Breakthrough study reveals that cancer risk is set before birth

Cancer has long been considered a disease driven by genetic mutations, but new research suggests that your risk may be determined before birth. Scientists at the Van Andel Institute have uncovered evidence that developmental epigenetics—changes in how genes are regulated—may set the stage for cancer decades before it appears.

Their study, published in Nature Cancer, reveals that two distinct epigenetic states emerge during development, influencing lifetime cancer risk.

One of these states is associated with a lower likelihood of cancer, while the other increases the chances of developing the disease. The type of cancer that forms also varies between these states.

People with the lower-risk state are more likely to develop blood cancers, such as leukemia or lymphoma. Those with the higher-risk state face a greater chance of developing solid tumors, including lung or prostate cancer.

“Our findings change the way we think about cancer risk,” said J. Andrew Pospisilik, Ph.D., chair of the institute’s Department of Epigenetics and a co-corresponding author of the study. “Most research focuses on mutations that accumulate over time, but our study shows that cancer susceptibility may be hardwired in early development.”

DNA mutations play a role in cancer, but many of these mutations exist in healthy tissues without leading to disease. What determines whether a mutation turns cancerous depends on the molecular environment surrounding it—an environment shaped by epigenetic regulation.

Epigenetics refers to chemical modifications to DNA that influence how genes are expressed without altering the genetic code itself. These modifications control when and where genes are turned on or off, guiding cell development and function. Disruptions in these processes can lead to disease, including cancer.

Epigenetic changes occur throughout life, but the most critical period is during early development. Small variations in epigenetic patterns, even among genetically identical individuals, can lead to significant differences in traits.

For instance, monozygotic twins often show subtle differences in appearance and health, despite sharing the same DNA. This phenomenon, known as intrinsic developmental heterogeneity, is driven by random fluctuations in epigenetic programming.

The Van Andel Institute study provides the first experimental proof that this variability influences cancer risk. Researchers used a mouse model with a specific genetic alteration in the Trim28 gene, which regulates epigenetic silencing. Mice with this alteration developed one of two distinct epigenetic patterns before birth. These patterns persisted into adulthood and influenced when, how, and what type of cancer developed.

“We often attribute cancer to bad luck,” said Ilaria Panzeri, Ph.D., the study’s first and co-corresponding author. “But bad luck alone doesn’t explain why some people develop cancer while others don’t. Our findings suggest that developmental epigenetics could be a major factor—and, unlike luck, epigenetics can be studied and potentially targeted for treatment.”

The Trim28 gene plays a crucial role in maintaining stable gene expression patterns across generations. In the study, mice with reduced Trim28 expression developed two distinct cancer risk states, despite having the same genetic code and being raised in identical environments. This provided a rare opportunity to isolate the effects of epigenetic variability from genetic and environmental influences.

The researchers discovered that these two risk states were linked to differences in DNA methylation—a key epigenetic mechanism that silences genes. Mice in the high-risk group showed lower levels of methylation in certain cancer-related genes, leaving them more vulnerable to abnormal growth. These same genes are frequently mutated in human cancers and are associated with poor survival outcomes.

Importantly, these epigenetic differences were established early in life, before external factors like diet, exposure to toxins, or aging could influence cancer susceptibility. This suggests that an individual’s cancer risk may be predetermined during fetal development, challenging conventional models that focus on lifestyle and environmental factors.

The discovery of developmentally programmed cancer risk has profound implications. If similar epigenetic patterns exist in humans, researchers could develop new early detection methods and preventive treatments.

“Understanding these early epigenetic states gives us a new angle to study cancer,” Pospisilik said. “If we can identify people who are in a higher-risk state before cancer develops, we could intervene earlier and improve outcomes.”

Future research will focus on identifying biomarkers that distinguish these epigenetic states in humans. If scientists can detect these differences in newborns, it may be possible to tailor preventive strategies, such as personalized screening plans or early lifestyle interventions, to reduce cancer risk before it manifests.

The study also highlights the potential for epigenetic therapies. Unlike genetic mutations, which are permanent, epigenetic modifications can sometimes be reversed. Drugs that target DNA methylation patterns are already being explored as treatments for certain cancers. Understanding how these patterns form in early development could open the door to new, more effective therapies.

The Van Andel Institute team plans to investigate whether these epigenetic risk states are universal across different types of cancer or specific to certain tissues. By mapping out the full extent of developmental epigenetic variation, they hope to uncover new ways to predict and prevent cancer before it begins.

This research challenges the long-held belief that cancer is purely a disease of genetic mutation and environmental exposure. Instead, it suggests that the seeds of cancer may be sown before birth, hidden in the molecular blueprint that shapes every person’s development.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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