Abstract

Whole genome sequencing permits exploration of the entirety of the cancer genome, per patient, revealing all causally-implicated driver mutations and mutational signatures that have arisen through carcinogenesis. Mutational signatures are the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis. First derived in breast cancers, they are biologically informative, providing clues regarding all the mutagenic processes that have contributed to the developmental history of each patient’s cancer. In this lecture, I shall provide an update on the field, focusing on validation of these abstract mathematical concepts, untangling the mechanisms underpinning mutation patterns in human cancers, and describing the new insights that we have gained through combinations of computational analysis and experiments in cell-based systems. We showcase how mutational-signature-based clinical algorithms have been developed, describe the path taken in translating these towards medical utility and for balance, highlight some of the hurdles that need to be navigated in genomic research.