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Relationship: 2973
Title
Genomic instability leads to endometrioid adenocarcinoma Type I
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite | Under Review |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
Sex Applicability
Sex | Evidence |
---|---|
Female |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages |
Key Event Relationship Description
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
Evidence Supporting this KER
Biological Plausibility
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
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
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
Quantitative Understanding of the Linkage
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
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
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