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Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma.

ABSTRACT: Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the approximately 12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1 beta (HNF-1 beta). We validated up-regulation of HNF-1 beta in CCC in terms of both mRNA and protein level using real-time quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Immunohistochemical analysis of 83 surgically resected ovarian cancers showed that almost all CCC specimens (21 of 22 cases) had nuclear staining for HNF-1 beta, whereas most non-CCC specimens (60 of 61 cases) showed no immunostaining or only focal and faint staining in the nucleus. Furthermore, we investigated the significance of HNF-1 beta expression in CCC using RNA interference. The reduction of HNF-1 beta expression by RNA interference induced apoptotic cell death in ovarian CCC cells, which was confirmed by terminal dUTP nick-end labeling and fluorescence-activated cell-sorting analyses. Our results suggest that HNF-1 beta is not only an excellent CCC-specific molecular marker but also a molecular target for therapy of ovarian CCC.

SUBMITTER: Tsuchiya A

PROVIDER: S-EPMC1892387 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma.

Tsuchiya Akira A Sakamoto Michiie M Yasuda Jun J Chuma Makoto M Ohta Tsutomu T Ohki Misao M Yasugi Toshiharu T Taketani Yuji Y Hirohashi Setsuo S

The American journal of pathology 20031201 6

Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the approximately 12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1 beta (HNF-1 beta). We validated up-regulatio ...[more]

PMID: 14633622

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Project description:BACKGROUND: Clear cell carcinomas are aggressive tumors with a distinct biologic behaviour. In a genome-wide screening for genes involved in chemo-resistance, NAPA was over-expressed in cisplatin-resistant cells. The NAPA (protein) Napsin A was described to promote resistance to cisplatin by degradation of the tumor suppressor p53. METHODS: Totally 131 patients were included in this study all in FIGO-stages I-II; 16 were clear cell tumors which were compared with 40 Type I tumors and 75 type II tumors according to the markers Napsin A, p21, p53 and p27 and some clinical features. For detection of the markers tissue microarrays and immunohistochemistry were used. RESULTS: Positivity for Napsin A was detected in 12 (80%) out of the 15 clear cell tumors available for analysis compared with 3 (4%) out of the Type I and II tumors in one group (p<0.001). Differences in p21 status, p53 status, and p21+p53- status were striking when clear cell tumors were compared with Type I, Type II, and Type I and II tumors in one group, respectively. The p21+p53-status was associated to positive staining of Napsin A (p=0.0015) and clear cell morphology (p=0.0003). In two separate multivariate logistic regression analyses with Napsin A as endpoint both clear cell carcinoma with OR=153 (95% C.I. 21-1107); (p<001) and p21+p53- status with OR=5.36 (95% C.I. 1.6-17.5); (p=0.005) were independent predictive factors. ROC curves showed that AUC for Napsin A alone was 0.882, for p21+p53- it was 0.720 and for p21+p53-Napsin A+AUC was 0.795. Patients with clear cell tumors had lower (p=0.013) BMI than Type I patients and were younger (p=0.046) at diagnosis than Type II patients. Clear cell tumors had a higher frequency (p=0.039) of capsule rupture at surgery than Type I and II tumors. CONCLUSIONS: Positivity of Napsin A in an epithelial ovarian tumor might strengthen the morphological diagnosis of clear cell ovarian carcinoma in the process of differential diagnosis between clear cell ovarian tumors and other histological subtypes.

Project description:BackgroundAdvanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets.Patients and methodsTumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis.ResultsThe most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%).ConclusionsThis large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.

Dataset Information

Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma.

Publications

Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma.

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