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Relationship: 346

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, Induced Mutations in Critical Genes leads to Tumorigenesis, Hepatocellular carcinoma

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, Induced Mutations in Critical Genes

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Tumorigenesis, Hepatocellular carcinoma

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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	Ted Simon (send email)	Open for citation & comment	Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

A mutation in codon 249 in the human p53 gene is observed up to 50% of liver cancers in Qidong, China (Hsu et al., Nature 350: 427-428, 1991) and in Mozambique, areas with high exposure to AFB1. A G:C to T:A transversion in the third base of codon 249 in p53 is observed in up to 75% of HCC in high-incidence areas of China and East Africa (Gouas et al., 2009). This specific mutation is very rare in HCC from no or low aflatoxin areas (Hsu et al., 1991 and Bressac et al. Nature, 350:429-431, 1991). This mutation is also very rare in other types of tumors (Gouas et al., 2009).

Evidence for temporality for mutation and HCC The Dycaico et al. (1996) Big Blue™ rat study and the Chen et al. Big Blue™ neonatal mouse study (2010) show that AFB1 can induce mutation (in a surrogate gene) following a relatively short in vivo exposure time.

The codon 249 mutation is detectable in exposed tissues ahead of cancer development (Gouas et al., Cancer Letters, 286: 29-37, 2009)

In a review of p53 mutation at codon 249 (R249S), Gouas et al., 2009 report that cancer patients have significantly higher levels of DNA fragments circulating in their blood than healthy individuals. Using restriction digestion methods (RFLP-PCR) R249S has been detected in patients from The Gambia, and this was strongly associated with HCC. The presence of this mutation in plasma was linked to the codon 249 p53 mutation in the tumors of individual patients. In addition, using a sensitive and quantitative mass spectrometric method, combined with other molecular techniques, Jackson et al., 2003 were able to detect the R249S mutation in the plasma of patients from The Gambia both before and after clinical diagnosis of HCC (in the same patient) (Jackson et al., 2003). These data provide good evidence of an appropriate temporal sequence of events: induction of the mutation precedes tumor formation.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Detecting mutation in the critical cancer gene following AFB1 exposure is technically challenging, and the techniques to do this are not widely available. Because there is no quantitative information for the induction of these mutations, there is no data-driven quantitative understanding of the relationship between the AFB1-induced critical cancer gene mutations and HCC.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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.

References

List of the literature that was cited for this KER description. More help

All references have been cited elsewhere in the AOP.