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Relationship: 3610

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

Endometrial squamous metaplasia, Increase leads to Increased, adenosquamous carcinomas of endometrium

Upstream event

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

Endometrial squamous metaplasia, Increase

Downstream event

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

Increased, adenosquamous carcinomas of endometrium

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
Early-life estrogen receptor agonism leading to endometrial adenosquamous carcinoma via promotion of sine oculis homeobox 1 progenitor cells	adjacent	Moderate	Not Specified	Travis Karschnik (send email)	Under Development: Contributions and Comments Welcome

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

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	Low	NCBI
mammals	mammals		NCBI

Sex Applicability

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

Sex	Evidence
Female	High

Life Stage Applicability

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

Term	Evidence
Adult	High

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

Metaplastic squamous epithelium provides the substrate that, once dysplastic/malignant, forms the squamous component of adenosquamous carcinoma. An increase in the incidence of squamous metaplasia leads to conditions necessary for one aspect of adenosquamous carcinomas of the endometrium.

Diagnosing adenosquamous carcinoma can be challenging because each of the components (adenocarcinoma and squamous cell carcinoma) have distinct histological features. Tumors may also be poorly differentiated generally which makes morphological identification difficult.

Subjectivity and interobserver variability aside, benign, atypical, and malignant metaplasia can all share cellular features like nuclear enlargement, hyperchomasia, and increased mitotic activity which makes it difficult to determine cancerous/non-cancerous tissue make-up.

Finally, there is a lack of reliable biomarkers to definitively distinguish benign from premalignant and malignant activity.

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

This Key Event Relationship was part of an Environmental Protection Agency effort to develop AOPs that establish scientifically supported causal linkages between alternative endpoints measured using new approach methodologies (NAMs) and guideline apical endpoints measured in Tier 1 and Tier 2 test guidelines (U.S. EPA, 2024) employed by the Endocrine Disruptor Screening Program (EDSP). A series of key events that represent significant, measurable, milestones connecting molecular initiation to apical endpoints indicative of adversity were identified based on scientific review articles and empirical studies. Additionally, scientific evidence supporting the causal relationships between each pair of key events was assembled and evaluated. The present effort focused primarily on empirical studies with laboratory rodents and other mammals.

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

Adenosquamous carcinoma is a malignant tumor with glandular (adenocarcinoma) and squamous carcinoma components. The presence of squamous metaplasia in the endometrium suggests that progenitor cell(s) may be undergoing squamous differentiation and thus may be predisposed to developing the squamous component of an adenosquamous carcinoma when malignant transformation occurs.

In a proliferative environment, metaplastic foci have a higher probability to accumulate genetic mutations that predispose them to malignant transformation.

Although not formally observed, there also exists the possibility of progressive metaplasia whereby cells undergo changes beginning with benign squamous metaplasia before progressing or giving rise to atypical squamous metaplasia and finally to squamous carcinoma.

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

Current data show coincidence of squamous metaplasia and adenosquamous carcinoma rather than a causative association. The diagnosis of adenosquamous carcinoma, which requires histological findings of adenocarcinoma and squamous cell carcinoma on the same lesion, definitionally limits the ability of a single precursor event to lead to the adverse outcome on its own.

Examples of this coincidental data are largely clinical studies in humans looking at endometrial carcinomas:

Haqqani and Fox 1976
Abeler & Kjørstad 1992
Pekin et al., 2001
Kaku et al., 1992

One study, Zidi et al., 2003, potentially supports the idea of a sequential change beginning with squamous metaplasia and progressing to carcinoma in the human model. This progression differs from the KER here in that it speaks to the malignancy of a single component of adenosquamous carcinoma.

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

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

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

Taxonomic Applicability

The evidence presented here derive from human females. The taxonomic applicability could plausibly be extended to other mammals expressing squamous metaplasia and having and endometrium.

Lifestage Applicability

The lifestage applicability is relevent to adulthood when adenosquamous carcinomas develop and are measured.

Sex Applicability

The sex applicability is limited to females as a consequence of the measurement occuring on endometrial tissue.

References

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

Abeler, V. M., & Kjørstad, K. E. (1992). Endometrial adenocarcinoma with squamdus cell differentiation. Cancer, 69(2), 488-495.

Haqqani, M. T., & Fox, H. (1976). Adenosquamous carcinoma of the endometrium. Journal of clinical pathology, 29(11), 959-966.

Kaku, T., Tsukamoto, N., Tsuruchi, N., Sugihara, K., Kamura, T., & Nakano, H. (1992). Endometrial metaplasia associated with endometrial carcinoma. Obstetrics & Gynecology, 80(5), 812-816.

Pekin, T., Yildizhan, B., Eren, F., Pekin, O., & Yildizhan, R. (2001). Adenocarcinoma, adenoacanthoma, and mixed adenosquamous carcinoma of the endometrium.

Zidi, Y. S. H., Bouraoui, S., Atallah, K., Kchir, N., & Haouet, S. (2003). Primary in situ squamous cell carcinoma of the endometrium, with extensive squamous metaplasia and dysplasia. Gynecologic oncology, 88(3), 444-446.