cyclin-d1 and Cystadenocarcinoma--Serous

Chemoresistance is the major obstacle to effective treatment in patients with serous ovarian carcinoma (SOC), which frequently related to the failure of chemotherapeutic agents to induce apoptosis. In this study, the immunohistochemical expression of Apaf-1, Cyclin D1, and Aquaporin-5 (AQP-5) was studied in 50 paraffin blocks of SOC. Data on overall survival (OS), disease-free survival (DFS) and response to the first-line chemotherapy were collected and then statistically analyzed. Apaf-1 expression was observed in 84% of the SOC cases with a significant down-regulation with higher tumor grade, lymph node metastasis, and advanced FIGO stage. Cyclin D1 expression was found in 70% of the cases with a significant up-regulation with higher tumor grade, lymph node metastasis, and advanced FIGO stage. Positive AQP-5 expression was noted in 84% of the cases with a significant positive association with higher tumor grade, lymph node metastasis, and advanced FIGO stage. During the follow-up period, the Apaf-1 expression had a significant negative association with OS and DFS (p < 0.001 for each), while both Cyclin D1 and AQP-5 expression had a significant positive association with unfavorable OS and DFS. The cases of SOC treated with suboptimal surgery revealed a significant association of low Apaf-1, high Cyclin D1, and strong AQPs with the poor response to the first-line chemotherapy (p = 0.047, p < 0.001, and 0.006 respectively).. Down-regulation of Apaf-1 protein and the overexpression of Cyclin D1 and AQP-5 proteins possibly contribute to an aggressive SOC with a high risk of recurrence and poor response to the first-line chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptotic Protease-Activating Factor 1; Aquaporin 5; Biomarkers, Tumor; Carboplatin; Cyclin D1; Cystadenocarcinoma, Serous; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Middle Aged; Neoplasm Grading; Ovarian Neoplasms; Paclitaxel; Prognosis; Survival Rate; Treatment Outcome

Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n=42), mutation (n=75), methylation (n=31), and SNP array analyses (n=75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1+ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P=0.016) compared with the p16 heterogeneous/RB1+ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1- subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1- subgroup showed a significant increase in overall survival (>60 months; P=0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1- subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1+ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1+ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical outcomes. Furthermore, deregulations identified in precursor lesions suggest a key role of this pathway in serous tumor development. Recognition of these categories may identify patients with increased sensitivity to chemotherapy and new opportunities for novel therapeutics.

Topics: Alleles; Biomarkers, Tumor; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p16; Cystadenocarcinoma, Serous; Disease-Free Survival; Female; Humans; Immunohistochemistry; Middle Aged; Mutation; Oncogene Proteins; Ovarian Neoplasms; Prognosis; Retinoblastoma Protein

Ovarian serous cancer is the most common subtype of epithelial ovarian cancer, and is the leading cause of death from gynecologic cancer. There is an important need for exploration of diagnostic and prognostic markers for this disease. β-catenin and cyclinD1 play central roles in the tumorigenesis for certain cancers. The role of β-catenin and cyclinD1 in diagnosis and prognosis of ovarian serous carcinoma is uncertain. In the present study, the expression of β-catenin and cyclinD1 was examined in 60 ovarian serous carcinomas patients with immunohistochemical staining. The relationship between expression of β-catenin and cyclinD1 and FIGO stage, pathological grade was analyzed. Kaplan-Meier survival function was used to analyze the prognosis. Overexpression of β-catenin is more often detected in patients with FIGO stage III and IV than in those with stage I, and II (P=0.003). No significant relationship was found between expression of β-catenin and pathological grade (P=0.817). Positive expression of β-catenin related to lower survival rate (P=0.034). The expression of cyclinD1 had no relationship with FIGO stage (P=0.829). Overexpression of cyclinD1 was positively to pathological grade (P=0.017) and survival rate (P=0.009). There is a significantly positive relationship between expression of β-catenin and cyclinD1 (P=0.014). No statistical significance was found between expression of β-catenin and cyclinD1 and other pathological parameters.. Expression of β-catenin and cyclinD1 may be used as predict markers for poor prognosis.

