The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

Background and Aims Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure–induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA‐mediated genomic alterations that could be implicated in human cancers with AA‐associated mutational signature. Approach and Results We subjected mice, including phosphatase and tensin homolog ( Pten )‐deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl 4 . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose‐dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl 4 ‐treated or Pten ‐deficient mice. AAI led to DNA damage and AAI‐DNA adduct that could initiate liver cancers through characteristic adenine‐to‐thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA‐associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI‐DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA‐implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA‐affected human tumors. Conclusions This study provides evidence for AA‐induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA‐associated human cancers, especially liver cancers.