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Relationship: 2829


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

Promotion, ovarian adenomas leads to Promotion, Ovarian Cancer

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia non-adjacent Moderate Low Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development

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
human Homo sapiens High NCBI
mice Mus sp. High 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

Ovarian tumors are abnormal mass of tissues grows on or in the ovaries of the aged females. Ovarian adenomas / cystadenomas are very common and benign type of tumors, which are found in epithelial tissues of the ovaries. Almost 60% of the ovarian tumors are due to the epithelial neoplasm (abnormal growth of tissue) of the ovary (Limaiem et al. 2022). Ovarian adenomas are classified into different categories such as serous cystadenoma, mucinous cystadenoma, endometrioid cystadenoma, clear cell cystadenoma and seromucinous systadenoma. Reports have shown that ovarian serous cystadenoma can turn progress to serous carcinoma (Cheng et al. 2004). Frequent mutations of two genes (BRAF and KRAS) are identified as the cause of the serous carcinoma.

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

Morphological features of the different ovarian adenomas in the epithelium tissue of adult female ovaries are distinct from the each other.  Endometrial hyperplasia in the ovaries of the aged female frequently observed as a consequence of the high level of the estrogen activity in the stroma cells.

MacDonald et al., had shown androstenedione production rate and estrogen level in the postmenopausal woman are five-fold higher than the normally expected level. Increased androstenedione production rate leads towards the formation of mucinous cystadenocarcinoma in the stromal cells of the ovary (MacDonald et al. 1976). Pascal et al., had reported ovarian mucinous cystadenoma with distinct feature  of luteinization of the stroma cells in a 32 year old female patient (Pascal and Grecco 1988). Epithelial neoplasma of the ovary classified as borderline ovarian tumors (BOT), which have separate distinguishing features than the carcinoma.  Ovarian cystadenomas are benign neoplasms present in the epithelial tissues of the patients are also categorised as borderline ovarian tumors. 

Evidence Supporting this KER

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

Nishida et al., had reported the development of adenoma malignum of the uterine cervix associated with the mucinous carcinoma in a female patient (Nishida et al. 1991).

Goedhals et al., had reported development of ovarian mucinous carcinoma arising from the mucinous cystadenoma of the ovary in a 68 yr old female patient (Goedhals et al. 2008).

Smith et al., had shown with the help of immunohistochemistry  the development of sebaceous adenoma arising within a benign ovarian mature cystic teratoma in a 52 yr old female patient (Smith et al. 2011).

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

Cheng et al., had reported the sub-classification of Ovarian adenomas / cystadenoma based on the cell types such as serous cystadenoma, mucinous cystadenoma and endometrioid cystadenoma (Cheng et al. 2004). Possible molecular genetic alteration associated with the high grade serous and endometrioid cystadenoma are mutation in TP53 gene and dysfunction of BRCA1 and/or BRCA 2 gene. Whereas, low grade serous carcinoma or borderline serous cystadenoma occurred via activation of the RAS-RAF signaling pathway and frequent mutations in BRAF or KRAS genes. Mucinous cystadenoma is originated in germ cells and often related with mutation in KRES gene (Beroukhim et al. 2021). Only 2-4% of the ovarian tumors are accounted for the endometrioid cystadenoma (Tsukahara et al. 1982). Endometrioid cystadenoma is related to the mutations in CTNNB1 and PTEN gene (Bell 2005, Sanseverino et al. 2005, Wei et al. 2012).

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

Balat  et al., had reported the detection of unthreatened late pregnancy with a large mucinous cyst adenoma of the ovary in a female patient (Balat et al. 2002). Vidhale et al., had reported the detection of serous cystadenoma in the ovary, which is benign in nature (Vidhale et al. 2022).  Mittal, et al., had reported the detection of benign type of mucinous cystadenoma in the ovary (Mittal et al. 2008).

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
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
Not know      
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Horn et al., had evaluated the 74 cases of borderline ovarian tumors and shown that majority of the cases are belongs to the serous borderline ovarian tumors (60.8%), followed by the mucinous borderline ovarian tumors (25.7%).  Adenoma in the borderline ovarian tumors was found in  86.5% cases. The report had suggested that the association of papillary tubal hyperplasia and salpingoliths   with the borderline ovarian tumors (Horn et al. 2017).

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

Observed in months to years

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

Not known

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

Observed in adult female (human) also in rodents.


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

Balat, O., Kutlar, I., Erkilic, S., Sirikci, A., Aksoy, F. and Aydin, A. (2002) Unthreatened late pregnancy with a huge mucinous cyst adenoma of the left ovary: report of an unusual case. Eur J Gynaecol Oncol 23(1), 84-85.

Bell, D.A. (2005) Origins and molecular pathology of ovarian cancer. Mod Pathol 18 Suppl 2, S19-32.

Beroukhim, G., Ozgediz, D., Cohen, P.J., Hui, P., Morotti, R., Schwartz, P.E., Yang, H. and Vash-Margita, A. (2021) Progression of Cystadenoma to Mucinous Borderline Ovarian Tumor in Young Females: Case Series and Literature Review. J Pediatr Adolesc Gynecol 35(3), 359-367.

