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Relationship: 2972

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

Increase, Hyperplasia (glandular epithelial cells of endometrium) leads to Genomic instability

Upstream event

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

Increase, Hyperplasia (glandular epithelial cells of endometrium)

Downstream event

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

Genomic instability

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
Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation	adjacent			Barbara Viviani (send email)	Under development: Not open for comment. Do not cite	Under Review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

Term	Evidence
All life stages

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

Enhanced proliferation (pathologic hyperplasia) can promote carcinogenesis by different means. Increase in mitotic activity increases the probability of mutations, as the activation of cell cycle reduces the G1 phase, a phase in which the repair systems are involved (Casarett and Doulls, 2008; Felsher et al. 1999). In addition, during cell division the DNA doubles and become unpacked, thus increasing the target size for mutagenic chemicals (Casarett and Doulls, 2008). Moreover, in case of increased proliferation proto-oncogenes are overexpressed (Feitelson et al. 2015).

Genomic mutations promoting further proliferation are positively selected from among the expanded cells, resulting in the accumulation of mutational errors and moving the organism further towards cancer. In particular, endometrial hyperplasia is a frequent precursor of endometrial carcinoma (Stopper et al. 2003). Endometrial hyperplasia sharing specific acquired genetic alterations in oncogenic genes supports its malignant potential (Robbins and Cotran, 2015).

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

Fidelity of DNA replication is guarantee by cell cycle checkpoints, regulatory pathways that monitor order and timing of the cell cycle. Checkpoints represent a stop in cell cycle to allow DNA repair and favour the transcriptions of genes that facilitate repair (Elledge 1996). DNA damage triggers G1/S and G2/S checkpoints to prevent cells from replicating damaged DNA and dividing with damaged DNA respectively (Swift et al. 2016). Enhanced mitotic activity is leading to the shortening of the G1 phase which leads to a reduced time available for DNA repair before replication leading to genomic instability (Casarett and Doulls, 2008).

Microsatellite instability (MI) characterizes 20% of endometrial hyperplasia associated with endometrioid (type I) cancers (atypical hyperplasia) (Sherman, 200). Microsatellites are short tract of repetitive DNA units, usually non-coding but predisposing to DNA replication errors, whose length is maintained by DNA repair in normal cells but is lost in atypical endometrial hyperplasia leading to MI. Occurrence of an altered length of these repetitive sequences is considered a marker of mismatch repair mechanism that could result in increased spontaneous mutation rates (Loeb, 1998).

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

All animal studies dealing with gene mutations falls in Tier 3 and has been excluded.

Estrogens - Empirical data correlating human exposure to unopposed estrogen administration and increased hyperplasia are available from multicenter, randomized, double -masked, placebo-controlled trial (The Writing Group for the PEPI Trial 1996). The effects of hormone replacement therapy on endometrial histology in postmenopausal women were investigated on 596 patients exposed to 0.625 mg conjugated equine estrogens (CEE) per os once a day for 3 years. An increased incidence of simple, complex or atypical hyperplasia was observed in CEE patients than placebo (27.7 vs. 0.8%, 22.7 vs. 0.8%, and 11.8 vs. 0%, respectively). Incidence of hyperplasia was 21, 24, and 17% in the first, second, and third years, respectively (The Writing Group for the PEPI Trial, 1996). Estrogen- induced increase of hyperplasia is dose and time dependent. As such, 0.3 mg esterified estrogens per os once a day for 2 years did not result in increased hyperplasia compared to placebo (Genant et al. 1997) but increased nine- fold endometrial cancer when administered for 8 years (Cushing et al., 1998). The incidence of hyperplasia increased to 28% in patients who received 0.625 mg of CEE to reach 53% in patients who received 1.25 mg of esterified estrogens for 2 years (Genant et al. 1997).

Plasma E2 levels dose-dependently increased after administration of esterified estrogens 0.3, 0.625 and 1.25 mg/day, reaching 28.67+2.8, 43.3 + 2.9 and 64 + 7.6 pg/ml after 12 months, respectively. These levels do not significantly change when measured at 18 and 24 months of exposure (Genant et al. 1997).

Robbins and Cotran 2015 – Mutations in the tumor suppressor gene PTEN, leading to loss of function, are found in 20% hyperplasia with and without atypia and in 30-80% endometrioid adenocarcinomas. Other mutations characterising endometrial hyperplasia are KRAS, found in approximately 25% of cases and DNA mismatch repair genes in about 20% of sporadic tumors.

