Uncovering Aristolochic Acid–Driven Mutational Signatures and Novel Biomarkers inPrimary Hepatic Angiosarcoma for Targeted Therapeutic Development
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Abstract
Primary hepatic angiosarcoma is a very rare and extremely aggressive malignancy that has had
few therapeutic options and has been closely linked to aristolochic acid which is a strong
environmental carcinogen commonly found in some herbal medicines. The hallmark mutational
signature of aristolochic acid is the observed A: T↔ T: A transversion at context-specific
trinucleotide motifs, and this pattern can be used to discriminatively identify AA-induced tumors
with genome-wide analyses. This signature can act as a molecular signature that has the potential
to explain the etiology of cancers, can aid retrospective exposure assessment, as well as
contribute to early diagnosis. Coincidently, the molecular profiling has highlighted new
biomarkers, serine/threonine kinase p53 pathways, aberrations of ERCC1 DNA repair enzyme,
and up-regulation of endothelial cell markers. which have collectively enhanced diagnosis and
stratification outcomes. These markers have been tested as potential predictive targets and
provide the basis of precision approaches that encompass PARP inhibitors that target DNA-repair
defects, targeted kinase inhibitors, and monoclonal antibodies against angiogenic pathways.
Combination therapies that include the targeted with conventional chemotherapy have been
shown to be more effective. Even more, the development of innovative technologies, including
liquid biopsy, single-cell sequencing, and artificial intelligence-mediated searches in mutational
signatures, further expand personalized medicine of Primary hepatic angiosarcoma and allow an
earlier manifestation and precision intervention.
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