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Relationship: 2973

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

Genomic instability leads to endometrioid adenocarcinoma Type I

Upstream event

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

Genomic instability

Downstream event

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

endometrioid adenocarcinoma Type I

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 Do not cite	Under Review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

Sex	Evidence
Female

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

Genes involved in DNA repair together with the growth promoting proto-oncogenes, the growth inhibiting tumor suppressor genes and genes involved in apoptosis regulation are the principal targets of cancer causing mutation. In particular, single mutations in DNA repair genes are not oncogenic themselves, but their abnormalities enhance the accumulation of mutations in other genes during the process of normal cell division: for example, mutations in the mismatch repair system may cause the accumulation of mutations in oncogenes and tumor-suppressor genes resulting in clonal expansion in the progeny of the altered cell (Lengauer et al., 1998). This, favours the acquisition of mutations at an accelerated rate leading to the so called mutator phenotype that is marked by genomic instability (Robbins and Coltran, 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

The development of endometrioid adenocarcinoma involves the progressive acquisition of several genetic alterations in tumor suppressor genes and oncogenes (Ellenson et al., 2015). For example, PTEN (phosphatase and tensin homolog) tumor suppressor gene mutations have been identified in 30% to 80% of endometrioid carcinomas and in atypical hyperplasia (more than 20%) [Mutter et al., 2000; Abal et al., 2006; Ellenson et al., 2015]; this may support the fact that atypical hyperplasia may be a precursor of endometrial carcinoma and that PTEN mutation may occur before the development of fully developed cancer (Ellenson et al., 2015). KRAS (Kirsten rat sarcoma virus) activating mutations were seen in 10% to 30% of type I endometrial cancers [Lax et al., 2000; Tashiro et al., 2014]; also mutated KRAS stimulates PI3K/AKT signaling [Ellenson et al., 2015]. PIK3CA(phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit), an oncogene that encodes the catalytic subunit of PI3K, is mutated in approximately 40% endometrioid carcinomas. It is rarely mutated in atypical hyperplasia, suggesting that this mutation may play a role in tumor development [Oda et al., 2005; Hayes et al., 2006]. Lastly, p53 is another gene that is mutated (10%-20%) in endometrial carcinomas (Risinger et al., 1992; Kihana et al., 1995). Since well differentiated endometrioid cancer are lacking in p53 mutations, these mutations are thought to be late event in tumor progression. Defects involving DNA mismatch repair genes are found in about 30%-40% sporadic endometrioid carcinomas and they are particularly prevalent in endometrial carcinomas in women from families with HNPCC (hereditary nonpolyposis colorectal carcinoma). This defect leads to a mutator phenotype, leading to more rapid accumulation of mutations in genes involved in cancer development (Esteller et al., 1999).

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

Human studies

Estrogen s- Empirical data correlating human exposure to unopposed estrogen administration and increased incidence of endometrial carcinoma are available. Administration of 0.3 mg CEE per os once a day for 8 years increased nine- fold endometrial cancer (Cushing et al., 1998). Administration of 0.3 mg/day esterified estrogens per os once a day for 2 years results in E2 plasma levels 28.67+2.8 pg/ml after 12 months and 25.98+2.5 pg/ml after 2y (Genant et al. 1997).

Estrogen concentrations in normal vs type I endometrial cancer tissue obtained from the same patient have been measured by radioimmunoassay and expressed on the weight of wet tissue or on mg protein (Berstein et al. 2003). Values are reported in the concordance table (Tab. 5) and refer to a total of 24 samples for normal endometrium and 42 samples for Type I cancer. Post-menopausal patients for each group are 18 providing normal endometrium and 31 providing tumoral tissue (Berstein et al. 2003).

TAM - IARC monography (2012) concludes that there is sufficient evidence in humans for the carcinogenicity of TAM in increasing the risk of endometrial cancer among women with breast cancer. The conclusion is supported by 9 adequate cohort study, 4 adequate case-control studies, 5 randomized controlled trials and 1 major chemoprevention trial (IARC 2012).

Animal studies

IARC monography (2012) collects only 2 studies addressing occurrence of uterine cancer in adult rodent after oral exposure to TAM (Carthew et.al, 1996; Mantyla et al. 1996). In Carthew et al. (1996) adult mice were exposed to TAM 0 or 420mg/kg diet for 8 wks, followed by 140 mg/kg diet for 22 mo and adult rats (Wistar) were exposed to a similar diet but only for 3 months. Mantyla et al. (1996) exposed Sprague Dawley rats to 0, 11.3, 45 mg/kg bw d for 13, 26 or 52 wks. Uteri from treated and control animals were analysed after one (Mantyla et al. 1996) o two (Carthew et.al, 1996) years. None of the study provided significant results and, when occurring, uterine tumors other than endometrioid adenocarcinoma were observed.

Essentiality

Robbins and Cotran 2015 – patients with Cowden syndrome, which is caused by germline mutations in PTEN, have a high incidence of endometrial 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

Incidence of uterine adenocarcinomas in rodents is dependent on the strain. While rodent strains used in chronic toxicity and carcinogenic studies such as Sprague-Dawley rats and Wistar rat have a low incidence of uterine carcinomas, other strains (Donryu, DA/Han, BDII/Han) have a high incidence of this type of tumor (Nagaoka et al. 1990; 1994; Kaspareit-Rittinghausen et al.1987). In Donryu rats there is a progression from endometrial hyperplasia with atypia at 8 months of age, with increasing incidence and severity degree over time to endometrial carcinoma at 15 months (Nagaoka et al. 1990; 1994). Interesting, these sequential changes are associated to an increased estrogen-to-progesterone ratio, that is 7 times higher at 12 months of age (Nagaoka et al. 1990; 1994).

