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Ovarian tumor AND Ovarian functional and neoplastic tumors [keywords]
- A 9-kg Ovarian Mucinous Cystadenoma in a 14-Year-Old Premenarchal Girl. [Journal Article]
- Am J Case Rep 2014.:326-9.
Background Although ovarian tumors are most commonly observed in adults, they relatively rarely occur in children. The majority of ovarian masses encountered in the premenarchal or childhood stages are non-neoplastic lesions such as benign functional cysts. Epithelial tumors account for 8-10% of all ovarian tumors and are histologically classified as mucinous or serous. The most common benign epithelial ovarian tumor is cystadenoma. Case Report We report the case of a 14-year-old premenarchal girl with chronic abdominal pain, constipation, and abdominal enlargement. A computed tomography detected a huge left ovarian cystic tumor. A 9-kg ovarian tumor was removed surgically. Pathology showed a benign mucinous cystadenoma (MCA). Conclusions Ovarian neoplasms in children present a diagnostic quandary, and very often the diagnoses are missed or delayed. When the diagnosis is made, a prompt and fertility-preserving surgical treatment must be performed and followed to prevent recurrence.
- Inferring probabilistic miRNA-mRNA interaction signatures in cancers: a role-switch approach. [JOURNAL ARTICLE]
- Nucleic Acids Res 2014 Mar 7.
Aberrant microRNA (miRNA) expression is implicated in tumorigenesis. The underlying mechanisms are unclear because the regulations of each miRNA on potentially hundreds of mRNAs are sample specific. We describe a novel approach to infer Probabilistic MiRNA-mRNA Interaction Signature ('ProMISe') from a single pair of miRNA-mRNA expression profile. Our model considers mRNA and miRNA competition as a probabilistic function of the expressed seeds (matches). To demonstrate ProMISe, we extensively exploited The Cancer Genome Atlas data. As a target predictor, ProMISe identifies more confidence/validated targets than other methods. Importantly, ProMISe confers higher cancer diagnostic power than using expression profiles alone. Gene set enrichment analysis on averaged ProMISe uniquely revealed respective target enrichments of oncomirs miR-21 and 145 in glioblastoma and ovarian cancers. Moreover, comparing matched breast (BRCA) and thyroid (THCA) tumor/normal samples uncovered thousands of tumor-related interactions. For example, ProMISe-BRCA network involves miR-155/183/21, which exhibits higher ProMISe coupled with coherently higher miRNA expression and lower target expression; oncomirs miR-221/222 in the ProMISe-THCA network engage with many downregulated target genes. Together, our probabilistic approach of integrating expression and sequence scores establishes a functional link between the aberrant miRNA and mRNA expression, which was previously under-appreciated due to the methodological differences.
- In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Proc Natl Acad Sci U S A 2014 Jan 21; 111(3):1102-7.
High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer.
- Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Cancer Res 2014 Feb 15; 74(4):1141-52.
The fallopian tube is now generally considered the dominant site of origin for high-grade serous ovarian carcinoma. However, the molecular pathogenesis of fallopian tube-derived serous carcinomas is poorly understood and there are few experimental studies examining the transformation of human fallopian tube cells. Prompted by recent genomic analyses that identified cyclin E1 (CCNE1) gene amplification as a candidate oncogenic driver in high-grade serous ovarian carcinoma, we evaluated the functional role of cyclin E1 in serous carcinogenesis. Cyclin E1 was expressed in early- and late-stage human tumor samples. In primary human fallopian tube secretory epithelial cells, cyclin E1 expression imparted malignant characteristics to untransformed cells if p53 was compromised, promoting an accumulation of DNA damage and altered transcription of DNA damage response genes related to DNA replication stress. Together, our findings corroborate the hypothesis that cyclin E1 dysregulation acts to drive malignant transformation in fallopian tube secretory cells that are the site of origin of high-grade serous ovarian carcinomas.
- Microtissue density prognostic factor evaluation based on antigens CD34 and CD 105 in ovarian cancer patients. [Journal Article]
- Ann Agric Environ Med 2013; 20(4):838-42.
Uncontrollable cell division and disorders of the apoptotic processes constitute the key phenomena in cancer transformation. The theory that the tumour growth above critical density is possible due to creation of the new blood vessels during angiogenesis process was put forward in 1971 by Folkman. The panendotelial antibodies targeted against such markers as CD34 are used most frequently in cancer vessel evaluation. The anti-CD34 reacts with the largest number of endoepithelial cells. The second group constitutes the antibodies that agglomerate with the antigens characteristic for proliferous endoepithelial cells. The most popular marker used for functional endothelial tissues is endoglin called CD105. The subject of this publication is to find the answer to a question whether the practical usage of the CD34 and CD 105 as a prognostic factor in predicting failure of a planned treatment, determining expected remission and the total survival rate is possible. 74 patients with the diagnosed ovarian cancer, treated in the I Clinic of Gynecology Oncology and Gynecology, Medical University in Lublin, between years 1999-2004 were included into the analysis. Representative paraffin blocks with the embedded ovarian cancer fragments were used for immunohistochemical research. Density of the microvessels was being evaluated basing on the expression of the antigen CD34 and CD105. Evaluation of the microvessel density with CD34 and CD105 markers is not useful in forecasting survival rate and disease recurrence in patients with ovary cancer.
