Mutational signatures and processes in hepatobiliary cancers

The evolutionary history of hepatobiliary cancers is embedded in their genomes. By analysing their catalogue of somatic mutations and the DNA sequence context in which they occur, it is possible to infer the mechanisms underpinning tumorigenesis. These mutational signatures reflect the exogenous and endogenous origins of genetic damage as well as the capacity of hepatobiliary cells to repair and replicate DNA. Genomic analysis of thousands of patients with hepatobiliary cancers has highlighted the diversity of mutagenic processes active in these malignancies, highlighting a prominent source of the inter-cancer-type, inter-patient, intertumour and intratumoural heterogeneity that is observed clinically. However, a substantial proportion of mutational signatures detected in hepatocellular carcinoma and biliary tract cancer remain of unknown cause, emphasizing the important contribution of processes yet to be identified. Exploiting mutational signatures to retrospectively understand hepatobiliary carcinogenesis could advance preventative management of these aggressive tumours as well as potentially predict treatment response and guide the development of therapies targeting tumour evolution. In this Review, Andersen and colleagues discuss exogenous and endogenous factors responsible for mutational signatures in hepatobiliary cancers such as hepatocellular carcinoma and biliary tract cancers. In addition, they explore the role of mutational signatures in hepatobiliary tumorigenesis. Key points In hepatobiliary cancer genomes, mutational signatures arise from diverse exogenous and endogenous insults as well as from cell-intrinsic repair mechanisms; a substantial proportion remains of unknown origin. Mutational signatures are variably active and clonal during disease initiation and exhibit aetiological associations in invasive tumours. Specific signatures exhibit high intertumour and intratumoural heterogeneity in hepatobiliary cancers, suggesting that distinct mutational processes might have key roles in subclonal diversification and disease relapse. Identifying exogenous exposures responsible for mutational signatures can guide the development of preventative health measures to avoid these genotoxicants. Mutational signatures might have important implications for response to diverse treatments (such as chemotherapy, targeted therapy and immunotherapy) given their molecular and pathobiological correlates in patients with hepatobiliary cancers. Advances in circul