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Aristolochic acid-associated cancers: a public health risk in need of global action

Abstract

Aristolochic acids (AAs) are a group of naturally occurring compounds present in many plant species of the Aristolochiaceae family. Exposure to AA is a significant risk factor for severe nephropathy, and urological and hepatobiliary cancers (among others) that are often recurrent and characterized by the prominent mutational fingerprint of AA. However, herbal medicinal products that contain AA continue to be manufactured and marketed worldwide with inadequate regulation, and possible environmental exposure routes receive little attention. As the trade of food and dietary supplements becomes increasingly globalized, we propose that further inaction on curtailing AA exposure will have far-reaching negative effects on the disease trends of AA-associated cancers. Our Review aims to systematically present the historical and current evidence for the mutagenicity and carcinogenicity of AA, and the effect of removing sources of AA exposure on cancer incidence trends. We discuss the persisting challenges of assessing the scale of AA-related carcinogenicity, and the obstacles that must be overcome in curbing AA exposure and preventing associated cancers. Overall, this Review aims to strengthen the case for the implementation of prevention measures against AA’s multifaceted, detrimental and potentially fully preventable effects on human cancer development.

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Fig. 1: Mechanistic underpinnings of the mutagenicity of AA.
Fig. 2: Summary of all whole-genome or whole-exome sequencing reports discussed in this Review.
Fig. 3: Global observations of AA-associated diseases and cancers and the global distribution of Aristolochia.

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Acknowledgements

This Review was prepared during the tenure of the International Agency for Research on Cancer (IARC) Postdoctoral Fellowship awarded to S.D. V.S.S. is supported by the US National Institute of Environmental Health Sciences grant R21 ES032855, the Laufer Family Foundation and the Zickler Family Foundation. The authors apologize to colleagues and collaborators in the field whose relevant work is hereby gratefully acknowledged but could not be cited due to space limitations. Views expressed in this article are those of the authors and do not necessarily reflect the decisions, policy or views of the IARC/World Health Organization (WHO).

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S.D., M.K., V.S.S., F.F-L.C. and J.Z. researched data for the article, contributed to discussions of the content of the article, contributed to the writing of the article and edited or reviewed the manuscript before submission. S.T. researched data for the article, contributed to the writing of the article and edited or reviewed the manuscript before submission.

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Correspondence to Felicia Fei-Lei Chung or Jiri Zavadil.

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Nature Reviews Cancer thanks Steven Rozen, Joelle Nortier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

AA signature SBS22: https://cancer.sanger.ac.uk/signatures/sbs/sbs22/

Global Biodiversity Information Facility (GBIF): https://www.gbif.org/species/2873978

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Glossary

Ayurvedic medicine

An ancient Indian medical system, also known as Ayurveda, that remains in practice to the present day.

Iatrogenic

A condition induced inadvertently as a result of diagnostic or therapeutic procedures undertaken on a patient.

Clear cell renal cell carcinoma

(ccRCC). The most commonly observed histological subtype of renal cancer, which represents between 70 and 75% of all RCCs.

Chromophobe RCC

(Chromophobe renal cell carcinoma). A histological subtype of renal cancer that represents approximately 5% of all malignant renal epithelial tumours.

Arseniasis

Chronic arsenic poisoning.

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Das, S., Thakur, S., Korenjak, M. et al. Aristolochic acid-associated cancers: a public health risk in need of global action. Nat Rev Cancer 22, 576–591 (2022). https://doi.org/10.1038/s41568-022-00494-x

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