Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

Terakawa, Jumpei; Serna, Vanida A.; Taketo, Makoto Mark; Daikoku, Takiko; Suarez, Adrian A.; Kurita, Takeshi

doi:10.1073/pnas.1814506116

Cited by 25 publications

(21 citation statements)

References 77 publications

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“…However, current models suggest that EIN/AH is a neoplastic process that arises in NAH, a physiologic process 35 . Activating mutations in EMC‐associated genes are often present in EIN/AH, 9,36‐38 in keeping with this model. Expanding these observations, we have shown that NAH harbors mutations, including the most common driver mutations in EMC, such as those involving PTEN , PIK3CA , and KRAS , and this suggests that it is neoplastic in the majority of cases.…”

Section: Discussionmentioning

confidence: 71%

Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma

Russo

Newell

Budurlean

et al. 2020

Cancer

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BACKGROUND: Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression. METHODS: Next-generation sequencing was performed on archived endometrial biopsy specimens from a retrospective cohort of women with endometrial hyperplasia. Cases were considered to be either progressing if the patient subsequently developed EMC or resolving if the patient had a subsequent negative tissue sampling or no cancer during medium-term follow-up (32 patients: 15 progressing and 17 resolving). Somatic mutations in endometrial hyperplasia were assessed for enrichment in progressing cases versus resolving cases, with an emphasis on genes commonly mutated in EMC. RESULTS: Several mutations were more common in progressing hyperplasia than resolving hyperplasia, although significant overlap was observed between progressing and resolving cases. Mutations included those in PTEN, PIK3CA, and FGFR2, genes commonly mutated in EMC. Mutations in ARID1A and MYC were seen only in progressing hyperplasia, although these were uncommon; this limited diagnostic sensitivity. Progressing hyperplasia demonstrated an accumulation of mutations in oncogenic signaling pathways similarly to endometrial carcinoma. CONCLUSIONS: Because of mutational differences between progressing and nonprogressing hyperplasia, mutational analysis may predict the risk of progression from endometrial hyperplasia to EMC. Cancer 2020;126:2775-2783.

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Section: Discussionmentioning

confidence: 71%

Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma

Russo

Newell

Budurlean

et al. 2020

Cancer

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“…Recent work (30) showed that genetic changes in Pten, phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha (Pik3ca), and catenin beta 1 (Ctnnb1) within the mouse uterine epithelium were not sufficient for malignant transformation.…”

Section: No Effect On the Frequency Of Poorly-differentiated Adenocarmentioning

confidence: 99%

“…However, ovarian insufficiency was required for malignant transformation of those "triple" mutant endometrial epithelial cells (30). To determine the effects of ovarian insufficiency in dcKO mice, both ovaries were removed, and uterine weight and histology were assessed.…”

Section: No Effect On the Frequency Of Poorly-differentiated Adenocarmentioning

confidence: 99%

“…Studies showed that triple mutant (Pten, Pik3ca, Ctnnb1) endometrial epithelial cells transformed with steroid hormone depletion in endometrial adenocarcinoma were responsive to progesterone (30). To examine the effects of long-term progesterone therapy, mice underwent removal of ovaries at six weeks and were randomized to either placebo or progesterone pellets at eight weeks.…”

Section: No Effect On the Frequency Of Poorly-differentiated Adenocarmentioning

confidence: 99%

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PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice

