Genetic approaches to combating colorectal cancer

Lead Research Organisation: University of Edinburgh

Abstract

Cancer of the large bowel is common, with 32,000 cases each year in the UK. Despite advances, most patients die from their disease as they present in the late stages of tumour progression. However, early detection offers real potential for curative treatment, including surgery. Hence identifying people with a high genetic risk of the disease affords the opportunity to introduce preventative measures as well as surveillance of the bowel for early tumours and even for benign precursors. Our work is focussed on understanding the causes of colorectal cancer and preventing it in the long term. This work is aimed at defining genes that predispose to tumours in the bowel and to use the information to target prevention and surveillance. The ultimate aim is reduction in the death rate from this frequently fatal disease.

Technical Summary

Objectives: To identify novel common low penetrance colorectal cancer susceptibility loci, including structural sequence variants. To build models to enable profiling of genetic and other risk in the general population for public health benefit. To identify novel rare high penetrance alleles, including structural sequence variants, responsible for colorectal cancer susceptibility. To define gene-environment interactions. To identify modifier alleles of known susceptibility alleles. To define the contribution of known genes predisposing to colorectal cancer in order to target clinical preventative measures including modifiable environmental risk factors. To determine the molecular mechanisms involved in the antitumour effect of aspirin and other NSAIDs to inform translational research in human chemoprevention.

Progress:

Colorectal Cancer susceptibility
We identified 10 new common colorectal cancer susceptibility loci through a genome-wide association (GWA) approach. We used Scottish GWA data to estimate the number of loci that would account for the entire genetic contribution to colorectal cancer and have estimated the number of loci required to provide 80% power to define genetic risk in the population. After fine mapping, we have undertaken molecular studies investigating the causal variants at a number of the associated loci we identified.

We continue to refine understanding of the role of defects in DNA mismatch repair genes in colorectal cancer susceptibility and establish gene prevalence and penetrance. This work led to ongoing translational research investigating the potential for primary and secondary prevention, including the first ever RCT. We have established the largest resource of DNA mismatch repair gene mutations and now embarked on a GWA approach to mapping genetic modifiers of Lynch Syndrome, the most colon dominant gene disorder predisposing to colorectal cancer.

Chemoprevention
We showed that aspirin modulates apoptotic response in colorectal cancer cells by a mechanism that is dependent on NF-kappaB transcription factor activation. We showed that aspirin induces signal-specific I-kappaB degradation and nuclear translocation of p65 in colorectal cancer cells. We engineered cells to constitutively express mutant IkappaB, resistant to phosphorylation and degradation and showed that these cells are resistant to aspirin induced NF-kappaB activation and to apoptosis.

We showed that sulindac, sulindac sulfone and indomethacin activate the NF-kappaB pathway in colorectal cancer cells and show that NSAIDs induce nucleolar translocation of the RelA subunit of NF-kappaB. Using RelA deleted for the previously described nucleolar localization signal, we demonstrated that this response is causally involved in the apoptotic effects of these agents. As well as providing new understanding of the molecular determinants of RelA function, these findings also have relevance to the development of novel chemotherapeutic and chemopreventative agents.

We have also shown that CDK4 inhibitors induce translocation of RelA/p65 from the cytoplasm to the nucleoplasm and then to the nucleolus. This was accompanied by a repression of NFkappaB-driven transcription and apoptosis of the cancer cells. When cells expressing this mutant protein were treated with the CDK4 inhibitor, RelA translocated from the cytoplasm to the nucleoplasm, but was excluded from the nucleolus. Furthermore, apoptosis induced by CDK4 inhibition RelA dependent. In this work we have further expanded understanding of the molecular mechanisms that regulate programmed cell death induced by disruption of the cyclin D1/CDK4 complex in colorectal cancer.

Our in vitro findings have been extended into clinical studies of patients with rectal cancer, showing that the p65 nuclear translocation induced by aspirin results in repression of NF-kappaB driven transcription by induction of repressive complexes.

