Hypermutation as a driving force for cancer: can there be too much of a good thing?

Primary Supervisor: Dr Ian Tomlinson

Project Overview:

DNA polymerases epsilon (POLE) and delta (POLD1) are essential for DNA replication. As part of this process, these enzymes have 3’-exonuclease proofreading activity, to check that the correct base has been incorporated on the new, growing DNA strand. Germline and somatic POLE mutations affecting polymerase proofreading are established drivers of carcinogenesis. The POLE mutations cause increased base substitution mutations in all dividing cells and thus ought to be found in many cancer types. However, the mutations are strongly associated with cancers of the bowel and uterus, for reasons that remain largely unclear.

One reason for the tissue specificity of POLE mutations could be that some tissues or cells can tolerate much higher mutation burdens than others. This project will investigate several aspects of POLE-driven tumorigenesis based on underlying principles of cancer evolution. One exemplar project is to explore the notion that there is a limit to the number of mutations a call can tolerate. In POLE mutant cancers, over 1,000,000 base substitution mutations can occur, so tolerance is known to be high. We will construct genetic mouse and cell models with even higher mutation rates (e.g. defects in polymerase proofreading and base excision repair) to determine the effects on cell viability and underlying mechanisms. These analyses will be backed up by analysis of large-scale sequencing data from human cancers. We will thus determine whether there is a limit to mutational burden in different cells and tissues. The results will have importance for cancer treatment, since some current therapies may work in part via hypermutation at the level of the DNA base.

Training Opportunities:

 • Train to collate, manipulate and analyse genomic and clinical data from human cancers, in association with experienced post-doctoral scientists

 • Develop and test conceptual models of how cancers evolve, and the therapeutic vulnerabilities that accrue as a result

 • Acquire skills in molecular analysis and histopathology of human and mouse tumours

• Acquire skills in tissue and cell culture

Relevant Publications:

Robinson, P.S., Coorens, T.H., Palles, C., Mitchell, E., Abascal, F., Olafsson, S., Lee, B.C., Lawson, A.R., Lee-Six, H., Moore, L. and Sanders, M.A., 2021. Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nature genetics, 53(10), pp.1434-1442.

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Palles C, 34 others, Tomlinson I. Nat Genet. 2013 Feb;45(2):136-44. doi: 10.1038/ng.2503. Epub 2012 Dec 23.