Understanding how an MLH1 promoter polymorphism predisposes to colorectal cancer - MRC
We will work out how the common genetic variant near MLH1 causes different risks of MLH1 repression. We think that 1) the high risk variant binds to proteins that cause DNA methylation and that this represses MLH1 activity, or 2) the high risk variant disrupts the binding of proteins necessary to keep MLH1 active, reducing MLH1 expression and allowing methylation to spread across the DNA causing further reduction in expression, or 3) the high risk variant just affects the binding of activating proteins and that the less active gene is more easily silenced by DNA methylation than occurs by chance.
We will test these alternatives by
1) studying the genetic variant and MLH1 methylation and repression in a large number of patients with colorectal tumours
2) using cell lines to look for proteins which bind the DNA preferentially on one of the variants, and to study how MLH1 methylation and repression occur over time
3) finding out how the genetic variant influences cancer growth in mouse models of the human disease
The knowledge from these studies will help us to understand the effects of MLH1 disruption on tumours and ultimately provide information to help with patient diagnosis, prognosis and therapy. New treatments which remove methylation in tumours are being developed, and our findings, and the cell and mice models we create, should help to determine if and when these therapies could be used to treat colorectal cancer patients with MLH1 repression.
Document Type: Research Article
Publication date: October 15, 2018
Impact is a series of high-quality, open access and free to access science reports designed to enable the dissemination of research impact to key stakeholders. Communicating the impact and relevance of research projects across a large number of subjects in a content format that is easily accessible by an academic and stakeholder audience. The publication features content from the world's leading research councils, policy groups, universities and research projects. Impact is published under a CC-BY Creative Commons licence.
- Subscribe to this Title
- Terms & Conditions
- Disseminating research in Impact
- Information about Impact
- Ingenta Connect is not responsible for the content or availability of external websites