Mutation and methylation profiles of ectopic and eutopic endometrial tissues

Li, Lihong; Antero, Maria Facadio; Zhang, Ming; Chu, Tiffany; Seckin, Tamer; Ayhan, Ayşe; Pisanic, Thomas R.; Wang, Tian‐Li; Cope, Leslie; Segars, James H.; Shih, Ie‐Ming

doi:10.1002/path.5778

Cited by 8 publications

(5 citation statements)

References 55 publications

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“…Implanted tissue proliferates at the affected sites, and eventually forms endometriotic lesions 3 . In support of this hypothesis, previous studies demonstrated that eutopic and ectopic endometrial tissue shared the same somatic gene variants 4 – 6 .…”

Section: Introductionmentioning

confidence: 58%

Establishment of a novel model of endometriosis-associated ovarian cancer by transplanting uterine tissue from Arid1a/Pten knockout mice

Ono

Miyamoto

Asaka

et al. 2023

Sci Rep

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Although endometriosis is primarily benign, it has been identified as a risk factor for endometriosis-associated ovarian cancer (EAOC). Genetic alterations in ARID1A, PTEN, and PIK3CA have been reported in EAOC; however, an appropriate EAOC animal model has yet to be established. Therefore, the present study aimed to create an EAOC mouse model by transplanting uterine pieces from donor mice, in which Arid1a and/or Pten was conditionally knocked out (KO) in Pax8-expressing endometrial cells by the administration of doxycycline (DOX), onto the ovarian surface or peritoneum of recipient mice. Two weeks after transplantation, gene KO was induced by DOX and endometriotic lesions were thereafter removed. The induction of only Arid1a KO did not cause any histological changes in the endometriotic cysts of recipients. In contrast, the induction of only Pten KO evoked a stratified architecture and nuclear atypia in the epithelial lining of all endometriotic cysts, histologically corresponding to atypical endometriosis. The induction of Arid1a; Pten double-KO evoked papillary and cribriform structures with nuclear atypia in the lining of 42 and 50% of peritoneal and ovarian endometriotic cysts, respectively, which were histologically similar to EAOC. These results indicate that this mouse model is useful for investigating the mechanisms underlying the development of EAOC and the related microenvironment.

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Section: Introductionmentioning

confidence: 58%

Establishment of a novel model of endometriosis-associated ovarian cancer by transplanting uterine tissue from Arid1a/Pten knockout mice

Ono

Miyamoto

Asaka

et al. 2023

Sci Rep

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“…We used laser capture-microdissection to enrich the epithelial cells. Genomic DNA from individual specimen was extracted using the QIAmp formalin-fixed and paraffin-embedded DNA tissue kit (Qiagen, 56404), as previously reported 5,25 …”

Section: Methodsmentioning

confidence: 99%

Morphologic and Molecular Heterogeneity of High-grade Serous Carcinoma Precursor Lesions

Chien,

Wang,

Huang

et al. 2024

American Journal of Surgical Pathology

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Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC (P<0.0001) and were found concurrently with HGSC (P<0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index (P<0.0001), presence of epithelial stratification (P<0.0001), and increased lymphocyte density (P<0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs (P<0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.

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“…Sequencing of epithelial and stromal cells in superficial and deep infiltrating lesions reveals characteristic somatic mutation profiles for each cell type derived from different clones suggesting each cell type is supported by their own stem/progenitor population ( 91 , 115 , 122 ). In support of this, both mesenchymal and epithelial stem/progenitor markers have been identified in ectopic lesions ( 25 , 29 , 29 , 76 , 123 – 125 ) ( Figure 3 ).…”

Section: Role Of Stem/progenitor Cells In Menstrual Disorders/regener...mentioning

confidence: 99%

Endometrial Stem/Progenitor Cells–Their Role in Endometrial Repair and Regeneration

Cousins

Filby

Gargett

2022

Front. Reprod. Health

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The human endometrium is a remarkable tissue, undergoing ~450 cycles of proliferation, differentiation, shedding (menstruation), repair, and regeneration over a woman's reproductive lifespan. Post-menstrual repair is an extremely rapid and scar-free process, with re-epithelialization of the luminal epithelium completed within 48 h of initiation of shedding. Following menstruation, the functionalis grows from the residual basalis layer during the proliferative phase under the influence of rising circulating estrogen levels. The regenerative capacity of the endometrium is attributed to stem/progenitor cells which reside in both the epithelial and stromal cell compartments of the basalis layer. Finding a definitive marker for endometrial epithelial progenitors (eEPCs) has proven difficult. A number of different markers have been suggested as putative progenitor markers including, N-cadherin, SSEA-1, AXIN2, SOX-9 and ALDH1A1, some of which show functional stem cell activity in in vitro assays. Each marker has a unique location(s) in the glandular epithelium, which has led to the suggestion that a differentiation hierarchy exists, from the base of epithelial glands in the basalis to the luminal epithelium lining the functionalis, where epithelial cells express different combinations of markers as they differentiate and move up the gland into the functionalis away from the basalis niche. Perivascular endometrial mesenchymal stem cells (eMSCs) can be identified by co-expression of PDGFRβ and CD146 or by a single marker, SUSD2. This review will detail the known endometrial stem/progenitor markers; their identity, location and known interactions and hierarchy across the menstrual cycle, in particular post-menstrual repair and estrogen-driven regeneration, as well as their possible contributions to menstruation-related disorders such as endometriosis and regeneration-related disorder Asherman's syndrome. We will also highlight new techniques that allow for a greater understanding of stem/progenitor cells' role in repair and regeneration, including 3D organoids, 3D slice cultures and gene sequencing at the single cell level. Since mouse models are commonly used to study menstruation, repair and regeneration we will also detail the mouse stem/progenitor markers that have been investigated in vivo.

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Mutation and methylation profiles of ectopic and eutopic endometrial tissues

Cited by 8 publications

References 55 publications

Establishment of a novel model of endometriosis-associated ovarian cancer by transplanting uterine tissue from Arid1a/Pten knockout mice

Establishment of a novel model of endometriosis-associated ovarian cancer by transplanting uterine tissue from Arid1a/Pten knockout mice

Morphologic and Molecular Heterogeneity of High-grade Serous Carcinoma Precursor Lesions

Endometrial Stem/Progenitor Cells–Their Role in Endometrial Repair and Regeneration

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