A person’s lifetime risk for cancer may begin before they are even born, reports a paradigm-shifting study by Van Andel Institute scientists.
The findings, published in Nature Cancer, identified two distinct epigenetic states that arise during development and are linked to cancer risk. One of these states is associated with a lower lifetime risk while the other is associated with a higher lifetime risk.
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 J. Andrew Pospisilik, Ph.D., chair of VAI’s Department of Epigenetics and co-corresponding author of the study. “Our identification of these two epigenetically different states opens the door to an entirely new world of study into the underpinnings of cancer.”
Open Access Paper:
TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states
Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28 +/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.