Johns Hopkins Medicine scientists report discovering a pattern of epigenetic "marks" in pancreatic cells transitioning between normal and cancerous states in mice. These normal cells can temporarily "remember" cancer-linked epigenetic changes without genetic mutations.

Epigenetic marks are chemical modifications that regulate gene expression without altering the DNA sequence — acting like software programming over the genetic hardware. The study, published March 28 in Genome Medicine and funded by the NIH, offers new insights into how inflammation and cellular damage push normal cells toward cancer.

“Epigenetic changes have long been suspected in the early stages of cancer," says Andrew Feinberg, M.D., Bloomberg Distinguished Professor at Johns Hopkins. "Our work shows cells can acquire a hybrid identity — a pre-cancerous state — without mutations, just through inflammation or damage."

Normally, inflamed pancreatic acinar cells, which secrete digestive enzymes, shift toward ductal cells that carry digestive juices — a protective response. Because the epigenome controls cell identity, Feinberg and co-leader Patrick Cahan, Ph.D., studied these transitioning mouse cells.

Their team, including first author Emily Lo, sequenced the genome of cells undergoing acinar-to-ductal metaplasia. They found epigenetic marks — but no DNA mutations — on pancreatic cancer-linked genes like PI3K and R/R/C GTPase. Previously, similar epigenetic changes were seen in human precancerous lesions caused by KRAS mutations. Yet here, in mice, these cancer-like marks appeared without any mutation.

Notably, when cells reverted to their acinar identity, they retained some cancer-linked epigenetic marks for at least seven days, suggesting a lingering "memory" that may heighten cancer risk over time.

"This work shows epigenetic memory can drive early cancer changes even without genetic mutations," says Feinberg. Cahan adds that this transitional state likely evolved as a protective response against inflammation but could inadvertently pave the way to cancer.

Feinberg further speculates that such epigenetic memory might help explain rising cancer rates in young people, who typically have fewer age-related genetic mutations.

Source: https://www.hopkinsmedicine.org/news/newsroom/news-releases/2025/04/pancreatic-cells-remember-epigenetic-precancerous-marks-without-genetic-sequence-mutations