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.

肝胆癌的进化史嵌入其基因组中。通过分析它们的体细胞突变目录和它们发生的 DNA 序列背景，可以推断出支持肿瘤发生的机制。这些突变特征反映了遗传损伤的外源性和内源性起源以及肝胆细胞修复和复制 DNA 的能力。对数千名肝胆癌患者的基因组分析突出了活跃于这些恶性肿瘤中的诱变过程的多样性，突出了临床观察到的癌症类型、患者间、肿瘤间和肿瘤内异质性的一个重要来源。然而，在肝细胞癌和胆道癌中检测到的很大一部分突变特征仍然未知原因，强调尚未确定的进程的重要贡献。利用突变特征来回顾性地了解肝胆癌的发生可以推进对这些侵袭性肿瘤的预防性管理，并可能预测治疗反应并指导针对肿瘤进化的疗法的开发。