A catalog of numerical centrosome defects in epithelial ovarian cancers
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ABSTRACT:
SUBMITTER: Dr. Renata Basto
PROVIDER: S-SCDT-EMM-2022-15670 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:BackgroundDespite our substantial understanding of molecular mechanisms and gene mutations involved in cancer, the technical approaches for diagnosis and prognosis of cancer are limited. In routine clinical diagnosis of cancer, the procedure is very basic: nuclear morphology is used as a common assessment of the degree of malignancy, and hence acts as a prognostic and predictive indicator of the disease. Furthermore, though the atypical nuclear morphology of cancer cells is believed to be a consequence of oncogenic signaling, the molecular basis remains unclear. Another common characteristic of human cancer is aneuploidy, but the causes and its role in carcinogenesis are not well established.MethodsWe investigated the expression of the nuclear envelope proteins lamin A/C in ovarian cancer by immunohistochemistry and studied the consequence of lamin A/C suppression using siRNA in primary human ovarian surface epithelial cells in culture. We used immunofluorescence microscopy to analyze nuclear morphology, flow cytometry to analyze cellular DNA content, and fluorescence in situ hybridization to examine cell ploidy of the lamin A/C-suppressed cells.ResultsWe found that nuclear lamina proteins lamin A/C are often absent (47%) in ovarian cancer cells and tissues. Even in lamin A/C-positive ovarian cancer, the expression is heterogeneous within the population of tumor cells. In most cancer cell lines, a significant fraction of the lamin A/C-negative population was observed to intermix with the lamin A/C-positive cells. Down regulation of lamin A/C in non-cancerous primary ovarian surface epithelial cells led to morphological deformation and development of aneuploidy. The aneuploid cells became growth retarded due to a p53-dependent induction of the cell cycle inhibitor p21.ConclusionsWe conclude that the loss of nuclear envelope structural proteins, such as lamin A/C, may underlie two of the hallmarks of cancer--aberrations in nuclear morphology and aneuploidy.
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Project description:Objective:To identify the frequency of BRCA mutation in patients with high grade epithelial ovarian cancer (EOC). Methods:Patients with EOC included fallopian tube cancer or peritoneal cancer with high grade serous or high grade endometrioid were recruited. BRCA1 and BRCA2 mutations were tested and analyzed by next generation sequencing system. Results:A total of 87 patients were recruited; majority of them (88.5%) were EOC, 5.7% fallopian tube cancer, 4.6% peritoneal cancer, and 1.1% synchronous primary ovarian and endometrial cancer. Seventy-four patients (85.1%) had high grade serous carcinoma and 13 patients (14.9%) had high grade endometrioid carcinoma. Germline BRCA mutation was detected in 19 patients (21.8%); 14 patients (16.1%) had BRCA1 mutation and 5 patients (5.7%) had BRCA2 mutation. All BRCA mutations were found in patients with high grade serous carcinoma (25.7%) but none in high grade endometrioid carcinoma. Six from 19 patients (31.6%) who had BRCA mutation had no family history of breast and ovarian cancers. Higher frequency of BRCA mutation was detected in patients with fallopian tube cancer; 3 in 5 patients (60%) followed by peritoneal cancer; 2 in 4 patients (50%), and EOC; 14 in 77 patients (18.2%). Conclusion:The frequency of BRCA mutation in high grade serous carcinoma was 25.7%, none was found in high grade endometrioid carcinoma. High cost, unavailability of genetic testing, limited number of geneticists, may be barriers in limited resource countries. Selected patients especially high grade serous carcinoma should be considered initially.
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Project description:Epithelial ovarian cancer (EOC) consists of 5 major histotypes: high-grade serous carcinoma (HGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), mucinous carcinoma (MC), and low-grade serous carcinoma (LGSC). Each can have a broad spectrum of morphologic appearances, and 1 histotype can closely mimic histopathologic features more typical of another. Historically, there has been a relatively high frequency of mixed, defined by 2 or more distinct histotypes present on the basis of routine histopathologic assessment, histotype carcinoma diagnoses (3% to 11%); however, recent immunohistochemical (IHC) studies identifying histotype-specific markers and allowing more refined histotype diagnoses suggest a much lower incidence. We reviewed hematoxylin and eosin-stained slides from 871 cases of EOC and found the frequency of mixed carcinomas to be 1.7% when modern diagnostic criteria are applied. Through international collaboration, we established a cohort totaling 22 mixed EOCs, consisting of 9 EC/CCC, 4 EC/LGSC, 3 HGSC/CCC, 2 CCC/MC, and 4 other combinations. We interrogated the molecular differences between the different components of each case using IHC, gene expression, and hotspot sequencing analyses. IHC data alone suggested that 9 of the 22 cases were not mixed tumors, as they presented a uniform immuno-phenotype throughout, and these cases most probably represent morphologic mimicry and variation within tumors of a single histotype. Synthesis of molecular data further reduces the incidence of mixed carcinomas. On the basis of these results, true mixed carcinomas with both morphologic and molecular support for the presence of >1 histotype within a given tumor represent <1% of EOCs.
