Subtypes Of Epithelial Ovarian Carcinoma Research Articles

Metabolism of primary high-grade serous ovarian carcinoma (HGSOC) cells under limited glutamine or glucose availability

BackgroundHigh-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive subtype of epithelial ovarian carcinoma. It is primarily diagnosed at stage III or IV when the 5-year survival rate ranges between 20% and 40%. Here, we aimed to validate the hypothesis, based on HGSOC cell lines, that proposed the existence of two distinct groups of HGSOC cells with high and low oxidative phosphorylation (OXPHOS) metabolism, respectively, which are associated with their responses to glucose and glutamine withdrawal.MethodsWe isolated and cultivated primary cancer cell cultures from HGSOC and nontransformed ovarian fibroblasts from the surrounding ovarium of 45 HGSOC patients. We tested the metabolic flexibility of the primary cells, particularly in response to glucose and glutamine depletion, analyzed and modulated endoplasmic reticulum stress, and searched for indices of the existence of previously reported groups of HGSOC cells with high and low OXPHOS metabolism.ResultsThe primary HGSOC cells did not form two groups with high and low OXPHOS that responded differently to glucose and glutamine availabilities in the cell culture medium. Instead, they exhibited a continuum of OXPHOS phenotypes. In most tumor cell isolates, the responses to glucose or glutamine withdrawal were mild and surprisingly correlated with those of nontransformed ovarian fibroblasts from the same patients. The growth of tumor-derived cells in the absence of glucose was positively correlated with the lipid trafficking regulator FABP4 and was negatively correlated with the expression levels of HK2 and HK1. The correlations between the expression of electron transport chain (ETC) proteins and the oxygen consumption rates or extracellular acidification rates were weak. ER stress markers were strongly expressed in all the analyzed tumors. ER stress was further potentiated by tunicamycin but not by the recently proposed ER stress inducers based on copper(II)-phenanthroline complexes. ER stress modulation increased autophagy in tumor cell isolates but not in nontransformed ovarian fibroblasts.ConclusionsAnalysis of the metabolism of primary HGSOC cells rejects the previously proposed hypothesis that there are distinct groups of HGSOC cells with high and low OXPHOS metabolism that respond differently to glutamine or glucose withdrawal and are characterized by ETC protein levels.

Expression of Wilms tumor gene protein (WT1) in different histologic subtypes of ovarian carcinoma

Background: Ovarian carcinoma is the seventh most common cancer among women worldwide and the eighth leading cause of death. Ovarian cancer develops in the ovary's tissues. Methods: This cross-sectional descriptive study was carried out at the Department of Pathology, RMC and Department of Pathology, BSMMU, Dhaka, Bangladesh from July 2019 to June 2021 carried out with 31 histopathologically confirmed ovarian carcinomas. All cases were subjected to WT1 immunostaining followed by histopathological examination. The collected data were analyzed using Statistical Package for Social Sciences (SPSS) software, version-23.0. The ethical clearance of this study was obtained from the Institutional Review Board (IRB) of Rajshahi, Medical College, Rajshahi, Bangladesh. Results: A total of 31 histopathologically confirmed ovarian carcinoma patients were included in this cross-sectional descriptive study. All cases were subjected to WT1 immunostaining followed by histopathological examination. The age of the study sample ranged from 20 to 75 years. The mean age of the respondent was 45.10±13.78 years. According to the histologic subtypes, WT1 was mainly expressed in serous carcinoma. All the serous carcinoma (16/16) showed a positive reaction for WT1. Among them, 14 cases (87.5%) showed >50% (3+) WT1 score and two (2) cases (12.5%) showed 11% to 50 % (2+) scores. Regarding endometrioid carcinoma four (4) (66.6%) of six (6) were negative whereas one (1) (16.6%) showed 1%-10% (1+) and one (1) (16.6%) showed 11%-50% (2+) WT1 scores. All the mucinous (4/4) and all the clear cell carcinoma (3/3) were negative with less than 1 % of the tumor cells stained two (2) cases of undifferentiated carcinoma were also negative. There was a significant relation between WT1 expression and different histologic subtypes of epithelial ovarian carcinoma with a p value of 0.001 (p<0.05). Conclusions: WT1 can be applied by both the histopathologist and clinician as an effective marker regarding diagnosis and patient management.

