Abstract
Simple SummaryAristolochic 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.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.
Highlights
Cancers involving the oro-gastrointestinal tract (OGITCs) account for amongst the highest rates of leading cancers worldwide in both sexes
Our results suggest that Aristolochic acids (AAs) is probably not the main factor driving tumorigenesis in oro-gastrointestinal tract cancer (OGITC) compared to renal cell cancers (RCCs), hepatocellular cancers (HCC), bladder cancers (BCs), and urinary tract urothelial cell carcinoma (UTUC)
De novo mutational signature analysis revealed that only GA33 exhibited AA signatures having characteristics of A-to-T transversions and associated transcriptional strand bias
Summary
Cancers involving the oro-gastrointestinal tract (OGITCs) account for amongst the highest rates of leading cancers worldwide in both sexes. The prevalence of OGITCs is estimated to be at 4.8 million, with 3.4 million related deaths based on statistics gathered in 2018, with esophageal and gastric cancers leading in Asia [1]. Factors such as ageing [2], exposure to carcinogens (e.g., smoking [3,4] and UV exposure [5]), diet, and lifestyle changes are established contributors to the underlying causation of genomic mutations leading to increased cancer burden and mortality. By accounting for somatic mutations that have accumulated as a consequence of the mentioned processes, large-scale consortia [6–9] have attributed and revealed the many mutational signatures associated with human cancer types and etiology. Conclusion: AA signatures in OGITCs are rare and unlikely to be a major contributing factor in oro-gastrointestinal tract tumorigenesis
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