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Project description:ObjectiveTo describe how population-based statistics for rare epithelial ovarian cancers are evolving.MethodsThis is a retrospective observational study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2016. Overall survival (OS) of clear cell (OCCC), mucinous (MOC), and low-grade serous (LGSOC) ovarian cancers were compared to high-grade serous ovarian cancer (HGSOC) by fitting a propensity score matching.ResultsAmong 113,365 ovarian malignancies, 5780 OCCCs (5.1%), 7561 MOCs (6.7%), and 2021 LGSOCs (1.8%) were compared to 38,199 HGSOCs. OCCCs and MOCs were more likely to be diagnosed with stage I disease compared to HGSOC (57.0-59.5% versus 8.6%, P<0.001). For early-stage disease, OCCC (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.82-1.01) and MOC (HR 0.94, 95%CI 0.85-1.04) had similar OS to HGSOC whereas LGSOC had superior OS (HR 0.93, 95%CI 0.89-0.97) versus HGSOC. Conversely, for advanced-stage disease, OCCC (HR 1.42, 95%CI 1.32-1.53) and MOC (HR 1.11, 95%CI 1.09-1.13) had poorer OS whereas LGSOC (HR 0.86, 95%CI 0.84-0.89) had superior OS compared to HGSOC. OCCC (HR range, 1.92-2.45) and MOC (HR range, 1.73-2.22) had particularly poorer OS in the first three years following diagnosis compared to HGSOC. Population-level statistics for advanced-stage disease showed that 5-year OS rates have increased in HGSOC (16.9% to 36.8%, P<0.001) and LGSOC (50.8% to 66.4%, P=0.010); but remain unchanged for OCCC (21.0% to 28.2%, P=0.174) and MOC (21.4% to 16.5%, P=0.102).ConclusionOCCC, MOC, and LGSOC comprise 2-7% of ovarian malignancies, have distinct characteristics and survival compared to HGSOC. While these rare tumors have a favorable to comparable prognosis in early-stage disease, disproportionally poor survival in advanced-stage OCCC and MOC highlights the need for further research into novel treatment strategies.
| S-EPMC7526050 | biostudies-literature
Project description:Non-epithelial ovarian cancers (NEOC) are a group of uncommon malignancies that mainly includes germ cell tumours (GCT), sex cord-stromal tumours (SCST), and some extremely rare tumours, such as small cell carcinomas and sarcomas. Each of these classifications encompasses multiple histologic subtypes. The aetiology and molecular origins of each sub-group of NEOC require further investigation, and our understanding on the genetic changes should be optimised. In this article, we provide an update on the clinical presentation, pathology, genetics, treatment and survival of the main histological subtypes of the GCT and the SCST, as well as of ovarian small cell carcinomas. We also discuss miRNA expression profiles of NEOC and report the currently active clinical trials that include NEOC.
| S-EPMC8834485 | biostudies-literature
Project description:There has been significant progress in the understanding of the pathology and molecular biology of rare ovarian cancers, which has helped both diagnosis and treatment. This paper provides an update on recent advances in the knowledge and treatment of rare ovarian cancers and identifies gaps that need to be addressed by further clinical research. The topics covered include: low-grade serous, mucinous, and clear cell carcinomas of the ovary. Given the molecular heterogeneity and the histopathological rarity of these ovarian cancers, the importance of designing adequately powered trials or finding statistically innovative ways to approach the treatment of these rare tumors has been emphasized. This paper is based on the Rare Ovarian Tumors Conference for Young Investigators which was presented in Tokyo 2015 prior to the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG).
