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Inflammatory Bowel Disease Study Points to Role For Somatic Colon Mutations

NEW YORK – A team from the UK and the Netherlands has identified recurrent somatic mutations in gut samples that appear to be linked to non-neoplastic cases of inflammatory bowel disease (IBD) that do not progress to cancer.

"Our study revealed that somatic changes in the DNA sequence of the cells that line our gut may contribute to the development of IBD," co-senior author Carl Anderson, a researcher at the Wellcome Trust Sanger Institute, said in a statement.

As they reported in a paper published in Cell on Tuesday, the researchers used whole-genome sequencing to characterize mutations and copy number changes in almost 450 colonic "crypts" — in-pockets of epithelial tissue reaching into the colon — from 46 individuals with ulcerative colitis or Crohn's disease. They found that the IBD samples contained more than twice as many somatic mutations, on average, as those detected using more than 400 colonic crypt samples collected from 41 unaffected individuals for a prior study.

Along with recurrently mutated genes, clonal expansion events, and mutational signatures in the IBD samples, the team reported, the results pointed to a model for somatic mutation involvement in ulcerative colitis and Crohn's disease, which are marked by intermittent bursts of inflammation and ulceration.  

Moreover, Anderson noted, the findings highlight the possibility that "studying somatic mutations in all common diseases, not just IBD and cancers, has the potential to provide novel insights into disease biology and highlight potential drug targets."

While recent studies have started to reveal the extent to which somatic mutations, and evolution of these mutations, may occur in normal tissues, the team noted, less is known about potential somatic contributions to non-cancerous traits and diseases.

"In the setting of non-neoplastic diseases, chronic liver disease has had the most attention, with studies showing that compared to healthy liver, hepatic cirrhosis is associated with acquisition of new mutational processes, increased mutation burden, and larger clonal expansions," the authors wrote.

They reasoned that similar alterations could occur in IBD, owing to the tissue regeneration that occurs after bouts of ulceration and inflammation that characterize the conditions.

To explore that possibility, the team sequenced the genomes of 446 crypt sample biopsies obtained from 28 ulcerative colitis cases and 18 cases of Crohn's disease by laser capture dissection, which it compared to 412 crypt samples from 41 IBD-free individuals. They then searched for somatic substitutions, small insertions or deletions, and larger copy number changes or chromosomal alterations.

The researchers analyzed mutations in the colonic crypts in combination with information on IBD patients' age, the location of the tissue samples biopsied from the gut, and the extent of disease. Their search highlighted non-synonymous alterations affecting genes such as ARID1A, FBXW7, PIGR, ZC3H12A, and genes from the interleukin 17 and the Toll-like receptor pathways.

Along with more extensive clonal expansions involving somatic mutations in samples from the IBD-affected individuals, the team noted that mutations tended to occur in genes that appear to be subject to positive selection in individuals with IBD.

From these and other results, the authors proposed a model in which "recurrent cycles of inflammation, ulceration, and regeneration seen in IBD could impact the mutational and clonal structure of the intestinal epithelial cells."

"These approaches have given us unique insights into the effects of inflammatory bowel disease on the DNA sequence of the inflamed tissue," co-senior author Peter Campbell, also with the Wellcome Sanger Institute, said in a statement. He noted that the findings point to the possibility of using somatic alteration clues to understand IBD and other common diseases beyond cancer.

"It is exciting to see the methods that we and others have used to understand cancers now being applied to other common diseases," he said.