Epigenetic changes from colitis may increase colorectal cancer risk

Epigenetic changes in colon cells caused by colitis can increase susceptibility to developing colorectal cancer in the future.

Chronic gut inflammation (colitis) is known to increase the risk of bowel cancer, but the underlying biological mechanism has remained unclear. Researchers at the Broad Institute and Harvard University – both in Cambridge, Massachusetts – used a mouse model to show that colon cells retain an epigenetic memory of past inflammation. Epigenetic changes are chemical and structural modifications to DNA, which influence how easily genes are activated without altering the DNA sequence. After a cancer-driving mutation was introduced in the animals, previously inflamed tissues formed more aggressive tumours compared to those with no prior inflammation.

Professor Jason Buenrostro, senior author of this study and a professor of stem cell and regenerative biology at Harvard University, said: 'This finding is a great example of how our experiences and exposures affect our current health. We've shown that epigenetic changes are the missing piece in how inflammation leads to cancer.'

In this study, published in Nature, researchers induced colitis in mice and analysed over 52,000 cells for 'memory' signatures of chronic inflammation. They identified an epigenetic change in colonic stem cells that increased activity of the AP-1 transcription factor, which regulates cellular stress responses. This change persisted for over 100 days after the inflammation resolved and was passed on to new cells as the stem cells divided. When a cancer-causing mutation was introduced, mice that had recovered from colitis developed larger, faster-growing colorectal tumours than healthy control animals. Blocking AP-1 activity reduced tumour growth in previously inflamed tissue.

These results led the team to propose a 'one-two punch' model for colorectal cancer development. In this model, the epigenetic memory from prior inflammation represents the first 'hit', increasing AP-1 activity and creating a vulnerable cell population. A subsequent cancer-driving mutation provides the second 'hit', triggering tumour growth in this already susceptible group of cells.

Dr Anthony Letai, director of the National Cancer Institute, Bethesda, Maryland, who was not affiliated with this study, said: 'By spelling out how repeated cycles of injury in the gut may influence colorectal cancer risk, the authors have potentially opened avenues toward much-needed methods of early evaluation and therapy for a condition that is of increasing concern.'

This study is part of PROSPECT, an international effort investigating the rise of colorectal cancer in younger adults. Researchers are now exploring whether this epigenetic change can be detected in human stool samples, which could enable earlier identification of individuals at increased risk. In the longer term, the team hopes to develop therapies that target the epigenetic memory of colonic stem cells, offering a new strategy for preventing colorectal cancer.