PURPOSE: Loss of AT-rich DNA-interacting domain 1A (ARID1A) has been identified as a driving mutation of ovarian clear cell carcinoma (O-CCC), a triple-negative ovarian cancer that is intermediary between serous and endometrioid subtypes, in regards to molecular and clinical behaviors. However, about half of O-CCCs still express BAF250a, the protein encoded by ARID1A. Herein, we aimed to identify signatures of ARID1A-positive O-CCC in comparison with its ARID1A-negative counterpart. MATERIALS AND METHODS: Seventy cases of O-CCC were included in this study. Histologic grades and patterns of primary tumor, molecular marker immunohistochemistry profiles, and clinical outcomes were analyzed. RESULTS: Forty-eight (69%) O-CCCs did not express BAF250a, which were designated as "ARID1A-negative." The other 22 (31%) O-CCCs were designated as "ARID1A-positive." ARID1A-positive tumors were more likely to be histologically of high grades (41% vs. 10%, p=0.003), ERβ-positive (45% vs. 17%, p=0.011), and less likely to be HNF1β-positive (77% vs. 96%, p=0.016) and E-cadherin-positive (59% vs. 83%, p=0.028) than ARID1A-negative tumors. Patient age, parity, tumor stage were not significantly different in between the two groups. Cancer-specific survival was not significantly different either. CONCLUSION: We classified O-CCCs according to ARID1A expression status. ARID1A-positive O-CCCs exhibited distinct immunohistochemical features from ARID1A-negative tumors, suggesting a different underlying molecular event during carcinogenesis.
Adenocarcinoma, Clear Cell/*metabolism/mortality/pathology ; Adult ; Aged ; Biomarkers, Tumor/metabolism ; Cadherins/metabolism ; Estrogen Receptor beta/metabolism ; Female ; Humans ; Immunohistochemistry ; Middle Aged ; Mutation ; Neoplasm Proteins/*metabolism ; Nuclear Proteins/*metabolism ; Ovarian Neoplasms/*metabolism/mortality/pathology ; Transcription Factors/*metabolism

OBJECTIVETo investigate the factors favoring a positive prognosis for advanced primary peritoneal carcinoma (PPC).

METHODSTwenty-four cases meeting the criteria for PPC were analyzed retrospectively for the clinicopathologic profiles. Immunohistochemistry was used to determine the expressions of p53, Top2alpha, Ki-67 and Her-2/neu. Then all these clinicopathological factors and molecular markers were correlated with the prognosis.

RESULTSThere were 15 cases of primary peritoneal serous papillary carcinoma (PPSPC), 6 cases of mixed epithelial carcinoma (MEC) and 3 cases of malignant mixed Mullerian tumor (MMMT). All patients underwent cytoreductive surgery with optimal debulking achieved in 3 cases. Among those receiving first-line chemotherapy, 13 patients received the TP regimen (paclitaxel-cisplatin or carboplatin) and 7 patients received the PAC regimen (cisplatin-doxorubicin-cyclophosphamide). The median overall survival of all patients was 42 months, while the breakdown for survival time for patients with PPSPC, MMT and MEC was 44, 13 and 19 months, respectively. The expressions of p53, Top2alpha and Ki-67 were all demonstrated in 11 cases respectively. None showed the expression of Her-2/neu. There were significant differences in the median survival between patients with PPSPC and those with MMMT (44 months vs 13 months, P<0.05), also between patients receiving TP combination and those receiving the PAC regimen (75 months vs 28 months, P<0.05). Another significant difference in the median progression-free survival (PFS) was identified between patients with positive p53 immunostaining and those with negative p53 immunostaining (15 months vs 47 months, P<0.05), whereas age, menopausal status, residual tumor size and the other molecular factors did not significantly impact survival.

CONCLUSIONPatients with PPC should be treated with a comprehensive management plan including appropriate cytoreductive surgery and responsive chemotherapy. Overestimating an optimal debulking surgery may not benefit survival. The pathologic subtype, chemotherapy regimen and p53 overexpression were significant prognostic factors.

Adult ; Aged ; Antigens, Neoplasm ; metabolism ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Biomarkers, Tumor ; metabolism ; China ; epidemiology ; Combined Modality Therapy ; Cystadenocarcinoma, Papillary ; metabolism ; mortality ; pathology ; therapy ; DNA Topoisomerases, Type II ; metabolism ; DNA-Binding Proteins ; metabolism ; Female ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; metabolism ; Middle Aged ; Mixed Tumor, Mullerian ; metabolism ; mortality ; pathology ; therapy ; Ovarian Neoplasms ; metabolism ; mortality ; pathology ; therapy ; Peritoneal Neoplasms ; metabolism ; mortality ; pathology ; therapy ; Prognosis ; Receptor, ErbB-2 ; metabolism ; Survival Rate ; Tumor Suppressor Protein p53 ; metabolism

OBJECTIVETo evaluate the two-tier system for the grading of ovarian serous carcinomas, and to analyze Pax2, p53, Ki-67 protein expression and their prognostic values for low- and high-grade ovarian serous carcinomas.

