Recently, the ARID1A gene has been identified as a novel tumor suppressor in ovarian clear cell carcinoma. The prognostic significance of the loss of ARID1A expression is not known. The current study was designed to evaluate whether ARID1A was a prognostic factor for progression, survival, and chemoresistance in ovarian clear cell carcinoma. A total of 60 patients, who were surgically treated for primary ovarian clear cell adenocarcinoma, were enrolled. Surgical specimens were examined for ARID1A protein expression by immunohistochemistry. The correlations between the loss of ARID1A expression and clinicopathological characteristics, prognosis, and chemosensitivity were investigated. Loss of ARID1A expression was identified in 9 (15.0%) of 60 ovarian clear cell carcinoma samples. Loss of ARID1A staining intensity (0 þ ) was more frequently found in cells of clear cell carcinomas than in high-grade serous carcinomas (Po0.01). Loss of ARID1A expression was significantly correlated with advanced FIGO stage and high CA125 levels (P ¼ 0.02, 0.01). There were no significant correlations between loss of ARID1A expression and patient age, status of residual tumor, Ki-67 labeling index, or the status of endometriosis. Loss of ARID1A correlated with shorter progression-free survival of patients with clear cell carcinomas treated with platinum-based chemotherapy (Po0.01). Loss of ARID1A expression tended to correlate with shorter overall survival in patients with ovarian clear cell carcinomas treated with platinum-based chemotherapy. When data were stratified for the multivariate analysis, only the loss of ARID1A expression remained a significant (P ¼ 0.03) predictor of reduced progressionfree survival. Of the 60 patients with ovarian clear cell carcinomas, 14 patients had measurable residual tumor after primary cytoreductive surgery. Tumors with loss of ARID1A expression were more likely to be chemoresistant than tumors with positive ARID1A expression (100.0 vs 40.0%, P ¼ 0.04). This study demonstrates that loss of ARID1A in ovarian clear cell carcinoma is a negative prognostic factor in patients treated with platinum-based chemotherapy. Measurement of ARID1A expression may be a method to predict resistance to platinum-based chemotherapy in patients with ovarian clear cell carcinoma.

BACKGROUND:The goal of this study was to examine the clinical significance of ZNF217 amplification and assess whether ZNF217 could be a potential therapeutic target in ovarian clear cell carcinoma (OCCC). METHODS: ZNF217 expression and amplification in OCCC was assessed by immunohistochemistry, fluorescence in situ hybridization, and clinical data collected via a retrospective chart review. ZNF217 gene knockdown using silencing RNA (siRNA) was used to assess ZNF217 functions in OCCC cell lines. RESULTS: Gene amplification was identified in 12 of 60 (20.0%) OCCCs. ZNF217 copy number correlated significantly with ZNF217 protein expression (r ¼ 0.341; P<.01). ZNF217 amplification correlated significantly with shorter progression-free (P ¼.0042) and overall (P ¼.0199) survival. There were nonsignificant trends between high ZNF217 protein expression and poor progression-free (P ¼.2594) and overall (P ¼.2199) survival. Multivariate analysis revealed ZNF217 gene amplification to be an independent prognostic factor for progression-free and overall survival after standard platinum agent-based chemotherapy (P ¼.0339 and P ¼.031, respectively). Profound growth inhibition and apoptosis were observed in ZNF217 siRNA-treated cancer cells with gene amplification compared with cancer cells with ZNF217 moderate expression without ZNF217 gene amplification or with low ZNF217 expression. CONCLUSION: These findings indicate that ZNF217 overexpression is critical to growth and survival of OCCCs with ZNF217 gene amplification. Furthermore, they suggest that ZNF217 siRNAinduced phenotypes depend on amplification status of OCCCs. Therefore, ZNF217-targeted therapy may benefit OCCC patients with ZNF217 amplification.

