Dataset Information

Increased proliferation in atypical hyperplasia/endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors.

ABSTRACT: Uterine endometrioid carcinoma is the most common neoplastic disease in the female genital tract and develops from a common precursor lesion, atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN). Although the genomic landscape of endometrioid carcinoma has been recently revealed, the molecular alterations that contribute to tumour progression from AH/EIN to carcinoma remain to be elucidated. In this study, we used immunohistochemistry to determine if loss of expression of two of the most commonly mutated tumour suppressors in endometrioid carcinoma, PTEN and ARID1A, was associated with increased proliferation in AH/EIN. We found that 80 (70%) of 114 cases exhibited decreased or undetectable PTEN and 17 (15%) of 114 cases had focal loss of ARID1A staining. ARID1A loss was focal, while PTEN loss was diffuse, and all specimens with ARID1A loss had concurrent PTEN loss (p?=?0.0003). Mapping the distribution of PTEN and ARID1A staining in the same specimens demonstrated that all AH/EIN areas with ARID1A loss were geographically nested within the areas of PTEN loss. A significant increase in the proliferative activity was observed in areas of AH/EIN with concurrent loss of PTEN and ARID1A compared to immediately adjacent AH/EIN areas showing only PTEN loss. In a cell culture system, co-silencing of ARID1A and PTEN in human endometrial epithelial cells increased cellular proliferation to a greater degree than silencing either ARID1A or PTEN alone. These results suggest an essential gatekeeper role for ARID1A that prevents PTEN inactivation from promoting cellular proliferation in the transition of pre-cancerous lesions to uterine endometrioid carcinoma.

SUBMITTER: Ayhan A

PROVIDER: S-EPMC4939882 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Increased proliferation in atypical hyperplasia/endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors.

Ayhan Ayse A Mao Tsui-Lien TL Suryo Rahmanto Yohan Y Zeppernick Felix F Ogawa Hiroshi H Wu Ren-Chin RC Wang Tian-Li TL Shih Ie-Ming IeM

The journal of pathology. Clinical research 20150527 3

Uterine endometrioid carcinoma is the most common neoplastic disease in the female genital tract and develops from a common precursor lesion, atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN). Although the genomic landscape of endometrioid carcinoma has been recently revealed, the molecular alterations that contribute to tumour progression from AH/EIN to carcinoma remain to be elucidated. In this study, we used immunohistochemistry to determine if loss of expression of two of ...[more]

PMID: 27499903

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Project description:Endometrial cancer is the most common gynecologic malignancy in developed countries. Estrogen-dependent tumors (type I, endometrioid) account for 80% of cases and non-estrogen-dependent (type II, non-endometrioid) account for the rest. Endometrial cancer type I is generally thought to develop via precursor lesions along with the increasing accumulation of molecular genetic alterations. Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia is the least common type of hyperplasia but it is the type most likely to progress to type I cancer, whereas endometrial hyperplasia without atypia rarely progresses to carcinoma. MicroRNAs are a class of small, non-coding, single-stranded RNAs that negatively regulate gene expression mainly binding to 3'-untranslated region of target mRNAs. In the current study, we identified a microRNAs signature (miR-205, miR-146a, miR-1260b) able to discriminate between atypical and typical endometrial hyperplasia in two independent cohorts of patients. The identification of molecular markers that can distinguish between these two distinct pathological conditions is considered to be highly useful for the clinical management of patients because hyperplasia with an atypical change is associated with a higher risk of developing cancer. We show that the combination of miR-205, -146a, and -1260b has the best predictive power in discriminating these two conditions (>90%). With the aim to find a biological role for these three microRNAs, we focused our attention on a common putative target involved in endometrial carcinogenesis: the oncosuppressor gene SMAD4. We showed that miRs-146a,-205, and-1260b directly target SMAD4 and their enforced expression induced proliferation and migration of Endometrioid Cancer derived cell lines, Hec1a cells. These data suggest that microRNAs-mediated impairment of the TGF-β pathway, due to inhibition of its effector molecule SMAD4, is a relevant molecular alteration in endometrial carcinoma development. Our findings show a potential diagnostic role of this microRNAs signature for the accurate diagnosis of Endometrial hyperplasia with atypia/Endometrial Intraepithelial Neoplasia and improve the understanding of their pivotal role in SMAD4 regulation.

