Mutational Processes in Genomic and Exonic DNA in Colorectal Cancer
Primary Supervisor: Professor Ian Tomlinson
Second Supervisor: Dr Joe Ward
Project Overview
Mutation signatures are a powerful tool in cancer genomics, providing insight into the underlying mechanism(s) that underpin specific mutational processes. Examples of this include the TCT>TAT mutations that underpin SBS10a (https://cancer.sanger.ac.uk/signatures/sbs/sbs10a/), which is found in cancers with DNA polymerase epsilon (POLE) exonuclease domain mutations.
A significant proportion of the previously described single-base substitution (SBS) mutation signatures have no definitive underlying aetiology, while the mutation signatures extracted from whole-genome versus whole-exome sequencing reveal potentially important differences in mutation channels and mechanisms.
In this project, we seek to assess the differences in the mutation profile of colorectal cancers in genomic and exonic DNA, using data available in the UK 100,000 Genomes Project. From this data, we aim to identify unique mechanisms of mutation between distinct regions of the genome, providing insight into tumour biology and cancer evolution. The project aims to also address the differing mutational processes in mismatch repair-proficient and mismatch repair-deficient cancers, where the differences between genomic and exonic DNA may be more apparent.
Training Opportunities
This project provides an excellent training environment. The student will gain hands-on experience in:
- Mutation signature extraction from genomic sequencing data
- Use of large whole-genome sequencing datasets (including the UK 100,000 Genomes Project)
- Coding skills, primarily using C++ and R
References
Alexandrov, L.B., Nik-Zainal, S., Wedge, D.C., Aparicio, S.A., Behjati, S., Biankin, A.V., Bignell, G.R., Bolli, N., Borg, A., Børresen-Dale, A.L. and Boyault, S., 2013. Signatures of mutational processes in human cancer. nature, 500(7463), pp.415-421. https://www.nature.com/articles/nature12477
Cornish, A.J., Gruber, A.J., Kinnersley, B., Chubb, D., Frangou, A., Caravagna, G., Noyvert, B., Lakatos, E., Wood, H.M., Thorn, S. and Culliford, R., 2024. The genomic landscape of 2,023 colorectal cancers. Nature, 633(8028), pp.127-136. https://www.nature.com/articles/s41586-024-07747-9
Ward, J.C., Soriano, I., Thorn, S., Fernández-Tajes, J., Sherwood, K., Gül, G., Scheffers, J., Frangou, A., Kinnersley, B., Kafetzopoulos, I. and Sproul, D., 2025. Replication-associated mechanisms contribute to an increased CpG> TpG mutation burden in mismatch repair-deficient cancers. Genome Medicine, 17(1), p.95. https://link.springer.com/article/10.1186/s13073-025-01525-6