Uncovering the evolutionary history of IBD-associated colorectal cancer

Bethan Warman Posted in General News, Publications 11 July 2018

Photo credit: Graham Hodson

A team of researchers from the BCI, led by Prof Trevor Graham, Lead of the Evolution and Cancer Biology Laboratory, have reported the genetic events involved in the early development of bowel cancer in patients with inflammatory bowel disease (IBD). Such knowledge may be able to be exploited to design simple diagnostic tests to stratify patients with IBD at high risk of developing cancer.

IBD more than doubles an individual’s lifetime risk of developing bowel cancer, and the risk increases significantly if they have suffered with IBD for a sustained period of time. With this in mind, the study published yesterday in Gut- performed in collaboration with researchers from St Mark’s Hospital, led by Prof Ailsa Hart, and the University of Oxford, led by Prof Simon Leedham- set out to understand the genetics of how CRC develops in people with IBD.

Prof Graham said:

Predicting who with IBD is going to go on to develop bowel cancer is a big unmet need. 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. Here we have determined which genetic mutations tend to occur early in IBD-associated bowel cancer development. These mutations could form the basis of a simple diagnostic test for predicting who is at high risk.

The team has recently received funding from Cancer Research UK (CRUK) through the Early Detection funding stream to validate that these genetic indicators are indeed effective markers of cancer risk. This is in addition to ongoing support from Barts Charity to identify prognostic biomarkers for bowel cancer in other IBD patient groups.

Establishing a sequence of genetic events

The team looked at the genetic sequences of cancerous and non-cancerous tissue samples collected from patients with IBD-associated CRC. By comparing the sequences, the researchers were able to establish a timeline of events leading to the development of malignancy.

test tubeNotably, the analysis identified some genetic alterations that tended to occur early in the progression to cancer, such as changes to the ‘tumour suppressor’ protein known as p53. Changes to p53 that result in the alteration or loss of its function usually occur later in the development of bowel cancers that are not associated with IBD, highlighting some genetic differences between CRC cases that have developed from IBD and those that have not.

Changes in the number of copies of some chromosomes- the structures that carry our genetic information in the form of genes- were also common in the large majority of IBD-associated bowel cancer samples and accumulated early in their evolutionary timeline.

The team hopes that spotting these early genetic changes could be used as indicators to identify which patients with IBD are at immediate risk of bowel cancer, prompting close surveillance of the patient and permitting timely interception with the best treatment options. On the other hand, IBD sufferers not at risk of cancer development could be spared unnecessary worry.

Future directions

First author Dr Annie Baker said:

In this exciting research we studied how IBD-associated bowel cancer develops over time, identifying crucial genetic changes that occur either prior to or at the onset of malignancy. 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.

This research was supported by Crohn’s and Colitis UK, Barts Charity, the Bowel and Cancer Research Charity, CRUK, the Medical Research Council, the Derek Willoughby Fund for Inflammatory Research, UKRI Innovation/Rutherford Fund and the NIHR Oxford Biomedical Research Centre Programme.

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