Rare Occurrence of Aristolochic Acid Mutational Signatures in Oro-Gastrointestinal Tract Cancers

SIMPLE SUMMARY: Aristolochic acids (AAs) are a family of carcinogenic phytochemical compounds commonly found in plants of the Aristolochia and Asarum genera. Comprehensive genomic profiling of genitourinary and hepatobiliary cancers has highlighted the widespread prevalence of Aristolochic acid (AA) signatures in cancer patients across parts of Asia, particularly in Taiwan. The aim of our study was to determine in oro-gastrointestinal tract cancers (OGITCs), the prevalence, role and significance that AA plays as a driver of tumorigenesis as AA-containing products are commonly administered orally. This suggests a possible etiological relationship between OGITCs. However, in this study, the rarity of AA mutational signatures in OGITCs suggests that AA is unlikely to drive carcinogenesis in OGITCs through direct exposure. Our study is valuable because it shows that AA exposure is not an equal driver of tumorigenesis in different organs and represents an important piece of information in the field. ABSTRACT: Background: Aristolochic acids (AAs) are potent mutagens commonly found in herbal plant-based remedies widely used throughout Asian countries. Patients and Methods: To understand whether AA is involved in the tumorigenesis of the oro-gastrointestinal tract, we used whole-exome sequencing to profile 54 cases of four distinct types of oro-gastrointestinal tract cancer (OGITC) from Taiwan. Results: A diverse landscape of mutational signatures including those from DNA mismatch repair and reactive oxygen species was observed. APOBEC mutational signatures were observed in 60% of oral squamous cell carcinomas. Only one sample harbored AA mutational signatures, contradictory to prior reports of cancers from Taiwan. The metabolism of AA in the liver and urinary tract, transient exposure time, and high cell turnover rates at OGITC sites may explain our findings. Conclusion: AA signatures in OGITCs are rare and unlikely to be a major contributing factor in oro-gastrointestinal tract tumorigenesis.