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 genomic instability and endometrioid adenocarcinoma Type I after estrogen exposure is lacking. TAM 20mg/d increased the incidence of K-ras mutation in the endometrium after 2 to 4 y of treatment in post-menopausal women with breast cancer., Increased risk of endometrial cancer is observed in women with breast cancer after 2-5 y of treatment with TAM (20-40 mg/d).

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

Abal, M., Planaguma, J., Gil-Moreno, A., Monge, M., Gonzalez, M., Baro, T., Garcia, A., Castellvi, J., Ramon Y Cajal, S., Xercavins, J., Alameda, F., & Reventos, J. (2006). Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors. Histology and histopathology, 21(2), 197–204. https://doi.org/10.14670/HH-21.197

Berstein LM, Tchernobrovkina AE, Gamajunova VB, Kovalevskij AJ, Vasilyev DA, Chepik OF, Turkevitch EA, Tsyrlina EV, Maximov SJ, Ashrafian LA, Thijssen JH. Tumor estrogen content and clinico-morphological and endocrine features of endometrial cancer. J Cancer Res Clin Oncol. 2003 Apr;129(4):245-9. doi: 10.1007/s00432-003-0427-9. Epub 2003 Apr 15. PMID: 12695909.

Carthew P, Edwards RE, Nolan BM et al. (1996a). Tamoxifen associated uterine pathology in rodents: relevance to women. Carcinogenesis, 17: 1577–1582. doi:10.1093/carcin/17.8.1577 PMID:8761412

Cushing KL, Weiss NS, Voigt LF, McKnight B, Beresford SA (1998). Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens. Obstet Gynecol 91:35–39.

Ellenson L.H., Pirog E.C. In: Robbins and Cotran Pathologic Basis of Disease. 9th ed. Kumar V., Abbas A.K., Aster J.C., editors. Elsevier/Saunders; 2015. The female genital tract; pp. 280-296

Hayes, M. P., Wang, H., Espinal-Witter, R., Douglas, W., Solomon, G. J., Baker, S. J., & Ellenson, L. H. (2006). PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clinical cancer research : an official journal of the American Association for Cancer Research, 12(20 Pt 1), 5932–5935. https://doi.org/10.1158/1078-0432.CCR-06-1375

Kaspareit-Rittinghausen, J.; Deerberg, F.; Rapp, K. Mortality and incidence of spontaneous neoplasms in BDII/Han rats. Z. Versuchstierkd. 1987, 30, 209–216

Kihana, T., Hamada, K., Inoue, Y., Yano, N., Iketani, H., Murao, S., Ukita, M., & Matsuura, S. (1995). Mutation and allelic loss of the p53 gene in endometrial carcinoma. Incidence and outcome in 92 surgical patients. Cancer, 76(1), 72–78. https://doi.org/10.1002/1097-0142(19950701)76:1<72::aid-cncr2820760110>3.0.co;2-3

Lax, S. F., Kendall, B., Tashiro, H., Slebos, R. J., & Hedrick, L. (2000). The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer, 88(4), 814–824.

Lengauer, C., Kinzler, K. W., & Vogelstein, B. (1998). Genetic instabilities in human cancers. Nature, 396(6712), 643–649. https://doi.org/10.1038/25292

Mäntylä ETE, Karlsson SH, Nieminen LS (1996). Induction of Endometrial Cancer by Tamoxifen in the rat. In: Hormonal Carcinogenesis II Proceedings of the 2nd International Symposium on Hormonal Carcinogenesis. Li JJ, Li SA, Gustafsson JA et al., editors. New York: Springer Verlag, pp. 442–445.

Mutter G. L. (2001). Pten, a protean tumor suppressor. The American journal of pathology, 158(6), 1895–1898. https://doi.org/10.1016/S0002-9440(10)64656-1

Nagaoka, T.; Onodera, H.; Matsushima, Y.; Todate, A.; Shibutani, M.; Ogasawara, H.; Maekawa, A. Spontaneous uterine adenocarcinomas in aged rats and their relation to endocrine imbalance. J. Cancer Res. Clin. Oncol. 1990, 116, 623–628.

Nagaoka, T.; Takeuchi, M.; Onodera, H.; Matsushima, Y.; Ando-Lu, J.; Maekawa, A. Sequential observation of spontaneous endometrial adenocarcinoma development in Donryu rats. Toxicol. Pathol. 1994, 22, 261–269

Oda, K., Stokoe, D., Taketani, Y., & McCormick, F. (2005). High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer research, 65(23), 10669–10673. https://doi.org/10.1158/0008-5472.CAN-05-2620

Risinger, J. I., Dent, G. A., Ignar-Trowbridge, D., McLachlan, J. A., Tsao, M. S., Senterman, M., & Boyd, J. (1992). p53 gene mutations in human endometrial carcinoma. Molecular carcinogenesis, 5(4), 250–253. https://doi.org/10.1002/mc.2940050403

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.

Tashiro, H., Katabuchi, H. (2014). The Relationship Between Estrogen and Genes in the Molecular Pathogenesis of Endometrial Carcinoma. Curr Obstet Gynecol Rep 3, 9–17. https://doi.org/10.1007/s13669-013-0074-3