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Open Access Understanding how an MLH1 promoter polymorphism predisposes to colorectal cancer - MRC

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Colorectal cancer affects 1 in 20 people in the western world. Mutations that cause colorectal cancer can be inherited or, more often, acquired during a patient's lifetime. There are also some common genetic variants (small differences found in the DNA of many people) that can increase their risk of cancer by a small percentage. These variants usually do not have a big effect on the gene, but may influence how active the gene is in particular cells. One such colorectal cancer risk variant is found near the MLH1 gene. MLH1 is disrupted in about 15% of colorectal cancers, but instead of mutations in its DNA, it is repressed by acquired chemical marks on the DNA (called DNA methylation or epimutation). The common variant near MLH1 is strongly linked to increased DNA methylation and MLH1 gene repression, but we do not yet understand exactly how and why this leads to a higher risk of this specific type of colorectal cancer. The main aim of this project is to answer these questions.

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.
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Document Type: Research Article

Publication date: October 15, 2018

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