Faster DNA Damage in IBD Underlies Higher Risk of Colorectal Cancer, Study Suggests

Faster DNA Damage in IBD Underlies Higher Risk of Colorectal Cancer, Study Suggests

A high rate of DNA damage in colon cells underlies the increased risk for colorectal cancer associated with inflammatory bowel disease (IBD), according to a recent study.

The study, “Somatic Evolution in Non-neoplastic IBD-Affected Colon,” was published in the journal Cell.

Somatic mutations — those acquired after birth, rather than being inherited — can contribute to cancer development, but their patterns, burden, and functional consequences in other diseases have been less frequently investigated.

In the study, researchers from the Wellcome Sanger Institute and Cambridge University Hospitals analyzed tissue from the colonic epithelium (cell layer that forms the lining of the colon) to investigate how somatic mutations arise and spread.

The colonic epithelium is organized into millions of folds called crypts, each containing a small population of continually-dividing and renewing stem cells.

The research team hypothesized that the cycles of inflammation, ulceration, and regeneration of the colon that occur over the course of IBD might increase DNA damage in these cells, leading to higher mutation rates. Understanding this process could provide insights into the relationship between IBD and colorectal cancer.

The team sequenced the genomes of 446 individual crypts from 46 IBD patients and compared their results to those of 412 crypts from 41 healthy people.

The researchers discovered that IBD-associated crypt cells contained over twice the number of somatic mutations as healthy tissue and that the number of mutations rose with the duration of IBD.

“We found that normal mutational processes that are operative in us all are accelerated in the IBD affected gut, leading to a more than two-fold increase in the rate at which some gut cells acquire mutations, and this underpins the increased cancer risk in IBD,” Tim Raine, PhD, a study author, said in a press release.

Roughly 80% of the increase in mutations — the mutation burden — came from alterations also found in healthy tissue. The researchers believe that the number of mutations increased during IBD progression due to the colon tissue needing to replace damaged cells more frequently.

Increased replication and a higher mutational rate might enable mutations to spread quickly throughout a greater region of the intestinal epithelia. This process places a positive selection pressure on cancer-associated mutations, the team suggested.

In fact, the researchers found several cancer-associated mutations under positive selection among the IBD samples analyzed. These included the tumor-suppressor genes ARID1A and FBXW7. Tumor suppressors act to limit cell division, preventing tumor development by holding cell growth in check. Mutations that disrupt a tumor suppressor’s function can lead to rapid cell growth, raising the risk of developing cancer.

The remaining mutational burden resulted from rarer mutational processes and/or from treatment. As an example, purine treatment is an established IBD therapy that reduces the amount of inflammatory immune cells by disrupting DNA synthesis; in the study, researchers attributed 150 mutations in 96 crypts from seven IBD patients to purine treatment.

“The role of somatic mutations in cancer susceptibility has long been appreciated,” said Peter Campbell, PhD, another study author. “It is exciting to see the methods that we and others have used to understand cancers now being applied to other common diseases. These approaches have given us unique insights into the effects of inflammatory bowel disease on the DNA sequence of the inflamed tissue.”

The team also discovered recurrent mutations in PIGR and ZC3H12A, two genes that, while unrelated to cancers, play important roles in immune system regulation within the gut.

PIGR, in particular, plays a role in fending off infection from bacteria found in the gut. The key feature of IBD is a debilitating immune reaction to one’s resident gut bacteria.

According to the team, the mutations detected appeared to remain relatively confined to regions near the crypts where they originated, and this may help explain why repeated flares of inflammation tend to affect the same patches of tissue in IBD, suggesting permanent changes to these areas.

“How our bodies continue to evolve during our lifetime is a fundamental part of our biology,” said Sigurgeir Olafsson, the study’s first author. “It has been fascinating to study the effect of a chronic disease on this process and uncover evidence that changes in the genetic sequence of gut cells could have a direct role in the onset of inflammatory bowel disease.”

Overall, the “results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis [development],” the team concluded.