Experimental systems for the analysis of mutational signatures: no ‘one-size-fits-all' solution

Cells constantly accumulate mutations, which are caused by replication errors, as well as through the action of endogenous and exogenous DNA-damaging agents. Mutational patterns reflect the status of DNA repair machinery and the history of genotoxin exposure of a given cellular clone. Computationally derived mutational signatures can shed light on the origins of cancer. However, to understand the etiology of cancer signatures, they need to be compared with experimental signatures, which are obtained from the isogenic cell lines or organisms under controlled conditions. Experimental mutational patterns were instrumental in understanding the nature of signatures caused by mismatch repair and BRCA deficiencies. Here, we describe how different cell lines and model organisms were used in recent years to decipher mutational signatures observed in cancer genomes and provide examples of how data from different experimental systems complement and support each other.