Mutations in specific genes often lead to cancer — but not always. Researchers have long wondered what biological mechanisms drive tumor development in one person with a high-risk of cancer but not another. 

In a recent study in Nature Cancer, scientists at the Van Andel Institute discovered that variations in epigenetics — DNA modifications that determine whether a gene is expressed or not — during development may determine cancer risk later in life (1). 

“It's really nice,” said Chao Lu, an epigenetics researcher at Columbia University who was not involved in the study. “In a very controlled way, [they’re] showing something that the field has long suspected but [been] unable to demonstrate.”

To investigate how epigenetic differences during development might affect cancer susceptibility later in life, the researchers, led by epigenetics researcher J. Andrew Pospisilik, introduced a single copy of the epigenetic gene regulator tripartite motif protein 28 (TRIM28) into a cancer-prone strain of mice. TRIM28 controls heterogeneity during development, and prior work from Pospisilik’s group showed that mice with just one copy of TRIM28 developed into two distinct body types (2,3).

In fact, when they examined the mice in this new study, Pospisilik was not surprised to see them separate into two groups: One had a “heavy” body morphology due to an accelerated growth pattern, and the other had a “light” composition with a more gradual growth pattern.

“These animals behave differently,” he said. “They're on a different developmental trajectory. Probably every single thing about their body is a little bit different.”

This is pretty unique because [the mice] might have the exact same mutation, but nonetheless, they are developing into two very distinct populations.
- Ilaria Panzeri, Van Andel Institute

When the researchers examined the DNA methylation profiles of the mice early in life — before they developed into the “light” or “heavy” groups — they saw two distinct methylation signatures that correlated with the “heavy” and “light” phenotypes. Mice in the cancer-prone “light” group had less methylation at certain genes compared to the “heavy” mice. Many hypomethylated genes in the “light” mice are known human oncogenes that reduce overall survival when mutated in people with cancer.

“What's cool about this paper,” Lu said, was the group's ability to “track the phenotypic behavior changes to the initial epigenetic changes.”

Pospisilik and his team plan to continue exploring the nuanced epigenetic regulatory mechanisms at play in the context of cancer. They hope that their research will offer insight into cancer risk assessment and improving clinical outcomes for at-risk individuals.

“TRIM28 causes a stable, predictable developmental bifurcation in these mice,” Pospisilik said. “If this kind of developmental stability exists in humans, it probably impacts everything.” 

References

1. Panzeri, I. et al. TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states. Nat Cancer  6, 385–403 (2025). 
2. Whitelaw, N.C. et al. Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise. Genome Biol  11, R111 (2010).
3. Dalgaard, K. et al. Trim28 haploinsufficiency triggers bi-stable epigenetic obesity. Cell  164, 353–364 (2016).