Genetic Changes Specific to IBD-associated Colorectal Cancer May Help Identify High-risk Patients

Genetic Changes Specific to IBD-associated Colorectal Cancer May Help Identify High-risk Patients
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Newly discovered genetic alterations that precede the development of colorectal cancer associated with inflammatory bowel disease (IBD) may help in the development of diagnostic tools to identify patients at the highest risk of this cancer, researchers say.

Findings were published in the study, “Evolutionary history of human colitis-associated colorectal cancer,” in the journal Gut.

“These mutations could form the basis of a simple diagnostic test for predicting who is at high risk,” Trevor Graham, PhD, the study’s senior author and a professor at Barts Cancer Institute at Queen Mary University of London, said in a press release. “If we could do it accurately, it would allow us to target care to those who need it most, and spare low-risk individuals unnecessary worry.”

Patients with IBD — mainly Crohn’s disease and ulcerative colitis — have a more than two times greater risk of developing colorectal, or bowel, cancer. This risk is significantly increased in IBD patients with extensive disease, longer disease duration, and/or greater severity.

While these patients are intensively monitored for colorectal cancer, the rate of cancer diagnosis after a negative screening test is still up to 30 percent. Previous studies have shown that IBD-related and sporadic colorectal cancers have different molecular features, namely the frequency and timing of specific mutations.

However, many of these differences in genetic alterations, as well as their patterns, remain unknown. A greater understanding of these events could help in the development of biomarkers to predict the risk level of colorectal cancer, and of new targeted therapies.

Researchers at Queen Mary University of London, in collaboration with researchers at St Mark’s Hospital and University of Oxford, investigated the sequence of genetic changes that underlie the development of colorectal cancer in IBD patients.

They compared the genetic material of cancerous and noncancerous tissue samples from IBD patients with colorectal cancer, as well as cancerous tissue samples of patients with sporadic colorectal cancer.

A total of 16 genes were found to be significantly more frequently mutated in IBD-associated cancer than in sporadic cancer, suggesting they could be involved in the specific development of IBD-related cancer.

Some genetic alterations, such as in those in the tumor suppressor gene p53, occurred earlier in the development of IBD-associated colorectal cancer than in cases not connected with IBD.

These findings highlight the genetic differences between colorectal cancer cases that develop from IBD and those that don’t.

The team of researchers also found that many of the mutations potentially characteristic of IBD-associated colorectal cancer were shared with the surrounding noncancerous tissue.

This suggests that these mutations could be common early events in tumor formation, and that the apparently normal surrounding tissue already bears some degree of potentially harmful mutations.

Changes in the number of copies of some chromosomes — rod-like structures that carry the person’s genetic information — were found to progressively accumulate during cancer progression in IBD patients.

The data suggests that IBD-related colorectal cancers have an increased burden of genetic mutations and changes in chromosome copy number that occurs long before the formation of colorectal cancer.

Researchers noted that while chronic inflammation did not seem to cause the mutations, it potentially accelerates the accumulation of genetic alterations.

“Our findings have provided a strong foundation for future work, which will focus on how we can use this knowledge to improve how doctors assess, monitor and treat IBD patients in the clinic,” said Annie Baker, PhD, the study’s first author from Barts Cancer Institute.

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