Chronic inflammation leaves epigenetic scars that increase future cancer risk

Chronic inflammation can raise a person's risk of cancer, and a new study reveals key details about how that might happen in the gut and points to better ways to identify and reduce risk.

Scientists at the Broad Institute and Harvard University have revealed in mice that after colitis, or chronic intestinal inflammation, seemingly healed gut tissues may retain the memory of earlier inflammation through molecular "scars" that make it easier for cancer to take hold later on. These memories are encoded as changes in the epigenome that are handed down from cell to cell through many generations of cell division, with long-lasting effects on gene activity that can later drive tumor growth.

Appearing in Nature, the work suggests a two-hit process over time in which alterations in the genome - an epigenetic change and a cancer mutation - can accelerate tumor growth. It also points to ways to potentially identify and possibly intervene on these cancer-promoting factors with new biomarkers and therapeutics.

"This finding is a great example of how our experiences and exposures affect our future health," said study senior author Jason Buenrostro, a Broad core member, professor at Harvard University in the Department of Stem Cell and Regenerative Biology, leader of the Biology of Adversity Project at the Broad, and a co-investigator on the Cancer Grand Challenges team PROSPECT. "We've shown that epigenetic changes are the missing piece in how inflammation leads to cancer."

Scars in the epigenome

Colorectal cancer has risen dramatically among younger people in recent decades, pointing to shifts in diet, lifestyle, or exposure to toxins that may be increasing risk rather than changes to heritable genetic variation, which can take thousands of years to arise.

"These factors are transient - your diet in adolescence is not your diet now, but it can affect your cancer risk over a lifetime," said study first author Surya Nagaraja, a postdoctoral researcher in the Buenrostro lab, a pathology fellow at Massachusetts General Hospital, and a member of team PROSPECT.

In the new study, the researchers focused on chronic inflammation, one of the biggest risk factors for cancer across tissues. In an animal model, the researchers triggered inflammation in the gut and then observed changes to cells in the colon.

The researchers developed a method to measure several things at once in individual cells: the transcriptional state, or which genes are being expressed; the epigenomic state, or what parts of the genome are accessible so that genes in those regions can be turned on or off; and the clonal history, which reveals a cell's family tree.

Even after the inflammation subsided and tissues appeared healed, the team observed that some cells retained a long-lasting epigenetic memory of the exposure, with certain DNA sites remaining open and accessible even as gene expression returned to normal.

When the scientists later introduced a cancer-promoting mutation, the tissues with epigenetic memory developed larger tumors that grew faster than those in tissues without prior inflammation. The tissues did so by activating sets of genes that contributed to cancer growth and were made more accessible - and hence more easily regulated - through memory of inflammation.

The study concludes that this epigenetic memory is the first of a "one-two punch" that can persist for life, allowing a later mutation to kickstart tumor growth. The team discovered that stem cells with the strongest epigenetic memory passed those changes on to their "daughter" cells, creating whole families of cells primed for cancer.

In the epigenome, we see this long-lived, robust effect, just waiting for its chance to affect gene expression, and we needed to look at the epigenetic layer in order to see these effects." 

Jason Buenrostro, a Broad core member, professor at Harvard University in the Department of Stem Cell and Regenerative Biology

He added that the group's findings could lead to a rethinking of how cancer arises. "We all walk around with cancer-related mutations, but we don't all have cancer. It's not just the genetic mutation that matters - the cell type and the experiences that cell has will determine disease outcomes."

The researchers are exploring whether these molecular scars can be spotted in human stool samples to identify individuals at increased risk. These new clues could also open the door to future treatments that target and correct the underlying mechanism.

"Team PROSPECT is working to uncover important insights into the rising global incidence of colorectal cancer in younger adults. If validated in humans, these latest findings suggest that chronic inflammation earlier in life could affect a person's risk of colon cancer decades later. Importantly, the discovery could help us understand who is most at risk and inform new approaches to prevent or intercept the disease at an earlier stage. It is a powerful example of the kinds of breakthroughs Cancer Grand Challenges was designed to achieve," said David Scott, Director, Cancer Grand Challenges.

The study is part of the team PROSPECT, an international research team investigating the global rise of colorectal cancers in younger adults led by Andy Chan and Yin Chao. PROSPECT is part of Cancer Grand Challenges, a global research initiative that identifies the toughest challenges in cancer research and empowers global, interdisciplinary teams to take them on. Through Cancer Grand Challenges, team PROSPECT is funded by Cancer Research UK, the US National Cancer Institute, the Bowelbabe Fund for Cancer Research UK and the French National Cancer Institute.