Topics: Adult; Aged; beta Catenin; Biomarkers, Tumor; Cyclin D1; Cystadenocarcinoma, Serous; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Up-Regulation; Young Adult

Gene methylation and other epigenetic modifications of gene regulation have been implicated in the growth of ovarian cancer, but the clinical significance of such modifications in the Notch pathway in high-grade serous ovarian cancer (HGS-OvCa) is not well understood. We used The Cancer Genome Atlas (TCGA) data to study the clinical relevance of epigenetic modifications of Notch superfamily genes.. We analyzed the interaction of DNA methylation and miRNAs with gene expression data for Notch superfamily members with the Spearman rank correlation test and explored potential relationships with overall survival (OS) with the log-rank test. We downloaded clinical data, level 3 gene expression data, and level 3 DNA methylation data for 480 patients with stage II-IV HGS-OvCa from the TCGA data portal. Patients were randomly divided into training and validation cohorts for survival analyses. In each set, patients were grouped into percentiles according to methylation and microRNA (miRNA) or messenger RNA (mRNA) levels. We used several algorithms to predict miRNA-mRNA interaction.. There were significant inverse relationships between methylation status and mRNA expression for PPARG, CCND1, and RUNX1. For each of these genes, patients with a lower methylation level and higher expression level had significantly poorer OS than did patients with a higher methylation level and lower expression level. We also found a significant inverse relationship between miRNAs and mRNA expression for CCND1, PPARG, and RUNX1. By further analyzing the effect of miRNAs on gene expression and OS, we found that patients with higher levels of CCND1, PPARG, and RUNX1 expression and lower expression levels of their respective miRNAs (502-5p, 128, and 215/625) had significantly poorer OS.. Epigenetic alterations of multiple Notch target genes and pathway interacting genes (PPARG, CCND1, and RUNX1) may relate to activation of this pathway and poor survival of patients with HGS-OvCa.

Topics: Core Binding Factor Alpha 2 Subunit; Cyclin D1; Cystadenocarcinoma, Serous; DNA Methylation; Epigenomics; Female; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Ovarian Neoplasms; PPAR gamma; Receptors, Notch; RNA, Messenger; Survival Analysis

Our previous study has suggested that the cell cycle-related kinase (CCRK) is a putative candidate oncogene in glioblastoma tumorigenesis. The potential oncogenic role of CCRK and its clinical/prognostic significance, however, in ovarian carcinoma are unclear. In this study, CCRK expression was examined by immunohistochemistry in a series of ovarian carcinoma tissues. Overexpression of CCRK was detected in 53% of the ovarian carcinomas, and it was positively correlated with an ascending histological grade and/or advanced clinical stage of the disease (p < 0.05). In addition, overexpression of CCRK in ovarian carcinoma was determined to be a strong and an independent predictor of short overall survival (p < 0.05). In ovarian carcinoma cells, CCRK knockdown by RNAi led to a G1 phase cell cycle arrest, while CCRK overexpression by stable transfection of CCRK-containing plasmid pcDNA-CCRK promoted cell proliferation in vitro and tumor growth in vivo. In addition, CCRK knockdown was found to reduce cyclin D1 expression. Consistently, CCRK overexpression increased cyclin D1 expression, and furthermore, a significant correlation between expression of CCRK and cyclin D1 in ovarian carcinomas was observed (p < 0.001). These findings suggest a potential important role of CCRK in the control of cell proliferation via regulation of cyclin D1 expression, and the overexpression of CCRK, as detected by immunohistochemistry, is an independent molecular marker for shortened survival time of patients with ovarian carcinoma.

Topics: Adult; Aged; Animals; Apoptosis; Blotting, Western; Case-Control Studies; Cell Proliferation; Cohort Studies; Cyclin D1; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Cystadenocarcinoma, Serous; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Mice; Mice, Inbred BALB C; Middle Aged; Ovarian Neoplasms; Ovary; Phosphorylation; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Survival Rate; Tissue Array Analysis; Tumor Cells, Cultured

