Sanger WGS Study Tracks Genetic Changes in IBD Linked to Cancer

Sanger WGS Study Tracks Genetic Changes in IBD Linked to Cancer
Credit: sefa ozel/Getty Images

A new whole-genome sequencing (WGS) study offers clues about the development of colon cancer in patients with inflammatory bowel disease (IBD).  Researchers found the rate of DNA change in cells affected by IBD was more than double that in healthy cells. The study also found that IBD-associated chronic inflammation disrupts the colon’s tissue structure, allowing cells to expand over an abnormally wide area. The study, was published today (21 July) in Cell.

“Colorectal cancer is one of the main clinical concerns when treating patients with IBD,” said Tim Raine, one of the study’s authors, clinical lead for the inflammatory bowel disease (IBD) service at Addenbrooke’s Hospital in Cambridge, and Honorary Faculty member at the Wellcome Sanger Institute.  “In this study, 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.”

IBD primarily refers to ulcerative colitis and Crohn’s disease, chronic illnesses characterized by inflammation of the digestive system, which affect approximately 6.8 million people. The causes of the inflammation in these conditions remain unknown, and people suffering from IBD are at an increased risk of developing gastrointestinal cancers. As a result, they may undergo surveillance or have their entire colon removed as a preventive measure.

In this new study, Addenbrooke’s Hospital provided colon tissue samples from 46 IBD patients, along with anonymized information about their medical history and treatment. Researchers at the Wellcome Sanger Institute then used laser-capture microdissection to cut out tiny cavities, called crypts, from the colon tissue for WGS. Results were then compared to sequences from 412 crypts from 41 individuals without IBD.

The team found that there were more than twice as many DNA changes in the diseased tissue than in normal, and the longer the duration of the disease, the greater this excess.

The study also uncovered evidence of an evolutionary process whereby mutations in particular genes are under positive selection, meaning they are more likely to arise in these circumstances. Some of these positively-selected mutations were enriched in genes associated with colorectal cancers, shedding light on the link between IBD and certain malignancies. The researchers also detected evidence of positive selection of mutations in genes associated with immune system regulation in the gut and the ability of the cells to fend off the bacteria in the colon.

Sigurgeir Olafsson, first author of the study and a researcher at the Wellcome Sanger Institute, said: “How our bodies continue to evolve during our lifetime is a fundamental part of our biology. 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.”

Carl Anderson, senior author, and from the Wellcome Sanger Institute, said: “We know that DNA changes contribute to the development of cancer, but their role in common non-cancerous diseases like inflammatory bowel disease (IBD) has not been extensively studied. Our study revealed that somatic changes in the DNA sequence of the cells that line our gut may contribute to the development of IBD. I strongly believe 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.”