Clinicopathological Significance of Loss of ARID1A Immunoreactivity in Ovarian Clear Cell Carcinoma

Abstract

Recent genome-wide analysis has demonstrated that somatic mutations in ARID1A (BAF250) are the most common molecular genetic changes in ovarian clear cell carcinoma (OCCC). ARID1A mutations, which occur in approximately half of OCCC cases, lead to deletion of the encoded protein and inactivation of the putative tumor suppressor. In this study, we determined the significance of loss of ARID1A immunoreactivity with respect to several clinicopathological features in a total of 149 OCCCs. First, we demonstrated that ARID1A immunohistochemistry showed concordance with the mutational status in 91% of cases with 100% sensitivity and 66% specificity. Specifically, among 12 OCCC cases for which ARIDA mutational status was known, ARIDIA immunoreactivity was undetectable in all 9 cases harboring ARID1A mutations and was undetectable in one of 3 cases with wild-type ARID1A. With respect to the entire cohort, ARID1A immunoreactivity was undetectable in 88 (59%) of 149 OCCCs. There was no significant difference between ARID1A negative and positive cases in terms of histopathologic features, age, clinical stage, or overall survival. In conclusion, this study provides further evidence that mutations in ARID1A resulted in loss of ARID1A protein expression in OCCC, although no significant differences between ARID1A positive and negative cases were observed with respect to any clinicopathological features examined.

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

“…In previous studies, molecular alterations in ovarian clear cell carcinomas, including ARID1A, PIK3CA, and ZNF217, were either not considered a prognostic factor or signified different conclusions. 22,24,[32][33][34][35][36][37] Our study is the first report on the prognostic impact of TERT promoter mutations in early-stage ovarian clear cell carcinomas. TERT promoter mutations may have a role in the development of chemoresistance, but more in-depth investigations are necessary.…”

“…22 The ARID1A immunoreactivities were divided into either undetectable or positive (weakly or strongly) for nuclear staining, and stromal cells were used as an internal positive control. 24 …”

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

“…2 In ovarian cancer, near half of the clear-cell subtype and 30% of the endometrioid subtype showed ARID1A mutations, 3 particularly those that are related to endometriosis. 4,5 In endometrial cancer, mutations in the ARID1A gene have been reported in approximately 30% of both low-and high-grade endometrioid endometrial cancers (EECs) but not in serous endometrial carcinomas. [6][7][8] ARID1A encodes a large nuclear protein involved in chromatin remodeling and interacts with several other proteins, including the core protein SMARCD3, to form the so-called switch/sucrose non-fermentable (SWI/SNF) complex.…”

Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

“…Lack of BAF250a, as a potential early event in the carcinogenesis, could possibly serve as screening for endometriotic lesions at high-risk for the development of ovarian clear cell carcinomas or endometrioid ovarian carcinomas. 29 We used immunohistochemical staining of BAF250a (ARID1A) as a surrogate marker for ARID1A mutations as previously validated, 7,11,13 as the small endometriotic samples obtained after laparoscopic biopsies would not yield a sufficient amount of DNA for screening ARID1A mutations after microdissection Figure 2 Immunoreactivity score in endometriosis and endometrium. The immunoreactivity score 14 for BAF250a was significantly lower in ovarian endometriosis compared with eutopic endometrium (Po0.0005), to peritoneal endometriosis (P ¼ 0.003) and to deep-infiltrating endometriosis (P ¼ 0.02), as represented in this chart diagram (calculated with a Kruskal-Wallis test).…”

“…After antigen retrieval with CC1m-heatinduced epitope retrieval, the slides were incubated with a monoclonal mouse ARID1A antibody (AB-GENT, code: AT1188a), as previously validated, 7,11,13 which was diluted 1:200 in Ventana dilution buffer. After incubation for 1 h at room temperature, the staining was further conducted with the Ventana Benchmark automated system (Ventana Medical Systems, Tuscon, AZ, USA).…”