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

The Journal of Pathology: Clinical Research

Ayse Ayhan²  Tsui-Lien Mao³  Yohan Suryo Rahmanto²  Felix Zeppernick²  Hiroshi Ogawa¹  Ren-Chin Wu²  Tian-Li Wang² 

[1] Department of Pathology, Hamamatsu University School of Medicine and Seirei Mikatahara Hospital, Hamamatsu, Japan;Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland;Department of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan

关键词: atypical hyperplasia;    endometrioid intraepithelial neoplasia;    PTEN;    ARID1A;    tumour suppressor;    proliferation;    immunohistochemistry;    co‐silencing;    in vitro cell culture model;   

DOI  :  10.1002/cjp2.22

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY-NC-ND   
© 2015 John Wiley and Sons Ltd and The Pathological Society of Great Britain and Ireland

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