Investigating the function of common genetic variants that increase colorectal cancer risk.

Over 1 in 20 people in the UK will be diagnosed with colorectal cancer (CRC) during their lifetime. Much of this risk is genetically inherited with estimates ranging from 12 to 40%. Known cancer syndromes with rare but highly penetrant mutations can account for around 5% of this risk. However, there are over 100 common genetic variants that are also associated with an increased CRC risk. These variants are usually just a single DNA nucleotide and can exist in a large proportion of the population. Most variants lie outside protein coding regions of the DNA and may regulate the level of expression of target genes.

In this project, the student will investigate two regions on human chromosome 11 recently associated with CRC risk. Variant cluster 1 lies in an intron of the DNA Polymerase Delta 3, accessory Subunit (POLD3) gene. POLD3 has no characterised role in CRC but forms part of the DNA replication and repair pathway, key to cancer predisposition and development. Variant cluster 2 lies within the chordin like 2 gene (CHRDL2). CHRDL2’s intestinal function is unknown, although it is part of the bone morphogenetic protein (BMP) pathway, which is critical for intestinal development, homeostasis and frequently disrupted in CRC. Thus both these genes are excellent targets for regulation by the risk variants on chromosome 11, but have unknown roles in CRC.

The project will have two main aims: to determine the gene regulation mechanism by which the variants modify POLD3 or CHRDL2 expression, and to investigate the role of POLD3 and CHRDL2 in colorectal cancer development. The student will need to investigate epigenetic marks and gene regulatory elements close to the variants, which the variant disrupts. They will also need to create and analyse model systems to test the effect of POLD3 and CHRDL2 on intestinal cancer development. The findings from this project could have implications for CRC screening, diagnosis, and identification of novel drug targets.

References:

Law, P. J. et al. Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nat Commun 10, 2154, doi:10.1038/s41467-019-09775-w (2019).

How to apply

If you are interested in applying for the above PhD topic please follow the steps below:

1. Contact the supervisor by email or phone to discuss your interest and find out if you would be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
2. Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
3. Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.

Good luck!

This is a self funded topic

Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: https://www.brunel.ac.uk/research/Research-degrees/Research-degree-funding. The UK Government is also offering Doctoral Student Loans for eligible students, and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.

Meet the Supervisor(s)

Annabelle Lewis - I am a lecturer in biomedical sciences and run a research laboratory. My research interest is cancer genetics and gene regulation, focusing on colorectal cancer. We use cell lines and animal models to study how common variants in the human genome affect the expression of key cancer genes, and increase the risk of an individual developing cancer.