title: 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.
authors: Department of PathologyJohns Hopkins Medical InstitutionsBaltimoreMaryland; Department of PathologyHamamatsu University School of Medicine and Seirei Mikatahara HospitalHamamatsuJapan.
authors: Ayse
authors: A
authors: Ayhan
authors: Department of Pathology National Taiwan University College of Medicine Taipei Taiwan.
authors: Tsui-Lien
authors: TL
authors: Mao
authors: Department of Pathology Johns Hopkins Medical Institutions Baltimore Maryland.
authors: Yohan
authors: Y
authors: Suryo Rahmanto
authors: Department of PathologyJohns Hopkins Medical InstitutionsBaltimoreMaryland; Department of Gynecology and ObstetricsUniversity Hospital AachenGermany.
authors: Felix
authors: F
authors: Zeppernick
authors: Department of Pathology Hamamatsu University School of Medicine and Seirei Mikatahara Hospital Hamamatsu Japan.
authors: Hiroshi
authors: H
authors: Ogawa
authors: Department of PathologyJohns Hopkins Medical InstitutionsBaltimoreMaryland; Department of PathologyChang Gung Memorial Hospital and Chang Gung University College of MedicineTaoyuanTaiwan.
authors: Ren-Chin
authors: RC
authors: Wu
authors: Department of Pathology Johns Hopkins Medical Institutions Baltimore Maryland.
authors: Tian-Li
authors: TL
authors: Wang
authors: Department of PathologyJohns Hopkins Medical InstitutionsBaltimoreMaryland; Department of Gynecology and ObstetricsJohns Hopkins Medical InstitutionsBaltimoreMaryland.
authors: Ie-Ming
authors: IeM
authors: Shih
keywords: ARID1A; PTEN; atypical hyperplasia; co‐silencing; endometrioid intraepithelial neoplasia; immunohistochemistry; in vitro cell culture model; proliferation; tumour suppressor