Investigating variations in two genes that increase the risk of bowel cancer

Our project investigates how variations in two genes increase the risk of bowel cancer.

Understanding the many genetic mutations and cellular changes that cause bowel cancer will advance bowel cancer research and help develop better and more personalised treatments and screening.

The role of genetic variations in bowel cancer

Small variations in our DNA can change our risk of developing colon cancer.

In this project, we have investigated two genes affected by this type of variation called CHRDL2 and POLD3.

Little was previously known about the role of these genes in cancer development. In our research, we are using modified cancer cell lines and intestinal organoids to examine what happens to cancer characteristics when we turn these genes up and down.

The need for personalised bowel cancer treatments

Bowel cancer is the fourth most common cancer in the UK, with almost 44,000 people in the UK being diagnosed every year.

If diagnosed at an early stage, bowel cancer can be successfully treated, but the survival trends for patients diagnosed at advanced stages are still poor.

Better and more personalised treatments and a better understanding of how patients respond to particular treatments are needed.

In order to develop personalised treatments, we first need to understand the many genetic mutations and cellular changes that drive bowel cancer development.

We want to contribute to this knowledge by studying variations in two genes that have been shown to statistically increase the risk of bowel cancer.

Our research project

Previous studies on these two genes in bowel cancer have simply looked to see how they correlate with cancer risk and prognosis.

We aim to use model systems to disrupt these genes and measure the changes this causes in the cells: how they grow, move and their sensitivity to drug treatments.

We will use traditional cell culture but also intestinal organoids - mini guts that can be grown in the laboratory that replicate a human intestine.

We wish to investigate in detail:

1. The effect of modifying POLD3 and CHRDL2 on bowel cancer cells including their growth, migration, and response to chemo/radiotherapy.

2. The effect of CHRDL2 overexpression on stem cell characteristics.

3. The effect of POLD3 loss on telomere maintenance. Telomeres are regions of repetitive DNA sequences at the end of a chromosome, which protect the ends of chromosomes from becoming frayed or tangled. We are carrying out the above investigations using standard cell line models as well as intestinal organoids.

We are also carrying out additional investigations on the mechanisms by which the DNA variants affect the expression of CHRDL2 and POLD3. Do they increase the expression of the genes, change the ratio of different versions of the proteins, or modify the DNA around the genes to influence their expression?