Wang

Wendel

Emerson

et al. 2020

Preprint

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Endometrial cancer remains the most common gynecological malignancy in the UnitedStates. While the loss of the tumor suppressor, PTEN (phosphatase and tensin homolog), is well studied in endometrial cancer, recent studies suggest that DICER1, the endoribonuclease responsible for miRNA genesis, also plays a significant role in endometrial adenocarcinoma. In an endometrial adenocarcinoma mouse model, which has a conditional uterine deletion of Pten, Dicer1 was also conditionally deleted.Conditional uterine deletion of Dicer1 and Pten resulted in high-penetrance, poorlydifferentiated endometrial adenocarcinomas. Poorly-differentiated endometrial adenocarcinomas expressed known markers of clear-cell adenocarcinoma, including Napsin A and HNF1B (hepatocyte nuclear factor 1 homeobox B). Adenocarcinomas were hormone-independent, and treatment with long-term progesterone did not mitigate poorly-differentiated adenocarcinoma, nor did it affect adnexal metastasis.Transcriptomic analyses of uteri or Ishikawa cells with deletion of DICER1 revealed unique transcriptomic profiles and global downregulation of miRNAs. Integration of downregulated miRNAs with upregulated mRNA targets revealed deregulated let-7 and miR-16 target genes, similar to published human DICER1-mutant endometrial cancers from TCGA (The Cancer Genome Atlas). Importantly, these miRNA-target genes, involved in ephrin-receptor and transforming growth factor-beta signaling, represent potential clinical targets for rare, yet deadly, poorly-differentiated endometrial adenocarcinomas in women. This mouse model represents poorly-differentiated endometrial adenocarcinoma and will allow for the discovery of novel mechanisms of hormone-independent endometrial adenocarcinoma from atrophic endometrium. Significance StatementEndometrial cancer is one of the few cancers with an increasing death rate in the United States. The most significant risk factor associated with death is high tumor grade, which occurs most frequently in postmenopausal women, where it develops within an atrophic endometrium. Here, we present a mouse model with conditional deletion of Dicer1, a key enzyme in miRNA genesis, and Pten, a tumor suppressor, that develops poorlydifferentiated, steroid hormone-independent, endometrial adenocarcinoma with adnexal metastasis. These high-grade adenocarcinomas develop from an atrophic endometrium and share molecular features with DICER1-mutant human endometrial adenocarcinomas. We anticipate that this preclinical model represents a move toward the discovery of novel mechanisms of hormone-independent development of endometrial adenocarcinoma from atrophic endometrium.

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“…In a transgenic mouse model of OC, malignant transformation in endometriosis with mutation of Kras and p53 deletion within the ovarian surface epithelium showed hyperproliferative endometrioid glandular morphology [154]. Endometrial endometroid cancer (EEC) may be developed in a mouse model by the concurrent involvement of loss of function in PTEN, gain of function of PI3K and CTNNB1 [155].…”

Section: Oncogenes and Tumor Suppressor Genesmentioning

confidence: 99%

How Benign is Endometriosis: Multi-Scale Interrogation of Documented Evidence

Ghosh

Anupa

et al. 2019

COGO

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Endometriosis is an inflammatory disease characterized by the presence of endometrium-like tissue outside the uterus primarily on pelvic organs and tissues. It affects up to 15% of women in the reproductive age group and is often associated with pelvic pain and subfertility. Different theories explain how retrograde menstruation gives rise to endometrial deposits at ectopic sites, and how several other factors are involved in the progression of the disease. Its final diagnosis is established through direct visualization at laparoscopy or surgery followed by histological confirmation. Available epidemiological reports along with histopathological observations and molecular studies shed interesting light on the pathogenetic basis of different variants of the disease like deep infiltrating endometriosis and ovarian endometriosis. Evidence also suggests that endometriosis is a neoplastic condition which serves as a precursor of ovarian and endometrial cancers. In the present review, we have attempted to take a stock of the current epidemiological and molecular knowledge regarding endometriosis associated cancers and develop a model of functional network with interactions among critical genomic factors regulating cellular processes leading to fibrotic reaction. It is being conjectured that cyclic bleeding associated with inflammatory and oxidative stress followed by repeated tissue injury and repair along with recurrent estrogenic stimulation and ovulatory events in the pelvic environment bring about the complex phenotype of atypical endometriosis and associated neoplasm with a trade-off malignant transformation in high risk population. Finally, we have presented an algorithm for pre-emptive monitoring and management of endometriosis-associated cancers.

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Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

Cited by 25 publications

References 77 publications

Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma

Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma

PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice

How Benign is Endometriosis: Multi-Scale Interrogation of Documented Evidence

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