To study the clinicopathological features and expression of cyclin D1 and p53 in epithelial ovarian tumors, and to investigate the correlation between pathogenesis of ovarian cancer and epithelial borderline tumors.. Fifty four cases of ovarian borderline tumors and 45 cases of ovarian carcinomas from the People's Hospital, Peking University were reviewed retrospectively. The clinical data and pathological findings were analyzed. Immunohistochemical study of cyclin D1 and p53 was performed in all 99 cases.. (1) In borderline tumors, the age of patients ranged from 14 - 82 (mean age = 42.5) years. International Federation of Gynecology and Obstetrics (FIGO) stage of borderline tumors was stage I in 48 cases, stage II in 3 cases, and stage III in 3 cases. In ovarian carcinomas, the age of patients ranged from 26 - 80 (mean age = 53.5) years. FIGO stage of carcinoma was stage I in 6 cases, stage II in 8 cases, stage III in 26 cases, and stage IV in 5 cases. In follow-up of 54 cases with borderline tumors the 5-year survival rate was 98% and of 45 cases with carcinomas a 5-year survival rate of 51% was noted. (2) In 54 cases of borderline tumors, mucinous types accounted for 56% (30/54) and serous types accounted for 30% (16/54). There were 5 cases with micropapillary pattern, 3 cases with peritoneal implants, 3 cases with lymph node involvement, 6 cases with microinvasion, one case with intraepithelial carcinoma, and one case with mural nodules. In 45 cases of carcinomas, serous carcinoma was the most (49%, 22/45). The remainder included 3 cases of mucinous types, 8 cases of endometrioid types, 6 cases of transitional cell types, 3 cases of mixed phenotype and 3 cases of undifferentiated types. (3) Overexpression of cyclin D1 and p53 was observed in 31% (14/45) and 56% (25/45) of ovarian carcinomas, respectively. There was a significant association between p53 overexpression and tumor grade. In the borderline tumor group, 69% (37/54) had overexpression of cyclin D1 and 6% (3/54) had overexpression of p53. There were significant differences in expression of cyclin D1 and p53 between conventional serous borderline tumors and high-grade serous carcinomas (cyclin D1: 91% vs 26%; p53: 0 vs 58%). However, micropapillary serous borderline tumors and low-grade serous carcinomas showed remarkably similar expression of cyclin D1 and p53.. Epithelial ovarian borderline tumors are distinct from ovarian cancer in clinical progress and prognosis, and histological types. Overexpression of cyclin D1 is common in ovarian borderline tumors and low grade carcinomas. And overexpression of p53 is more common in high grade ovarian carcinomas. Conventional serous borderline tumors are distinct from high-grade serous carcinomas in pathogenesis. Micropapillary serous borderline ovarian tumors may be closely related to low grade serous carcinomas.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cyclin D1; Cystadenocarcinoma, Mucinous; Cystadenocarcinoma, Serous; Female; Humans; Immunohistochemistry; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Tumor Suppressor Protein p53

Activation of mitogen-activated protein kinase (MAPK) occurs in response to various growth stimulating signals and as a result of activating mutations of the upstream regulators, KRAS and BRAF, which can be found in many types of human cancer. To investigate the roles of MAPK activation in tumors harboring KRAS or BRAF mutations, we inactivated MAPK in ovarian tumor cells using CI-1040, a compound that selectively inhibits MAPK kinase, an upstream regulator of MAPK and thus prevents MAPK activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated tumor cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. Long serial analysis of gene expression identified several differentially expressed genes in CI-1040-treated MPSC1 cells harboring an activating mutation in BRAF (V599L). The most striking changes were down-regulation of cyclin D1, COBRA1, and transglutaminase-2 and up-regulation of tumor necrosis factor-related apoptosis-induced ligand, thrombospondin-1, optineurin, and palladin. These patterns of gene expression were validated in other CI-1040-treated tumor cells based on quantitative PCR. Constitutive expression of cyclin D1 partially reversed the growth inhibitory effect of CI-1040 in MPSC1 cells. Our findings indicate that an activated MAPK pathway is critical in tumor growth and survival of ovarian tumors with KRAS or BRAF mutations and suggest that the CI-1040 induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian tumors.

Topics: Apoptosis; Benzamides; Calcium-Calmodulin-Dependent Protein Kinases; Cell Cycle; Cyclin D1; Cystadenocarcinoma, Serous; Female; Gene Expression Profiling; Genes, ras; Humans; Mitogen-Activated Protein Kinases; Mutation; Ovarian Neoplasms; Proto-Oncogene Proteins B-raf; Signal Transduction; Tumor Cells, Cultured

Dysregulation of cell cycle control, in particular G(1)-S-phase transition, is implicated in the pathogenesis of most human cancers, including epithelial ovarian cancer (EOC). However, the prognostic significance of aberrant cell cycle gene expression in EOC remains unclear.. The expression of selected genes from the pRb pathway that regulates G(1)-S-phase progression, including cyclin D1, p16(Ink4a), cyclin E, p27(Kip1), p21(Waf1/Cip1), and p53, was examined in a consecutive series of 134 serous EOC using immunohistochemistry and the results correlated to disease outcome.. Molecular markers predictive of reduced overall survival in univariate analysis were overexpression of cyclin D1 (P = 0.03) and p53 (P = 0.03) and reduced expression of p27(Kip1) (P = 0.05) and p21(Waf1/Cip1) (P = 0.02), with the latter three also being prognostic for a shorter progression-free interval. In addition, patients displaying overexpression of p53 with concurrent loss of p21(Waf1/Cip1) had a significantly shorter overall (P = 0.0008) and progression-free survival (P = 0.0001). On multivariate analysis, overexpression of cyclin D1 and combined loss of p21(Waf1/Cip1) in the presence of p53 overexpression were independent predictors of overall survival. Similarly, the combination of p21(Waf1/Cip1) loss and p53 overexpression was independently predictive of a shorter progression-free interval. Overexpression of p53 and cyclin E and reduced expression of p27(Kip1) and p21(Waf1/Cip1) were significantly associated with increasing tumor grade.. This study confirms that dysregulation of cell cycle genes is common in EOC, and that aberrant expression of critical cell cycle regulatory proteins can predict patient outcome in serous EOC.