METHODSA total of 38 cases of low-grade and 100 cases of high-grade ovarian serous carcinomas were selected based on the two-tier grading system. Immunohistochemistry was used to detect Pax2, p53 and Ki-67 protein expression in all cases. Correlation of the two-tier system with immunohistochemical results and prognostic parameters were performed.

RESULTS(1) The overall survival, disease-free survival and 5-year survival rates were significantly higher in the low-grade serous carcinoma cases than in the high-grade cases (P < 0.05). (2) Significant differences in protein expressions were found between the low- and high-grade serous carcinomas. The high-grade serous carcinomas had a significantly higher expression level of p53 (55.0% vs 13.2%, P < 0.05) and Ki-67 (42.1% vs 13.7%, P < 0.05), while low-grade carcinomas had a significantly higher expression level of Pax2 (65.8% vs 13.0%, P < 0.05). (3) Pax2 positive cases had a significantly better overall survival and 5-year survival rates than Pax2 negative cases (P < 0.05). The expressions of p53 and Ki-67 were found to have little correlation with overall survival and disease-free survival (P > 0.05).

CONCLUSIONSThe two-tier system for the grading of ovarian serous carcinomas has a good prognostic value. There are significantly differences in expressions of Pax2, p53 and Ki-67 between low- and high-grade ovarian serous carcinomas. Compared with p53 and Ki-67, Pax2 is likely a better prognostic indicator for ovarian serous carcinoma.

CA-125 Antigen ; metabolism ; Cystadenocarcinoma, Serous ; classification ; metabolism ; mortality ; pathology ; Disease-Free Survival ; Female ; Follow-Up Studies ; Humans ; Immunohistochemistry ; Ki-67 Antigen ; metabolism ; Membrane Proteins ; metabolism ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Ovarian Neoplasms ; classification ; metabolism ; mortality ; pathology ; Ovary ; pathology ; PAX2 Transcription Factor ; metabolism ; Survival Rate ; Tumor Suppressor Protein p53 ; metabolism

PURPOSE: Ovarian cancer (OC) is the most fatal of gynecological malignancies with a high rate of recurrence. We aimed to evaluate the expression of solute carrier family 6, member 12 (SLC6A12) and methylation of its promoter CpG sites in a xenograft mouse model of metastatic OC, and to investigate the regulatory mechanisms that promote aggressive properties during OC progression. MATERIALS AND METHODS: Expression of SLC6A12 mRNA was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), and DNA methylation status of its promoter CpGs was detected by quantitative methylation-specific PCR. The metastatic potential of SLC6A12 was evaluated by in vitro migration/invasion transwell assays. Gene expression and DNA methylation of SLC6A12 and clinical outcomes were further investigated from publicly available databases from curatedOvarianData and The Cancer Genome Atlas. RESULTS: SLC6A12 expression was 8.1–14.0-fold upregulated and its DNA methylation of promoter CpG sites was 41–62% decreased in tumor metastases. After treatment with DNA methyltransferase inhibitor and/or histone deacetylase inhibitor, the expression of SLC6A12 was profoundly enhanced (~8.0-fold), strongly supporting DNA methylation-dependent epigenetic regulation of SLC6A12. Overexpression of SLC6A12 led to increased migration and invasion of ovarian carcinoma cells in vitro, approximately 2.0-fold and 3.3-fold, respectively. The meta-analysis showed that high expression of SLC6A12 was significantly associated with poor overall survival [hazard ratio (HR)=1.07, p value=0.016] and that low DNA methylation levels of SLC6A12 at specific promoter CpG site negatively affected patient survival. CONCLUSION: Our findings provide novel evidence for the biological and clinical significance of SLC6A12 as a metastasis-promoting gene.
Animals ; Carrier Proteins/genetics/*metabolism ; Cell Line, Tumor ; Cell Migration Assays ; *CpG Islands ; *DNA Methylation ; Disease Progression ; Epigenesis, Genetic ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Neoplasm Invasiveness ; Neoplasm Transplantation ; Ovarian Neoplasms/genetics/*metabolism/mortality/pathology ; Polymerase Chain Reaction ; Prognosis ; *Promoter Regions, Genetic ; RNA, Messenger/*metabolism ; Up-Regulation