DNA Repair Footprint Uncovers Contribution of DNA Repair Mechanism to Mutational Signatures.

Cancer genomes accumulate a large number of somatic mutations resulting from imperfection of DNA processing during normal cell cycle as well as from carcinogenic exposures or cancer related aberrations of DNA maintenance machinery. These processes often lead to distinctive patterns of mutations, called mutational signatures. Several computational methods have been developed to uncover such signatures from catalogs of somatic mutations. However, cancer mutational signatures are the end-effect of several interplaying factors including carcinogenic exposures and potential deficiencies of the DNA repair mechanism. To fully understand the nature of each signature, it is important to disambiguate the atomic components that contribute to the final signature. Here, we introduce a new descriptor of mutational signatures, DNA Repair FootPrint (RePrint), and show that it can capture common properties of deficiencies in repair mechanisms contributing to diverse signatures. We validate the method with published mutational signatures from cell lines targeted with CRISPR-Cas9-based knockouts of DNA repair genes.