Tamoxifen – Simple endometrial hyperplasia (significant at the glandular epithelium) was diagnosed in 18 out of 20 post-menopausal women randomly assigned to TAM group (20 mg/d, 21d) compared to 2 out of 20 controls (Tregon et al. 2003). A different study observed an increase of K-ras mutation in the endometrium of post-menopausal women under TAM (20mg/d) as adjuvant hormonal treatment after undergoing surgery for breast cancer (Hachisuga et al. 2005). The prensence of K-ras mutation was significantly influenced by the duration of TAM treatment. In 62 postmenopausal-amenorrheic patients, K-ras mutation was found in 15.8% of patients with less than 23 months of TAM treatment, in 61.5% of 26 patients with 24 – 47 months of TAM treatment and in 52.9% of patients with more than 48 months of TAM treatment (Hachisuga et al. 2005).

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

Estradiol and PTEN mutation leading to uterine adenocarcinoma in rodents - After a systematic review addressing the accumulation of mutation as KE in a search strategy to define uterine adenocarcinoma, the effect for this KER was judged INADEQUATE EVIDENCE, since tier 3 studies only with paucity of data were available

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

A quantitative linkage between Increased proliferation (hyperplasia) and accumulation of mutation after estradiol exposure is lacking. TAM 20mg/d increased the incidence of simple endometrial hyperplasia after 21d of administration and K-ras mutation in the endometrium after 23 to 47 mo of treatment in post-menopausal women.

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

References

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

Casarett, L. J., Doull, J., & Klaassen, C. D. (2008). Casarett and Doull's toxicology: The basic science of poisons. New York: McGraw-Hill Medical Pub. Division.

Elledge SJ. Cell cycle checkpoints: preventing an identity crisis. Science. 1996 Dec 6;274(5293):1664-72. doi: 10.1126/science.274.5293.1664. PMID: 8939848.

Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, Niccolai E, Amin A, Ashraf SS, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Keith WN, Nowsheen S. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol. 2015 Dec;35 Suppl(Suppl):S25-S54. Doi: 10.1016/j.semcancer.2015.02.006.

Felsher, D. W., & Bishop, J. M. (1999). Transient excess of MYC activity can elicit genomic instability and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 96(7), 3940–3944. https://doi.org/10.1073/pnas.96.7.3940

Genant HK, Lucas J, Weiss S, Akin M, Emkey R, McNaney-Flint H, et al. (1997). Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med 157:2609–2615.

Hachisuga T, Tsujioka H, Horiuchi S, Udou T, Emoto M, Kawarabayashi T. K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene. Br J Cancer. 2005 Mar 28;92(6):1098-103. doi: 10.1038/sj.bjc.6602456. PMID: 15756272; PMCID: PMC2361944.

Loeb LA. Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 1994;54:5059–63.

Robbins, S. L. & Cotran, R. S. (2015). Robbins and Cotran pathologic basis of disease (9th ed), Kumar V., Abbas A., Aster JC editors, Philadelphia, PA: Saunders/Elsevier.

Sherman ME. Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol 2000; 13:295–308

Stopper H, Schmitt E, Gregor C, Mueller SO, Fischer WH. Increased cell proliferation is associated with genomic instability: elevated micronuclei frequencies in estradiol-treated human ovarian cancer cells. Mutagenesis. 2003 May;18(3):243-7. doi: 10.1093/mutage/18.3.243.

Swift L.H., R.M. Golsteyn, Chapter 22 - The Relationship Between Checkpoint Adaptation and Mitotic Catastrophe in Genomic Changes in Cancer Cells, Editor(s): Igor Kovalchuk, Olga Kovalchuk, Genome Stability, Academic Press, 2016, Pages 373-389, ISBN 9780128033098, https://doi.org/10.1016/B978-0-12-803309-8.00022-7.

The Writing Group for the PEPI Trial (1996). Effects of hormone replace- ment therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. JAMA 275:370–375.

Tregón ML, Blümel JE, Tarín JJ, Cano A. The early response of the postmenopausal endometrium to tamoxifen: expression of estrogen receptors, progesterone receptors, and Ki-67 antigen. Menopause. 2003 Mar-Apr;10(2):154-9. doi: 10.1097/00042192-200310020-00007. PMID: 12627041.