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

通过结肠隐窝动力学、体细胞突变及其在正常结直肠粘膜中的空间分布来定义结直肠癌的发展

• 批准号: MR/T027908/1
• 负责人: Kate Marks
• 金额: $ 51.22万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT027908%2F1
• 关键词: Defining; colorectal; cancer; development; through

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.

肠癌每年影响全球160万人，是英国第三大常见癌症，每年造成16，000人死亡。如果患者被诊断得更早，他们更有可能存活下来。更好的方法是首先了解肠癌是如何发展的，识别出那些风险最大的患者，并更早更频繁地进行筛查。然而，我们并不完全了解导致肠癌发展的所有事件，以及为什么有些患者会患上癌症，而另一些则不会。我们知道肠癌的生长是因为DNA密码发生了变化（突变）。这些突变是由许多因素引起的，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和积累。因此，了解正常肠道中的突变，它们积累的速度以及它们的局部影响是了解肿瘤生长的关键。通过了解这一过程，我们可能能够减少肠癌。本研究纳入的患者将是因肠癌接受手术的患者以及因癌症以外的其他原因接受手术的患者。我们会收集手术后剩下的多余组织。然后可以用化学染色剂处理这种肠组织，以便在显微镜下看到突变。将拍摄突变的数字照片，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因素如年龄、饮食、医疗条件、地理等而变化的。有很多问题我们想要探讨。首先，肠癌患者和非肠癌患者之间的突变是否存在差异？我们希望找到更多关于这些差异的细节，并确定可能导致这些差异的因素。其次，我们希望研究这些突变如何在整个肠道中传播。我们想看看突变是否聚集在一起，或者它们是否均匀分布，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组有关;生活在肠道中的细菌种群。整个肠道的微生物组可能不同，某些细菌可能聚集在不同的区域。通过研究突变模式，我们可能能够找到进一步的证据，他们与细菌的联系。第三，我们希望探索在英国的患者相比，来自世界各地的患者在突变的差异。我们知道，全球肠癌发病率差异的原因之一是由于饮食和生活方式的差异。我们的合作者来自世界各地的病理学实验室，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，以便我们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。我们希望我们的研究可以在未来用于调整肠癌筛查，以便某些更容易患肠癌的患者群体可以更早地进行筛查，并在非常早期和更可治疗的时候发现更多的癌症。

项目成果

Giant cell glioblastoma versus pleomorphic xanthroastrocytoma: a challenging case

巨细胞胶质母细胞瘤与多形性黄色星形细胞瘤：一个具有挑战性的病例

• DOI: 10.1016/j.mpdhp.2022.06.002
• 发表时间: 2022
• 期刊: Diagnostic Histopathology
• 作者: Marks K

A diffusion-like process enables expansion of advantaged gene mutations in human colonic epithelium

类似扩散的过程能够扩展人类结肠上皮中的有利基因突变

• DOI: 10.1101/2020.07.10.193748
• 发表时间: 2020
• 作者: Olpe C