Project description:Purpose:Report a case of corneal melt in a patient with conjunctival intraepithelial neoplasia (CIN) treated with topical interferon (IFN) alpha-2B. Observations:An 89-year-old man presented with gelatinous paralimbal lesions of the left eye extending onto the cornea with corneal neovascularization extending 5-6 clock hours. Nasally there was mild absence of the terminal vascular loops of the limbal palisades of Vogt and conjunctivalization. Diffuse punctate epithelial erosions were noted. The corneal graft displayed subepithelial and stromal edema. Anterior segment optical coherence tomography detected hyperreflectivity, sectional thickened epithelium, and abrupt transitions from normal to abnormal tissue. The patient was treated with excision of the corneal and conjunctival lesions with cryotherapy to the conjunctival borders. Excisional biopsy revealed CIN Grade 3 and carcinoma in situ of the cornea. Topical IFN alpha-2B four times daily was initiated postoperatively. Two months later, a central epithelial defect developed. The cornea progressively thinned and corneal melt ensued. The patient had several risk factors for corneal melt including neurotrophic cornea, early limbal stem cell deficiency, history of cryotherapy, keratoconjunctivitis sicca, and chronic use of glaucoma medications and steroid medications. Conclusions:Interferon alpha-2B is an effective first line treatment for CIN with few side effects. It's side effects include punctate epithelial erosions, conjunctival hyperemia, and follicular conjunctivitis. We report a case of pre-existing keratoconjunctivitis sicca, early limbal stem cell deficiency, neurotrophic cornea, and newly diagnosed CIN Grade 3; it was treated with surgical excision, cryotherapy, and topical IFN alpha-2b with development of corneal melt 2 months later. Caution should be taken when using interferon alpha -2b in patients with pre-existing keratoconjunctivitis sicca, neurotrophic cornea, or limbal stem cell deficiency as it could exacerbate these conditions resulting in corneal melt.

Project description:IntroductionPrevious studies have suggested that metformin use may enhance the therapeutic effect of progestin therapy for endometrial hyperplasia or malignancy. However, it is not known how the impact of concurrent metformin may be altered by route of progestin therapy, either locally via an intrauterine device or systemically. This study examined the effectiveness of concurrent metformin use and progestin therapy for women with complex atypical hyperplasia stratified by progestin route (systemic vs local).MethodsThis single-institution retrospective study examined consecutive women with complex atypical hyperplasia who received progestin therapy from 2003 to 2018. Time-dependent analyses for complete response rate were performed comparing concurrent metformin users versus non-users in the oral progestin group and in the levonorgestrel-releasing intrauterine device group.ResultsAcross the study cohort (n=245), there were 137 (55.9%) women who responded to progestin therapy. In the oral progestin group (n=176), the median age and body mass index were 36 years and 37.7 kg/m2, respectively. 36 (20.5%) of women on oral progestins also took metformin. After controlling for diabetes status, women taking both oral progestins and metformin had a complete response rate similar to those not taking metformin (6 month cumulative rates, 23.1% vs 27.8%, adjusted hazard ratio (aHR) 0.71, 95% confidence interval (95% CI) 0.36 to 1.41). In the levonorgestrel-releasing intrauterine device group (n=69), the median age and body mass index were 35 years and 39.9 kg/m2, respectively. There were 15 (21.7%) women who took metformin in addition to the levonorgestrel-releasing intrauterine device. After controlling for diabetes status, women who had the levonorgestrel-releasing intrauterine device and took metformin had a significantly higher complete response rate compared with those not taking metformin (6 month cumulative rates, 86.7% vs 58.9%, aHR 2.31, 95% CI 1.09 to 4.89).ConclusionIn a predominantly obese population, concurrent metformin may possibly offer treatment benefit when used with the levonorgestrel-releasing intrauterine device.

Dataset Information

Increased proliferation in atypical hyperplasia/endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors.

Publications

Increased proliferation in atypical hyperplasia/endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors.

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