Defining colorectal cancer development through colonic crypt dynamics, somatic mutations and their spatial distribution in normal colorectal mucosa

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Bowel cancer affects 1.6 million individuals globally every year and is the third most common cancer in the UK causing 16,000 deaths per year. Patients are more likely to survive if they are diagnosed earlier. Even better still is to understand how bowel cancer develops in the first place, identify those patients who have the greatest risk and screen them earlier and more often. However, we do not fully understand all the events that led up to bowel cancer developing and why some patients will develop cancer and others will not. We know that a bowel cancer grows because changes occur in the DNA code (mutations). These mutations are caused by many factors such as diet, smoking, alcohol, bacteria in stool. We also know that these mutations occur and accumulate in the normal healthy bowel before a cancer starts growing. Therefore understanding mutations in normal bowel, how quickly they accumulate and their local effects is key to understanding what causes tumours to grow in the first place. By understanding this process we may be able to reduce bowel cancer.Patients included in this study will be patients undergoing surgery for bowel cancer as well as patients who have surgery for other reasons other than cancer. We will collect spare tissue that is left over from their operation. This bowel tissue can then be treated with chemical stains that allow mutations to be seen under the microscope. Digital pictures will be taken of the mutations and a computer programme will tell us information about them. We can then look at how mutations vary with patient factors such as age, diet, medical conditions, geography etc.There are a number of questions we want to explore. Firstly, are there are any differences in mutations between patients with bowel cancer and those without? We hope to find out more detail about these differences and identify factors that could potentially be contributing to them.Secondly, we want to study how these mutations are spread throughout the bowel. We want to look at whether mutations cluster or if they are spread evenly and if they are spread differently between the right side of the bowel and the left side of the bowel. This is because they may be related to the microbiome; the populations of bacteria that live in the bowel. The microbiome can be different throughout the bowel and certain bacteria may cluster in different areas. By studying mutation patterns we might be able to find further evidence to their link with the bacteria.Thirdly we wish to explore differences in mutations from patients in the UK compared to patients from difference locations around the world. We know that one of the reasons for the differences in the rates of bowel cancer worldwide is due to differences in diet and lifestyle. We have collaborators from pathology laboratories worldwide in Vietnam, Argentina, Chile, South Africa and Russia. They will collect tissue and send it to be included in our study so that we can compare the mutation rates in the UK cohort to the mutation rates from the cohorts of other countries. This may shed some insight into the differences in the rates of bowel cancer worldwide.We hope that our research can be used in the future to adapt bowel cancer screening so that certain groups of patients who are more at risk of developing bowel cancer can be screened earlier and pick up more cancers when they are very early and more treatable.