Topics: Biomarkers, Tumor; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Cystadenocarcinoma, Serous; Disease Progression; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Odds Ratio; Ovarian Neoplasms; Proportional Hazards Models; Risk; Time Factors; Treatment Outcome; Tumor Suppressor Protein p53

Malignant transformation of endometriosis, an uncommon phenomenon, can occur in gonadal and extragonadal sites and results in a wide histological range of tumors. Published series reporting malignant transformation of endometriosis have largely been confined to clinical and histopathological discussions with no studies reporting oncoprotein expression and genetic alterations. We report three cases of carcinomas arising in ovarian endometriosis: a serous cystadenocarcinoma, an endometrioid carcinoma with squamous differentiation, and a pure squamous cell carcinoma. Each tumor was analyzed immunohistochemically to compare oncoprotein expression (p53, bcl2, cyclin D1, and c-erb B2) between the tumors and the endometriotic tissue as well as with comparative genomic hybridization (CGH) to compare genetic alterations. All three tumors expressed nuclear p53, in contrast to the endometriotic tissue in which no p53 expression was found. Both endometrial and tumor tissue expressed bcl-2. No expression of cyclin D1 or c-erb B2 was detected in endometriotic or tumoral tissues. The CGH analysis revealed one or two chromosomal aberrations in each of the three tumors with gains on chromosomes 1q, 8q, and 13q, and losses on chromosome 10p. The endometriotic tissue, as expected, showed a normal genetic profile. These results suggest that p53 protein abnormalities and chromosomal aberrations may be involved in malignant transformation of endometriosis in the ovary. However, our results are limited by the number of cases examined and a definite conclusion on the pathogenesis of this process should be followed by future studies with a larger number of cases.

Topics: Adult; Carcinoma, Endometrioid; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Chromosome Aberrations; Cyclin D1; Cystadenocarcinoma, Serous; DNA; Endometriosis; Female; Humans; Immunohistochemistry; Middle Aged; Nucleic Acid Hybridization; Ovarian Diseases; Ovarian Neoplasms; Receptor, ErbB-2; Tumor Suppressor Protein p53

Although early stage ovarian cancer can be effectively treated with surgery and chemotherapy, the majority of cases present with advanced disease, which remains essentially incurable. Unfortunately, little is known about the genes important for the development and progression of this disease. In this study, the expression of 68 phosphatases was determined in immortalized ovarian epithelial cells (IOSE) and compared to ovarian cancer cell lines. CL100, a dual specificity phosphatase, displayed 10-25-fold higher expression in normal compared to malignant ovarian cell lines. Immunohistochemical staining of normal ovaries and 68 ovarian cancer specimens confirmed this differential expression. Re-expression of CL100 in ovarian cancer cells decreased adherent and non-adherent cell growth and induced phenotypic changes including loss of filopodia and lamellipodia with an associated decrease in cell motility. Induced expression of CL100 in ovarian cancer cells suppressed intraperitoneal tumor growth in nude mice. These results show for the first time that CL100 expression is altered in human ovarian cancer, that CL100 expression changes cell morphology and motility, and that it suppresses intraperitoneal growth of human ovarian epithelial cancer. These data suggest that down-regulation of CL100 may play a role in the progression of human ovarian cancer.

Topics: Adenocarcinoma, Papillary; Animals; Blotting, Northern; Blotting, Western; Cell Adhesion; Cell Cycle Proteins; Cell Differentiation; Cell Movement; Cyclin D1; Cystadenocarcinoma, Serous; DNA Primers; Down-Regulation; Dual Specificity Phosphatase 1; Epithelial Cells; Female; Humans; Immediate-Early Proteins; Immunoenzyme Techniques; Luciferases; Mice; Mice, Nude; Ovarian Neoplasms; Phosphoprotein Phosphatases; Phosphoric Monoester Hydrolases; Polymerase Chain Reaction; Protein Phosphatase 1; Protein Tyrosine Phosphatases; RNA; Tumor Cells, Cultured