Mutational Processes in Hepatocellular Carcinoma: The Story of Aristolochic Acid

Abstract

Each hepatocellular carcinoma displays dozens of mutations in driver and passenger genes. The analysis of the types of substitutions and their trinucleotide context defines mutational signatures that recapitulate the endogenous and exogenous mutational processes operative in tumor cells. Aristolochic acid is present in plants from the genus Aristolochia and causes chronic nephropathy. Moreover, aristolochic acid has genotoxic properties responsible for the occurrence of urothelial carcinoma. Metabolites of aristolochic acid form DNA adducts on adenine residues leading to a specific mutational signature with almost exclusively A:T to T:A transversions, preferentially in a CTG trinucleotide context. Interestingly, this mutational fingerprint has been identified in a subset of hepatocellular carcinomas suggesting that aristolochic acid is a new risk factor for hepatocellular carcinoma. More data are warranted to capture the real impact of exposure to aristolochic acid in hepatocellular carcinoma occurrence worldwide.

Multiregional whole‐genome sequencing of hepatocellular carcinoma with nodule‐in‐nodule appearance reveals stepwise cancer evolution

“…The ratio of C:G>T:A substitutions was higher in kataegistic clusters than in trunk and IN-unique mutations ( Figure 4D,E). In addition, as reported in a previous paper [32], the majority of these substitutions were C:G>T:A at TpCpX sites (COSMIC signature 2), a representative mutational pattern associated with the APOBEC family ( Figure , whereas the branch mutations were highly associated with signature 22 represented by T>A transversions in the context of CTG trinucleotides, which is linked to aristolochic acid, a new risk factor for liver cancer ( Figure 4G,H) [33]. In addition, in most cases, signature 12 (liver cancer) and signature 4 (smoking) tended to be enriched at the trunk level, whereas signatures 3 and 15 (mismatch repair deficiency-associated) tended to be enriched at the branch level (supplementary material, Figures S6-S9).…”

“…Mutational signature analysis also elucidated the different contribution of representative liver cancer‐associated COSMIC signatures between trunk and branch mutations. For example, in case 3, most of the trunk mutations were liver cancer‐associated COSMIC signatures 12 and 16, whereas the branch mutations were highly associated with signature 22 represented by T>A transversions in the context of CTG trinucleotides, which is linked to aristolochic acid, a new risk factor for liver cancer (Figure 4G,H) [33]. In addition, in most cases, signature 12 (liver cancer) and signature 4 (smoking) tended to be enriched at the trunk level, whereas signatures 3 and 15 (mismatch repair deficiency‐associated) tended to be enriched at the branch level (supplementary material, Figures S6–S9).…”

Systematic Overview of Aristolochic Acids: Nephrotoxicity, Carcinogenicity, and Underlying Mechanisms

“…Genomic heterogeneity analyses provide strong evidence that AAs potentially contribute to the development of liver cancer (Poon et al, 2013; Lin et al, 2017). Recently, a specific mutational signature of AA exposure has been exhibited in whole exome sequencing of hepatocellular carcinomas, suggesting a plausible conclusion that AAs and their derivatives might be one of the culprits triggering liver cancer in Asia (Totoki et al, 2014; Letouze et al, 2017; Ng et al, 2017; Nault and Letouze, 2019). AAs can also affect the initiation and/or progression of renal cell carcinoma (Scelo et al, 2014; Jelakovic et al, 2015a; Hoang et al, 2016) or bladder urothelial tumor (Lemy et al, 2008; Poon et al, 2015; Sun et al, 2015).…”

Genomics of Viral Hepatitis-Associated Liver Tumors

“…This work also demonstrated a dose-dependent association between aristolochic acid exposure and the development of HCC in HBV-infected patients. This suggests a cooperation between HBV and aristolochic acid promoting carcinogenesis [ 106 ].…”