Uncovering Aristolochic Acid–Driven Mutational Signatures and Novel Biomarkers inPrimary Hepatic Angiosarcoma for Targeted Therapeutic Development

Primary hepatic angiosarcoma is a very rare and extremely aggressive malignancy that has hadfew therapeutic options and has been closely linked to aristolochic acid which is a strongenvironmental carcinogen commonly found in some herbal medicines. The hallmark mutationalsignature of aristolochic acid is the observed A: T↔ T: A transversion at context-specifictrinucleotide motifs, and this pattern can be used to discriminatively identify AA-induced tumorswith genome-wide analyses. This signature can act as a molecular signature that has the potentialto explain the etiology of cancers, can aid retrospective exposure assessment, as well ascontribute to early diagnosis. Coincidently, the molecular profiling has highlighted newbiomarkers, serine/threonine kinase p53 pathways, aberrations of ERCC1 DNA repair enzyme,and up-regulation of endothelial cell markers. which have collectively enhanced diagnosis andstratification outcomes. These markers have been tested as potential predictive targets andprovide the basis of precision approaches that encompass PARP inhibitors that target DNA-repairdefects, targeted kinase inhibitors, and monoclonal antibodies against angiogenic pathways.Combination therapies that include the targeted with conventional chemotherapy have beenshown to be more effective. Even more, the development of innovative technologies, includingliquid biopsy, single-cell sequencing, and artificial intelligence-mediated searches in mutationalsignatures, further expand personalized medicine of Primary hepatic angiosarcoma and allow anearlier manifestation and precision intervention.