Early detection of clinically-relevant mutational signatures

Principal Investigator: Dr Serena Nik-Zainal, MRC Cancer Unit

Funded by: CRUK Early Detection Project Award

Mutational-signatures in human cancers are the final outcome of combinations of DNA damage and DNA repair processes. Direct DNA damage incurred by tobacco smoke, UV light or other environmental mutagens and direct abnormalities of a DNA repair pathway like homologous recombination (HR) repair or mismatch repair (MMR) leave characteristic imprints on the genome. However, abnormal cellular processes like replication stress can result in mutagenesis as well, albeit indirectly. Mutational-signatures are therefore simply a read-out of a spectrum of cellular abnormalities and can thus be thought of and exploited in that way. In this Early Detection Project, we aim to identify on-going mutational-signatures that can be used as a surrogate for particular cancer development processes and determine signatures that may be informative for therapeutic intervention. Apart from identifying these clinically-relevant mutational signatures, we aim to design mutational-signature-based clinical assays that could be used for early detection. We will test our assays, optimize their performance and demonstrate how well they perform in a clinical screening setting.