Exploring the biological processes underlying mutational signatures identified in cancers. (360G-Wellcome-100183_Z_12_B)

Somatic mutations in cancer genomes have been generated by multiple DNA damage processes, the effects of which may have been mitigated by the cellular repertoire of DNA repair mechanisms. Each process will leave a characteristic imprint, or mutational signature, on the cancer genome. Our understanding of these signatures and their underlying mutational processes is remarkably limited. The overarching theme of this proposal is to explore the biological basis of mutational signatures that emerge f rom sequencing whole cancer genomes. The first aim is to systematically manipulate components of the DNA repair/replicative machinery in model systems, by targeted disruption or over-expression, followed by re-sequencing of clones to define genome-wide mutational signatures generated by these engineered abnormalities. The second main aim is to establish a resource of induced pluripotent stem cells (iPSCs) and/or lymphoblastoid cell lines (LCLs) from patients with naturally occurring germline defects in genes involved in DNA repair/replication to study mutational patterns in these patients. Thirdly, the large projected datasets generated from these experiments will require computationally demanding exploration and downstream analyses. Ultimately, experimentally generated datasets will be compared to mutational signatures extracted from large-scale sequencing of cancer genomes, giving us insight into the perturbations that happen during cancer development.