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

• DOI: 10.1002/hep.30863
• Publication Date: 2019-07-20T08:10:16Z
• Authors: Zhao‐Ning Lu; Qing Luo; Li‐Nan Zhao; Yi Shi; Na Wang; Lan Wang; Ze‐Guang Han
• Keywords: Aristolochic Acid; Human liver

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