Cheng, E.J., Kurman, R.J., Wang, M., Oldt, R., Wang, B.G., Berman, D.M. and Shih, I.-M. (2004) Molecular genetic analysis of ovarian serous cystadenomas. Laboratory Investigation 84(6), 778-784.

Chodankar, R., Kwang, S., Sangiorgi, F., Hong, H., Yen, H.Y., Deng, C., Pike, M.C., Shuler, C.F., Maxson, R. and Dubeau, L. (2005) Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells. Curr Biol 15(6), 561-565.

Dey, P., Nakayama, K., Razia, S., Ishikawa, M., Ishibashi, T., Yamashita, H., Kanno, K., Sato, S., Kiyono, T. and Kyo, S. (2022) Development of Low-Grade Serous Ovarian Carcinoma from Benign Ovarian Serous Cystadenoma Cells. Cancers (Basel) 14(6).

Goad, J., Ko, Y.-A., Kumar, M., Jamaluddin, M.F.B. and Tanwar, P.S. (2018) Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling. Carcinogenesis 39(9), 1105-1116.

Goedhals, J., van der Merwe, J., Yazbek, V.A. and Beukes, C.A. (2008) Adenoma malignum-like mucinous ovarian carcinoma. Histopathology 53(3), 352-354.

Horn, L.C., Angermann, K., Hentschel, B., Einenkel, J. and Hohn, A.K. (2017) Frequency of papillary tubal hyperplasia (PTH), salpingoliths and transition from adenoma to borderline ovarian tumors (BOT): A systematic analysis of 74 BOT with different histologic types. Pathol Res Pract 213(4), 305-309.

Limaiem, F., Lekkala, M.R. and Mlika, M. (2022) Ovarian Cystadenoma.

MacDonald, P.C., Grodin, J.M., Edman, C.D., Vellios, F. and Siiteri, P.K. (1976) Origin of estrogen in a postmenopausal woman with a nonendocrine tumor of the ovary and endometrial hyperplasia. Obstet Gynecol 47(6), 644-650.

Mittal, S., Gupta, N., Sharma, A.K. and Dadhwal, V. (2008) Laparoscopic management of a large recurrent benign mucinous cystadenoma of the ovary. Arch Gynecol Obstet 277(4), 379-380.

Nishida, T., Ushijima, K., Oda, T., Sugiyama, T., Tsuji, Y., Imaishi, K. and Yakushiji, M. (1991) Minimal deviation adenocarcinoma (adenoma malignum) of the uterine cervix associated with mucinous ovarian carcinoma. Kurume Med J 38(4), 265-269.

Pascal, R.R. and Grecco, L.A. (1988) Mucinous cystadenoma of the ovary with stromal luteinization and hilar cell hyperplasia during pregnancy. Hum Pathol 19(2), 179-180.

Saloniemi, T., Lamminen, T., Huhtinen, K., Welsh, M., Saunders, P., Kujari, H. and Poutanen, M. (2007) Activation of androgens by hydroxysteroid (17beta) dehydrogenase 1 in vivo as a cause of prenatal masculinization and ovarian benign serous cystadenomas. Mol Endocrinol 21(11), 2627-2636.

Sanseverino, F., D'Andrilli, G., Petraglia, F. and Giordano, A. (2005) Molecular pathology of ovarian cancer. Anal Quant Cytol Histol 27(3), 121-124.

Smith, J., Crowe, K., McGaughran, J. and Robertson, T. (2011) Sebaceous adenoma arising within an ovarian mature cystic teratoma in Muir-Torre syndrome. Ann Diagn Pathol 16(6), 485-488.

Tsukahara, Y., Shiozawa, I., Sakai, Y., Ishii, J., Iwai, S. and Fukuta, T. (1982) Study on the histogenesis of ovarian tumors--with special reference to five clinical cases with common epithelial tumors detected during the preclinical stage. Nihon Sanka Fujinka Gakkai Zasshi 34(7), 959-965.

Vidhale, S.A., Chavarkar, S.P., Sudhamani, S. and Rao, R. (2022) Cholesterolosis of ovary associated with benign serous cystadenoma. Indian J Pathol Microbiol 65(2), 496-498.

Wei, X., Lu, Q.J., Sun, H.X., Qi, Y.F., Wang, J.O. and Cao, C.C. (2012) [Expression and significance of p-AKT, p-GSK3beta and beta-catenin in epithelial carcinoma of ovary]. Zhonghua Bing Li Xue Za Zhi 41(2), 86-90.

Yamagata, S., Yamamoto, K., Tsuchida, S., Kawamura, N., Matsumoto, Y., Ueki, S. and Sugawa, T. (1989) Estrogen production in epithelial tumors of the ovary--clinical and endocrinological study in postmenopausal women. Nihon Sanka Fujinka Gakkai zasshi 41(11), 1761-1768.