Publications

10 25 50

 
Description Major contribution to UK national clinical guideline development - Member of the guideline development panel and steering committee - British Society of Gastroenterology guideline on inflammatory bowel disease - currently under review with Gut
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Major contribution to UK national clinical guideline development relevant to GI disorders - Member of the guideline development panel and steering committee Association of Coloproctology of GB and Ireland - Guideline on surgical management of inflammatory bowel disease
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description Member of guideline development panel and steering committee - British Society of Gastroenterology guideline on clinical management and surveillance of heritable GI cancer susceptibility syndromes.
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description EU COST Action BM1206. "Cooperation Studies on Inherited Susceptibility to Colorectal Cancer" 
Organisation August Pi i Sunyer Biomedical Research Institute
Country Spain 
Sector Academic/University 
PI Contribution We led/are leading several aspects of the discovery of the genetic contribution to colorectal cancer..
Collaborator Contribution They have provided samples and data to enable us to genotype and analyse whole genome data with phenotype data
Impact A number of papers. Hosted a meeting in Edinburgh. Attended collaborators meetings Forged and strengthened links with several European groups Shared data and samples
Start Year 2014
 
Description EU COST Action BM1206. "Cooperation Studies on Inherited Susceptibility to Colorectal Cancer" 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution We led/are leading several aspects of the discovery of the genetic contribution to colorectal cancer..
Collaborator Contribution They have provided samples and data to enable us to genotype and analyse whole genome data with phenotype data
Impact A number of papers. Hosted a meeting in Edinburgh. Attended collaborators meetings Forged and strengthened links with several European groups Shared data and samples
Start Year 2014
 
Description EU COST Action BM1206. "Cooperation Studies on Inherited Susceptibility to Colorectal Cancer" 
Organisation University of Oxford
Department Department of Physiology, Anatomy and Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution We led/are leading several aspects of the discovery of the genetic contribution to colorectal cancer..
Collaborator Contribution They have provided samples and data to enable us to genotype and analyse whole genome data with phenotype data
Impact A number of papers. Hosted a meeting in Edinburgh. Attended collaborators meetings Forged and strengthened links with several European groups Shared data and samples
Start Year 2014
 
Description MOMA Consortium 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Initiated and Lead. Conduct all wet lab and analysis.
Collaborator Contribution Assembling a very large data and sample set is essential for this work. The consortium has enabled this.
Impact Assembled the largest ever biological and data resource of DNA mismatch repair gene carriers. Enabling study of genetic modifiers of colorectal cancer risk in HNPCC (Lynch Syndrome) and will be applicable to sporadic colorectal cancer risk in the general population.
Start Year 2007
 
Description MOMA Consortium 
Organisation University of Barcelona
Country Spain 
Sector Academic/University 
PI Contribution Initiated and Lead. Conduct all wet lab and analysis.
Collaborator Contribution Assembling a very large data and sample set is essential for this work. The consortium has enabled this.
Impact Assembled the largest ever biological and data resource of DNA mismatch repair gene carriers. Enabling study of genetic modifiers of colorectal cancer risk in HNPCC (Lynch Syndrome) and will be applicable to sporadic colorectal cancer risk in the general population.
Start Year 2007
 
Description MOMA Consortium 
Organisation University of Melbourne
Country Australia 
Sector Academic/University 
PI Contribution Initiated and Lead. Conduct all wet lab and analysis.
Collaborator Contribution Assembling a very large data and sample set is essential for this work. The consortium has enabled this.
Impact Assembled the largest ever biological and data resource of DNA mismatch repair gene carriers. Enabling study of genetic modifiers of colorectal cancer risk in HNPCC (Lynch Syndrome) and will be applicable to sporadic colorectal cancer risk in the general population.
Start Year 2007
 
Description Presented and participated at the Lynch Syndrome information day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Lynch Syndrome education for patients and their carers
Year(s) Of Engagement Activity 2017