Epigenetic marks—chemical modifications that regulate gene expression without altering the DNA sequence—are often compared to software programming layered on the genetic code’s hardware. These marks play a critical role in defining a cell’s identity and function.

New research from Johns Hopkins Medicine, published March 28 in Genome Medicine and funded by the National Institutes of Health, sheds light on how normal cells begin to transition into cancer cells. The study highlights the role of inflammation and cellular stress in driving this change, even in the absence of genetic mutations.

Epigenetic changes have long been linked to cancer progression, says Dr. Andrew Feinberg, Bloomberg Distinguished Professor at Johns Hopkins. Our findings show that cellular transformation begins with an altered or hybrid identity—often triggered by inflammation or damage—that can predispose cells to cancer, even without mutations that typically drive the disease.

In the pancreas, inflammation prompts acinar cells  to convert into ductal cells (which transport digestive fluids)—a process known as acinar-to-ductal metaplasia. This shift serves as a protective mechanism but also initiates epigenetic reprogramming.

Feinberg and co-lead investigator Dr. Patrick Cahan, associate professor of biomedical engineering at Johns Hopkins, studied this transformation in mouse pancreatic cells. Their team, including first author Emily Lo, sequenced the genomes of cells undergoing this change. They discovered epigenetic marks on cancer-associated genes—such as PI3K and R/R/C GTPase families—even though no mutations were present in the DNA.

Notably, these same epigenetic marks had previously been found in human pancreatic precancer lesions (PanINs) driven by KRAS mutations. Yet, in this mouse model, the marks appeared without such mutations, suggesting that cells in transition can acquire precancerous epigenetic features independently of genetic alterations.

Remarkably, even after the cells reverted to their original acinar identity, some of these cancer-linked epigenetic marks persisted for at least seven days—evidence of an epigenetic memory.

This study highlights the importance of epigenetic memory in cancer development—even in the absence of genetic mutations, Feinberg explains.

Cahan adds, This transition state may be a normal defense mechanism against inflammatory stress, but it could also create vulnerabilities that lead to cancer.

Feinberg suggests that further research into these epigenetic shifts could help explain rising cancer rates in younger populations, who may not yet carry age-related genetic mutations but still experience environmental or inflammatory stressors that trigger precancerous changes.

Source: https://www.bme.jhu.edu/news-events/news/pancreatic-cells-remember-epigenetic-precancerous-marks-without-genetic-sequence-mutations/