- c-FOS suppresses ovarian cancer progression by changing adhesion. [Journal Article, Research Support, Non-U.S. Gov't]
- Br J Cancer 2014 Feb 4; 110(3):753-63.
C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown.Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis.Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis.In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces.
- Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer. [Journal Article, Research Support, Non-U.S. Gov't]
- Cancer Immunol Immunother 2014 Mar; 63(3):215-24.
The programmed death-1 (PD-1) pathway is important in the maintenance of peripheral tolerance and homeostasis through suppression of T cell receptor signaling. As such, it is employed by many tumors as a means of immune escape. We have investigated the role of this pathway in human ovarian cancer (OC) to assess its potential role as a diagnostic and/or prognostic marker and therapeutic target, following recent clinical trial success of antibody therapy directed at this pathway. We show programmed death ligand-1 (PD-L1) expression on monocytes in the ascites and blood of patients with malignant OC is strikingly higher than those with benign/borderline disease, with no overlap in the values between these groups. We characterize the regulation of this molecule and show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T cells present in the ascites and blood showed a correlation of PD-1 expression with malignant tumors versus benign/borderline, in a similar manner to PD-L1 expression on monocytes. Finally, we demonstrate functional links between PD-L1 expression on monocytes and OC tumor cells with suppression of T cell responses. Overall, we present data based on samples obtained from women with ovarian cancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use with PD-1/PD-L1-directed antibody immunotherapy.
- Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1. [Journal Article]
- Am J Hum Genet 2013 Dec 5; 93(6):1046-60.
The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.
- Ets-1 regulates its target genes mainly by DNA methylation in human ovarian cancer. [Journal Article, Research Support, Non-U.S. Gov't]
- J Obstet Gynaecol 2013 Nov; 33(8):877-81.
Ovarian cancer is the second most common gynaecological cancer worldwide, and its molecular mechanism has not been completely understood. Ets-1 is a member of the Ets transcription family and can play important roles in the regulation of extracellular matrix remodelling, invasion, angiogenesis and drug resistance in several malignancies, including ovarian cancer. In the current study, we downloaded two datasets from Gene Expression Omnibus database and sought to explore the regulation mechanism of Ets-1 in ovarian cancer by computational analysis of gene expression profiles. Microarray analysis identified a total of 548 genes that were regulated by Ets-1 in ovarian cancer. Functional annotation of these genes revealed that Ets-1 may be involved in several biological processes, both physiological and pathological, such as system development, response to stimulus, vascular endothelial growth factor (VEGF) production, morphogenesis, cell proliferation, cell adhesion and signal transduction. Further, DNA methylation analysis of the DEGs found that 26.5% (145) of them were differentially methylated genes in ovarian cancer. Our results provide insight into the mechanism of Ets-1 regulating the transcription of its target genes in the complex and multistep process of ovarian cancer progression.
- [Presumed benign ovarian tumors during pregnancy]. [English Abstract, Journal Article]
- J Gynecol Obstet Biol Reprod (Paris) 2013 Dec; 42(8):842-55.
The incidence of ovarian tumors diagnosed during pregnancy is between 0.3 and 5.4% (LE2). The most common ovarian tumors diagnosed during pregnancy are functional cysts diagnosed incidentally during the first trimester ultrasound (LE2) and spontaneous regression is often observed. Dermoid cysts and cystadenoma are the most frequent organic benign ovarian tumors diagnosed during pregnancy (LE2). The main complication of presumed benign ovarian tumor (PBOT) during pregnancy is adnexal torsion and is estimated at around 8% (LE2), especially at the end of the first trimester and during the second trimester (LE4). Tumor markers are not reliable during pregnancy to assess the risk of malignancy of ovarian tumor (LE2). Ultrasound remains the gold standard for characterizing an ovarian tumor during pregnancy (LE3), but with a lower specificity for the diagnosis of malignancy. Pelvic MRI is accurate in the diagnosis of ovarian tumors during pregnancy and brings additional information to ultrasound (LE4). Ultrasound-guided aspiration of ovarian tumors is not recommended during pregnancy (grade C). Expectation is recommended in cases of PBOT during pregnancy, which does not enlarge (grade C). Whatever the gestational age, surgery is recommended in patients with symptoms suggesting an adnexal torsion (grade C). Laparoscopy is possible during the first and second trimester of pregnancy for the management of symptomatic PBOT (LE3). The risk of miscarriage following surgery (laparoscopy and laparotomy) for ovarian tumor during pregnancy is estimated at 2.8% (LE3). The route of delivery should not be modified by the ovarian tumour, except in case of praevia cyst requiring a cesarean section, a complication or suspicion of malignancy (grade C). Surgical treatment of PBOT may be performed during a cesarean section indicated for another reason. The risk of torsion is increased during the postpartum period (LE4).