceiving and as we raise our children, so we don’t program these long-term consequential diseases [into existence].” 

This ties into recent discussions about the high consumption of ultra-processed food and high fructose corn syrup in America versus Europe, which is seen as a major health concern, Pospisilik notes. “That’s another set of future experiments—to what extent are dietary exposures from mothers, for instance, influencing cancer.”