Genetic approaches to combating colorectal cancer

对抗结直肠癌的遗传学方法

• 批准号: MC_UU_00007/1
• 负责人: Malcolm Dunlop
• 金额: $ 84.35万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00007%2F1
• 关键词: Genetic; approaches; combating; colorectal; cancer

Cancer of the large bowel, is a common and frequently fatal disease, affecting 43,000 people in the UK annually and causing ~16,000 deaths. Genes and environment both play a role in development of this cancer. Our research focuses on understanding the interplay of genes and environment on bowel cancer susceptibility and how these cause cancer at a molecular, cellular and whole-person level. We use state-of-the-art technologies to understand the complete picture of genetic and environmental effects on bowel cancer risk and find new genetic changes causally linked with cancer risk. This includes sequencing the entire genetic code (DNA) of human research subjects, and using genotyping arrays to tag parts of the human genetic makeup. We study the effects of these genetic variants in model systems from humans and animals. We aim to identify new ways to prevent cancers forming, and have begun clinical studies in humans to explore the beneficial effects of vitamin D on the lining of the human bowel. We are also able to change the genetic code in cells that we grow from the human bowel (intestinal organoids) using a system called “genome-editing”. This allows us to directly test the effects of genetic signals associated with cancer risk. We can also use genome editing approaches to reverse these effects and test the beneficial effects of drugs, and dietary components, on organoid and animal model systems. In future, we plan to test the effects of these agents in human studies. With our unique blend of discovery science, disease models and ability to translate laboratories findings to the clinic, we are extremely well-placed to make beneficial impact in human health in the field of a common cancer killer through early detection and cancer prevention.

大肠癌是一种常见且经常致命的疾病，每年影响英国43，000人，造成约16，000人死亡。基因和环境都在这种癌症的发展中发挥作用。我们的研究重点是了解基因和环境对肠癌易感性的相互作用，以及这些因素如何在分子，细胞和整个人水平上导致癌症。我们使用最先进的技术来了解遗传和环境对肠癌风险影响的全貌，并发现与癌症风险有因果关系的新遗传变化。这包括对人类研究对象的整个遗传密码（DNA）进行测序，并使用基因分型阵列标记人类遗传组成的部分。我们研究了这些遗传变异在人类和动物模型系统中的影响。我们的目标是找到预防癌症形成的新方法，并已开始在人类中进行临床研究，以探索维生素D对人类肠道内壁的有益影响。我们还能够使用一种称为“基因组编辑”的系统改变我们从人类肠道（肠道类器官）中生长的细胞中的遗传密码。这使我们能够直接测试与癌症风险相关的遗传信号的影响。我们还可以使用基因组编辑方法来逆转这些影响，并测试药物和饮食成分对类器官和动物模型系统的有益影响。未来，我们计划在人体研究中测试这些药物的效果。凭借我们独特的发现科学，疾病模型和将实验室发现转化为临床的能力，我们非常有能力通过早期检测和癌症预防在常见癌症杀手领域对人类健康产生有益的影响。

项目成果

Plasma N-glycans in colorectal cancer risk.

• DOI: 10.1038/s41598-018-26805-7
• 发表时间: 2018-06-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Doherty M;Theodoratou E;Walsh I;Adamczyk B;Stöckmann H;Agakov F;Timofeeva M;Trbojević-Akmačić I;Vučković F;Duffy F;McManus CA;Farrington SM;Dunlop MG;Perola M;Lauc G;Campbell H;Rudd PM
• 通讯作者: Rudd PM

Aspirin Rescues Wnt-Driven Stem-like Phenotype in Human Intestinal Organoids and Increases the Wnt Antagonist Dickkopf-1.

• DOI: 10.1016/j.jcmgh.2020.09.010
• 发表时间: 2021
• 期刊: Cellular and molecular gastroenterology and hepatology
• 影响因子: 7.2
• 作者: Dunbar K;Valanciute A;Lima ACS;Vinuela PF;Jamieson T;Rajasekaran V;Blackmur J;Ochocka-Fox AM;Guazzelli A;Cammareri P;Arends MJ;Sansom OJ;Myant KB;Farrington SM;Dunlop MG;Din FVN
• 通讯作者: Din FVN

Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

• DOI: 10.1101/809517
• 发表时间: 2019-10
• 期刊: bioRxiv
• 作者: Karen J Dunbar;A. Valanciuté;V. Rajasekaran;T. Jamieson;Paz Freile Vinuela;Ana Lima;J. Blackmur;Anna-Maria Ochocka-Fox;M. Arends;O. Sansom;K. Myant;S. Farrington;M. Dunlop;F. Din

Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis.

• DOI: 10.1038/s41416-020-01211-x
• 发表时间: 2021-03
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Culliford R;Cornish AJ;Law PJ;Farrington SM;Palin K;Jenkins MA;Casey G;Hoffmeister M;Brenner H;Chang-Claude J;Kirac I;Maughan T;Brezina S;Gsur A;Cheadle JP;Aaltonen LA;Dunlop MG;Houlston RS
• 通讯作者: Houlston RS