Is Lifetime Cancer Risk Established before Birth?

The results of a study in mice by Van Andel Institute (VAI) scientists suggest that a person’s lifetime risk for cancer may begin before they are even born. Headed by J. Andrew Pospisilik, PhD, chair of VAI’s department of epigenetics, the researchers identified in a mouse model two distinct epigenetic states that arise during development and are linked to cancer risk.

They found one of these states is associated with a lower lifetime risk while the other is associated with a higher lifetime risk. The results indicated that if cancer does develop in the lower risk state, it is more likely to be a liquid tumor, such as leukemia or lymphoma. If cancer develops in the higher risk state, it is more likely to be a solid tumor, such as lung or prostate cancer.

“Because most cancers occur later in life and are understood as diseases of mutation, or genetics, there hasn’t been a deep focus on how development might shape cancer risk. Our findings change that,” said Pospisilik. “Our identification of these two epigenetically different states open the door to an entirely new world of study into the underpinnings of cancer.”

Pospisilik is co-corresponding author of the team’s published paper in Nature Cancer, titled “TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states.” In their paper the team concluded, “…the provocative implication from our data is that individual cancer susceptibility may have as much to do with the epigenetic ‘background’ we are born with as it does with DNA mutation, external environment and cell of origin.”

Cancer risk increases as people age, thanks to an accumulation of DNA damage and other factors. But not every abnormal cell goes on to become cancer. “Cancer is triggered by oncogenic DNA mutations,” the authors wrote. “However, these mutations are also found at high rates in otherwise ‘healthy’ tissues, and not every mutation is oncogenic across all tissues.” This indicates that the oncogenic potential of DNA mutations is “…cell, tissue and temporal specific,” the authors continued. “The molecular basis of this context specificity comprises one of the biggest unanswered questions in cancer biology.”

In recent years, scientists have identified other influences, such as epigenetic errors, as additional contributors to cancer. Epigenetics are processes that affect how and when the instructions in DNA are carried out. Problems with epigenetics can derail cellular quality control processes, enabling sick cells to survive and spread. “Pioneering studies over the last decades have implicated epigenetic regulation as a key mediator of tumorigenesis,” the team further noted, suggesting that collective research data “…suggest that tumors can emerge as a result of epigenetic (dys) regulation.”

For their reported study Pospisilik and collaborators focused on TRIM28 (also known as KAP1), an epigenetic regulator that has an important role in heterochromatic gene silencing. “TRIM28 loss-of-function models have implicated the protein in cancer in a complex and tissue-specific manner,” the investigators noted. “TRIM28, however, is also a master regulator of organism-level developmental heterogeneity.”

 

Studying a unique mouse model of intrinsic developmental heterogeneity (Trim28^+/D9) the team found that animals with reduced levels of the gene Trim28 can have one of two patterns of epigenetic marks on cancer-related genes, despite being otherwise identical. These patterns are established during development, and the strength of the patterns determines which of the two cancer risk states occur. “We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility,” the authors noted. “We identify a signature of DNA hypomethylated genes, installed before weaning, that stratify mice for cancer susceptibility and outcome. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis, suggesting that, if conserved, this mode of action has the potential to impact a broad portion of the population.”

The team found evidence of the two epigenetic states throughout tissues in the body, which suggests that developmental epigenetic risk may be common across cancers. “Our data suggest that interindividual differences in early-life epigenome organization influence differential cancer development, prevalence and survival,” the team further stated. In the future, they plan to explore the effects of these two states in individual cancer type.

Ilaria Panzeri, PhD, a research scientist in the Pospisilik Lab and the study’s first and co-corresponding author, commented, “Everyone has some level of risk but, when cancer does arise, we tend to think of it just as bad luck. However, bad luck doesn’t fully explain why some people develop cancer and others don’t. Most importantly, bad luck cannot be targeted for treatment. Epigenetics, on the other hand, can be targeted. Our findings show that cancer’s roots may start during the sensitive period of development, offering a new perspective to study the disease and potential new options for diagnosis and treatment.”