Molecular Pathogenesis of Ovarian Clear Cell Carcinoma

Gounaris, Ioannis; Brenton, James D.

doi:10.2217/fon.15.45

Cited by 29 publications

(25 citation statements)

References 127 publications

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“…This is in contrast with a previous study that stated that, in gastric cancer, reduced ARID1A expression down-regulates E-cadherin transcription 25. We suspect a hidden significance of HNF1β overexpression here 26. The functional role of HNF1β overexpression in O-CCC has not yet been derived,15 although it may also be mediated by E-cadherin: knock down of HNF1 has been shown to reduce E-cadherin expression and promote epithelial-mesenchymal transition 16.…”

Section: Discussioncontrasting

confidence: 74%

Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

et al. 2017

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PurposeLoss 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 MethodsSeventy 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.ResultsForty-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.ConclusionWe 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.

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Section: Discussioncontrasting

confidence: 74%

Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

et al. 2017

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“…Ovarian clear cell carcinoma (OCCC) accounts for approximately 5–25% of epithelial ovarian cancers (EOCs) with varying incidence by population . Though rare, it presents a unique treatment challenge.…”

Section: Introductionmentioning

confidence: 99%

Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma

Bixel

Saini

Bid

et al. 2017

Intl Journal of Cancer

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Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy. STAT3 expression and activation has been shown to regulate tumor progression in various human cancers, though has not been well studied in OCCC. Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples. Significantly, pSTAT3 is expressed in the absence of other forms of activated STAT (pSTAT1, 2, 6). Therefore, this work was planned to investigate the role of STAT3 and examine the efficacy of a novel anti-cancer compound -HO-3867, which is an inhibitor of STAT3, using known OCCC cell lines. Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant. STAT3 overexpression increased the migration capability in OVTOKO cells in vitro and led to an increased tumor size when injected in vivo. The inhibitory effect of HO-3867 on cell proliferation and cell survival was accompanied by increased apoptosis, within 24 h post treatment. Treatment with HO-3867 resulted in a decrease in Bcl-2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867. In addition, HO-3867 significantly inhibited formation of HUVEC cells capillary-like structures and invasion at both 5 and 10μM concentrations. STAT3 expression plays an important role in the spread of OCCC in vitro as well as in vivo. Thus, we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in OCCC cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standard chemotherapy regimens.

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“…HGSOC are thought to be derived from fallopian tube secretory epithelial cells through foci of endosalpingiosis existing as inclusion cysts lined with tubal epithelium at the ovarian and peritoneal surface 2 . In contrast, CCOC, ENOC, and sero-endometrioid carcinomas appear to develop from endometriosis 3,4 . MOC resembles adenocarcinoma of the gastric pylorus, intestine, or endocervix and the majority of these tumors show gastrointestinal differentiation 5 .…”

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confidence: 96%

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Phelan¹,

Kuchenbaecker²,

Tyrer³

et al. 2017

Nat Genet

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423

454

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To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3, 9q31.1) and one for endometrioid EOC (5q12.3). We then meta-analysed the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified an additional three loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a novel susceptibility gene for low grade/borderline serous EOC.

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Molecular Pathogenesis of Ovarian Clear Cell Carcinoma

Cited by 29 publications

References 127 publications

Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

Ovarian Clear Cell Carcinoma Sub-Typing by ARID1A Expression

Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

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