Background:The aim of this study was to investigate the patterns of epidermal growth factor receptor (EGFR) overexpression, EGFR gene amplification, and the presence of activating mutations in the tyrosine kinase domain of this gene in squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas of the uterine cervix.Methods:The EGFR expression, amplification, and mutation in cervical carcinomas were assessed by immunohistochemistry, fluorescence in situ hybridisation, and PCR–SSCP, respectively, and correlated with clinical data collected by a retrospective chart review. A functional assessment was performed by inactivating EGFR in cervical cancer cells with the potent inhibitor AG1478.Results:Immunohistochemical analysis revealed that 6 out of 59 (10.2%) cervical squamous cell carcinomas showed significant amplification of the EGFR locus, whereas none of the 52 adeno/adenosquamous cell carcinomas had detectable EGFR amplification (P<0.05). The EGFR amplification significantly correlated with shorter overall survival (P=0.001) in cervical squamous cell carcinomas. Multivariate analysis showed that EGFR gene amplification was an independent prognostic factor for overall survival (P=0.011). None of the squamous cell carcinomas (0%: 0 out of 32) had detectable oncogenic mutations in EGFR exons 18 through 21. The frequencies of KRAS and BRAF mutations were very low in both squamous and adeno/adenosquamous cell carcinomas. Sensitivity of cervical cancer cells to AG1478 depended on the presence of EGFR overexpression. AG1478-induced EGFR inactivation in cell lines with EGFR overexpression significantly suppressed tumour development and progression in a mouse xenograft model.Conclusion:Our data suggest that EGFR signalling is important in a subset of cervical squamous cell carcinomas and that anti-EGFR therapy may benefit patients who carry the 7p11.2 amplicon in their tumours.

This study examined the clinical significance of Notch3 expression and assessed its usefulness as a potential therapeutic target in chemoresistant ovarian cancer. Notch3 expression was assessed with immunohistochemical examination, and clinical variables were collected with a retrospective chart review. Notch3 siRNA or γ-secretase inhibitor was used to assess Notch3 function in ovarian cancer cell lines. Notch3 overexpression correlated with shorter progression-free/overall survival in patients with advanced stage (stage III, IV) ovarian carcinoma treated with platinum and taxane. Three of 5 patients showed increased Notch3 immunostaining in recurrent tumors compared with corresponding primary tumors. Notch3 overexpression was observed in both the cisplatin-resistant KFr13 and cisplatin/paclitaxel-resistant KFr13Tx cells. Inactivation of Notch3 by γ-secretase inhibitor or siRNA decreased cell proliferation and induced apoptosis in the KFr13 and KFr13Tx cells. Our findings suggest that Notch3 expression may be related to chemoresistance and that the Notch3 pathway may represent a novel therapeutic target for advanced stage chemoresistant ovarian cancer.

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The clinicopathological significance of amplification was investigated of the gene encoding cyclin E (CCNE1) and we assessed whether CCNE1 was a potential target in endometrioid endometrial carcinomas. CCNE1 amplification and CCNE1 or F-box and WD repeat domain-containing 7 (FBXW7) expression in endometrial endometrioid carcinoma was assessed by immunohistochemistry and fluorescence in situ hybridization. CCNE1 knockdown by small interfering RNA (siRNA) was used to assess the CCNE1 function. The results showed that CCNE1 amplification was present in 9 (8.3%) of 108 endometrial carcinomas. CCNE1 amplification was correlated with high histological grade (Grade 3; P=0.0087) and lymphovascular space invasion (P=0.0258). No significant association was observed between CCNE1 amplification and FIGO stage (P=0.851), lymph node metastasis (P=0.078), body mass index (P=0.265), deep myometrial invasion (P=0.256), menopausal status (P=0.289) or patient age (P=0.0817). CCNE1 amplification was significantly correlated with shorter progression-free and overall survival (P=0.0081 and 0.0073, respectively). CCNE1 protein expression or loss of FBXW7 expression in endometrial endometrioid carcinoma tended to be correlated with shorter progression-free and overall survival; however, this difference was not statistically significant. Multivariate analysis showed that CCNE1 amplification was an independent prognostic factor for overall survival but not for progression-free survival (P=0.0454 and 0.2175, respectively). Profound growth inhibition was observed in siRNA-transfected cancer cells with endogenous CCNE1 overexpression compared with that in cancer cells having low CCNE1 expression. CCNE1 amplification was independent of p53, HER2, MLH1 and ARID1A expression but dependent on PTEN expression in endometrial carcinomas. These findings indicated that CCNE1 amplification was critical for the survival of endometrial endometrioid carcinomas. Furthermore, the effects of CCNE1 knockdown were dependent on the CCNE1 expression status, suggesting that CCNE1-targeted therapy may be beneficial for patients with endometrial endometrioid carcinoma having CCNE1 amplification.

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