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Project description:Purpose: DNA damage defects are common in ovarian cancer and can be used to stratify treatment. Although most work has focused on homologous recombination (HR), DNA double-strand breaks are repaired primarily by nonhomologous end joining (NHEJ). Defects in NHEJ have been shown to contribute to genomic instability and have been associated with the development of chemoresistance.Experimental Design: NHEJ was assessed in a panel of ovarian cancer cell lines and 47 primary ascetic-derived ovarian cancer cultures, by measuring the ability of cell extracts to end-join linearized plasmid monomers into multimers. mRNA and protein expression of components of NHEJ was determined using RT-qPCR and Western blotting. Cytotoxicities of cisplatin and the PARP inhibitor rucaparib were assessed using sulforhodamine B (SRB) assays. HR function was assessed using γH2AX/RAD51 foci assay.Results: NHEJ was defective (D) in four of six cell lines and 20 of 47 primary cultures. NHEJ function was independent of HR competence (C). NHEJD cultures were resistant to rucaparib (P = 0.0022). When HR and NHEJ functions were taken into account, only NHEJC/HRD cultures were sensitive to rucaparib (compared with NHEJC/HRC P = 0.034, NHEJD/HRC P = 0.0002, and NHEJD/HRD P = 0.0045). The DNA-PK inhibitor, NU7441, induced resistance to rucaparib (P = 0.014) and HR function recovery in a BRCA1-defective cell line.Conclusions: This study has shown that NHEJ is defective in 40% of ovarian cancers, which is independent of HR function and associated with resistance to PARP inhibitors in ex vivo primary cultures. Clin Cancer Res; 23(8); 2050-60. ©2016 AACR.
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Project description:Mobile elements comprise about half of the human genome. Three active mobile element families (L1, Alu, and SVA) possibly cause diseases such as cancer. We conducted mobile element insertion (MEI) profiling of 44 epithelial ovarian cancers using exome-sequencing data. We identified a total of 106 MEIs using the Mobster program, 8 of which were novel exonic MEIs.
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Project description:Neural network analyses of circulating miRNAs have shown potential as non-invasive screening tests for ovarian cancer. A clinically useful test would detect occult disease when complete cytoreduction is most feasible. Here we used murine xenografts to sensitize a neural network model to detect low volume disease and applied the model to sera from 75 early-stage ovarian cancer cases age-matched to 200 benign adnexal masses or healthy controls. The 14-miRNA model efficiently discriminated tumor bearing animals from controls with 100% sensitivity down to tumor inoculums of 50,000 cells. Among early-stage patient samples, the model performed well with 73% sensitivity at 91% specificity. Applied to a population with 1% disease prevalence, we hypothesize the model would detect most early-stage ovarian cancers while maintaining a negative predictive value of 99.97% (95% CI 99.95%-99.98%). Overall, this supports the concept that miRNAs may be useful as screening markers for early-stage disease.
| S-EPMC9068948 | biostudies-literature
Project description:ObjectiveTo evaluate the diagnostic ability of magnetic resonance imaging (MRI) based radiomics and traditional characteristics to differentiate between Ovarian sex cord-stromal tumors (SCSTs) and epithelial ovarian cancers (EOCs).MethodsWe consecutively included a total of 148 patients with 173 tumors (81 SCSTs in 73 patients and 92 EOCs in 75 patients), who were randomly divided into development and testing cohorts at a ratio of 8:2. Radiomics features were extracted from each tumor, 5-fold cross-validation was conducted for the selection of stable features based on development cohort, and we built radiomics model based on these selected features. Univariate and multivariate analyses were used to identify the independent predictors in clinical features and conventional MR parameters for differentiating SCSTs and EOCs. And nomogram was used to visualized the ultimately predictive models. All models were constructed based on the logistic regression (LR) classifier. The performance of each model was evaluated by the receiver operating characteristic (ROC) curve. Calibration and decision curves analysis (DCA) were used to evaluate the performance of models.ResultsThe final radiomics model was constructed by nine radiomics features, which exhibited superior predictive ability with AUCs of 0.915 (95%CI: 0.869-0.962) and 0.867 (95%CI: 0.732-1.000) in the development and testing cohorts, respectively. The mixed model which combining the radiomics signatures and traditional parameters achieved the best performance, with AUCs of 0.934 (95%CI: 0.892-0.976) and 0.875 (95%CI: 0.743-1.000) in the development and testing cohorts, respectively.ConclusionWe believe that the radiomics approach could be a more objective and accurate way to distinguish between SCSTs and EOCs, and the mixed model developed in our study could provide a comprehensive, effective method for clinicians to develop an appropriate management strategy.
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