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Formation, Pro-mutagenic DNA Adducts 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||Moderate||Ted Simon (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
Formation of the pro-mutagenic DNA adduct, N7-AFB1-G (or its conversion product, N7-AFB1-FAPy) is the first step in the initiation of a process that may finish in development of hepatocellular carcinoma (HCC). These steps (pro-mutagenic adduct formation and HCC) are indirectly linked through insufficient/mis-repair of DNA and induction of a mutation in a critical gene and clonal expansion/cell proliferation with formation of altered hepatic foci (AHF).
Evidence Supporting this KER
While there is no specific information for AFB1, it is widely recognized that pro-mutagenic adducts formed by AFB1 metabolites may be repaired/removed or may result in mutations. The fidelity of the repair processes and probability of mis-repair determine whether mutations arise in tumor-critical genes. The altered hepatic foci (AHF) are believed to result from mutations expressed in cells that demonstrate reduced apoptosis and increased proliferation, likely linked to the mutations. (Alekseyev et al., 2004; Zhang et al., 2003; Giri et al., 2002; Bailey et al., 1996; Lin et al., 2014). The further development of AHF to HCC is believed to be a continuum of these same processes over time. These are discussed in a previous section and include effects on apoptosis, inflammation, the development of a tumor microenvironment, interference with the anti-oxidant response, and likely others.
Uncertainties and Inconsistencies
The direct KER relationships between adducts and mutations (MIE→KE#2) and from mutations to AHF (KE#2→KE#3) and from AHF to HCC (KE#3→AO) determine this indirect relationship. Unfortunately, there is a paucity of data to support quantification of a relationship between adducts and HCC; neither are there data to address an AFB1-related dose-response for both KEs.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
HCC has been observed essentially universally in AFB1-treated mammals, birds, and fish examined (Pottenger et al., 2014; Kensler et al., 2011; Kimura et al., 2004; Cullen et al., 1990; Kirby et al., 1990).
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Zhang YJ, Chen Y, Ahsan H, Lunn RM, Lee PH, et al (2003) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma. Int J Cancer 103: 440-444.