Aristolochic acids I and II, classified by IARC as carcinogenic to humans (Group 1), are present in many species of Aristolochia and Asarum, which are used in a variety of traditional herbal remedies, mainly in Asia (IARC, 2012). Dietary exposure to aristolochic acid can elicit severe nephrotoxic effects (aristolochic acid nephropathy [AAN]) and give rise to urologic and hepatobiliary cancers via specific damage of the DNA in the target tissues. This specific damage, or mutational signature, is also observed in other organs, such as the oesophagus and the duodenum. Aristolochic acid has recently been recognized as one of the most potent human mutagenic carcinogens.

Major breakthroughs in the understanding of the causes and the clinicopathological features of AAN and associated cancers have been achieved by multidisciplinary research on two major occurrences of AAN in Europe. One setting involves endemic nephropathy in particular farming areas of south-eastern Europe and is an example of chronic environmental exposure to aristolochic acid due to environmental/dietary contamination. The other occurrence, recorded in Belgium in the 1990s, was an outbreak of AAN due to alternative medical treatment and unsatisfactory regulation of traditional herbal medicines.

The Epigenomics and Mechanisms Branch (EGM) performs molecular analyses in the framework of these two well-studied settings in order to devise profiling methodologies and develop biomarkers of exposure and cancer formation. These can be applied in molecular cancer epidemiology studies because of their potential to reliably identify exposure–disease associations in archived biospecimens. The identified mutational signature of aristolochic acid (Figure 1) can serve as a key molecular marker of exposure to aristolochic acid, and the characteristic mutation spectra have been investigated for their functional impact to elucidate the molecular bases of the aristolochic acid-associated tumours. Overall, the ARISTOCANCERS project has the potential to provide the evidence base for the successful introduction of preventive measures aimed at the populations in the affected regions.

Figure 1 Effects of aristolochic acid observed in upper tract urothelial carcinomas (UTUCs) from the endemic nephropathy (EN) regions. (A) Aristolochia clematitis, found to contaminate wheat fields in the affected regions. (B) The chemical structure of the mutagenic and carcinogenic aristolochic acids I and II. (C) Mutational signatures identified in the EN UTUC tumours (COSMIC SBS22 = aristolochic acid mutational signature). Adapted from Karanović et al. (2022), © 2021 IARC. Int J Cancer, published by John Wiley & Sons Ltd on behalf of UICC.