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

肠癌每年影响全球160万人，是英国第三大常见癌症，每年导致1.6万人死亡。如果及早诊断，患者存活的可能性更大。更好的是首先了解肠癌是如何发展的，确定那些风险最大的患者，并更早、更频繁地对他们进行筛查。然而，我们并不完全了解导致肠癌发生的所有事件，以及为什么有些患者会患上癌症，而有些则不会。我们知道肠癌的发展是因为DNA编码发生了变化（突变）。这些突变是由许多因素引起的，比如饮食、吸烟、酒精、粪便中的细菌。我们还知道，在癌症开始生长之前，这些突变会在正常健康的肠道中发生并积累。因此，了解正常肠道中的突变、它们积累的速度和局部影响，是了解肿瘤生长原因的关键。通过了解这一过程，我们也许能够减少肠癌。本研究的患者包括接受肠癌手术的患者以及因癌症以外的其他原因接受手术的患者。我们将收集手术后留下的多余组织。这种肠道组织可以用化学染色剂处理，在显微镜下可以看到突变。这些突变的数码照片将被拍摄下来，计算机程序将告诉我们有关它们的信息。然后，我们可以看看突变是如何随着患者的年龄、饮食、医疗条件、地理等因素而变化的。我们想探索的问题有很多。首先，肠癌患者和非肠癌患者在基因突变方面有什么不同吗？我们希望找到这些差异的更多细节，并确定可能导致这些差异的因素。其次，我们想研究这些突变是如何在肠道中传播的。我们想看看突变是聚集在一起的还是均匀分布的以及它们在肠道右侧和左侧之间的分布是否不同。这是因为它们可能与微生物群有关；肠道菌群生活在肠道中的细菌群肠道内的微生物群可能不同，某些细菌可能聚集在不同的区域。通过研究突变模式，我们可能能够找到它们与细菌联系的进一步证据。第三，我们希望探索英国患者与来自世界各地不同地区的患者在突变方面的差异。我们知道，世界范围内肠癌发病率差异的原因之一是饮食和生活方式的差异。我们有来自世界各地病理实验室的合作者，包括越南、阿根廷、智利、南非和俄罗斯。他们将收集组织并将其发送到我们的研究中，这样我们就可以将英国队列的突变率与其他国家队列的突变率进行比较。这可能会让我们对世界范围内肠癌发病率的差异有所了解。我们希望我们的研究可以在未来用于肠癌筛查，这样某些更容易患肠癌的患者群体就可以更早地进行筛查，在早期发现更多的癌症，也更容易治疗。

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.