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Increased, Induced Mutations in Critical Genes leads to Tumorigenesis, Hepatocellular carcinoma
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma (HCC)||non-adjacent||Moderate||Low||Agnes Aggy (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
There is no direct evidence addressing AFB1 induced critical gene mutations and the subsequent progression through AHF to HCC. In general it is clear that chemicals that induce the critical cancer gene mutations have a mutagenic MOA for the adverse outcome pathway for cancer. The cells that are mutant for the critical cancer gene undergo a change in phenotype and clonally expand into pre-neoplastic lesions, some of which go on to form hepatocellular carcinoma (HCC).
Evidence Supporting this KER
AFB1 can induce mutations in a wide number of species from bacteria to mammals. The primary mutation induced both in bacteria and mammalian cells is a G:C to T:A transversion, consistent with the pro-mutagenic DNA adducts formed by AFB1 (Foster et al., PNAS 80: 2695-2698 (1983), and also with the mutation observed in the p53 gene from the tumors observed in humans residing in high AFB1 exposure regions.
Uncertainties and Inconsistencies
No data on the relationship between cells with mutations in specific critical genes and the induction of HCC. A substantial body of general information and evidence, is, however available on the etiology of tumors and the involvement of mutations in cancer relevant genes in that etiology.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
While exposure to AFB1 does result in the formation of HCC in various species, experiments investigating codon 249 mutation in the tumors of nonhuman primates, ducks, rats and squirrels do not show a high frequency of this mutation.
Taxonomic Applicability (of this KER)
e.g., Rats, Mice, Woodchucks, Humans, Monkeys, Birds, Trout, Tree shrews This specific KER has not been directly measured; however, there is indirect evidence for rats, humans, and trout.
All references have been cited elsewhere in the AOP.