Exploring the cellular and molecular differences between ovarian clear cell carcinoma and high-grade serous carcinoma using single-cell RNA sequencing and GEO gene expression signatures

The two most prevalent subtypes of epithelial ovarian carcinoma (EOC) are ovarian clear cell carcinoma (OCCC) and high-grade serous ovarian carcinoma (HGSC). Patients with OCCC have a poor prognosis than those with HGSC due to chemoresistance, implying the need for novel treatment target. In this study, we applied single-cell RNA sequencing (scRNA-seq) together with bulk RNA-seq data from the GEO (Gene Expression Omnibus) database (the GSE189553 dataset) to characterize and compare tumor heterogeneity and cell-level evolution between OCCC and HGSC samples. To begin, we found that the smaller proportion of an epithelial OCCC cell subset in the G2/M phase might explain OCCC chemoresistance. Second, we identified a possible pathogenic OCCC epithelial cell subcluster that overexpresses LEFTY1. Third, novel biomarkers separating OCCC from HGSC were discovered and subsequently validated on a wide scale using immunohistochemistry. Amine oxidase copper containing 1 (AOC1) was preferentially expressed in OCCC over HGSC, while S100 calcium-binding protein A2 (S100A2) was detected less frequently in OCCC than in HGSC. In addition, we discovered that metabolic pathways were enriched in the epithelial compartment of the OCCC samples. In vitro experiments verified that inhibition of oxidative phosphorylation or glycolysis pathways exerted direct antitumor effects on both OCCC and HGSC cells, while targeting glutamine metabolism or ferroptosis greatly attenuated chemosensitivity only in OCCC cells. Finally, to determine whether there were any variations in immune cell subsets between OCCC and HGSC, data from scRNA-seq and mass cytometry were pooled for analysis. In summary, our work provides the first holistic insights into the cellular and molecular distinctions between OCCC and HGSC and is a valuable source for discovering new targets to leverage in clinical treatments to improve the poor prognosis of patients with OCCC.

Mechanism of Cell Death by Combined Treatment with an xCT Inhibitor and Paclitaxel: An Alternative Therapeutic Strategy for Patients with Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian carcinoma that responds poorly to chemotherapy. Glutathione (GSH) is a primary antioxidant, which protects cells against reactive oxygen species (ROS). High levels of GSH are related to chemotherapeutic resistance. The glutamine/cystine transporter xCT is essential for intracellular GSH synthesis. However, whether xCT inhibition can overcome the resistance to chemotherapeutic agents in OCCC remains unclear. This study demonstrated that combined treatment with paclitaxel (PTX) and the xCT inhibitor sulfasalazine (SAS) significantly enhanced cytotoxicity more than the individual drugs did in OCCC cells. Treatment with PTX and SAS induced apoptosis more effectively than did individual drug treatments in the cells with significant generation of ROS. Moreover, combined treatment with PTX and SAS induced ferroptosis in the cells with low expression of glutathione peroxidase (GPx4), high levels of intracellular iron and significant lipid ROS accumulation. Therefore, our findings provide valuable information that the xCT inhibitor might be a promising therapeutic target for drug-resistant OCCC. The strategy of combined administration of PTX and SAS can potentially be used to treat OCCC and help to develop novel therapeutic methods.

Ovarian cancer prevention by opportunistic salpingectomy is a new de facto standard in Germany

PurposeThe most prevalent and aggressive subtype of epithelial ovarian carcinoma (EOC), high-grade serous carcinoma (HGSC), originates in many cases from the fallopian tubes. Because of poor prognosis and lack of effective screening for early detection, opportunistic salpingectomy (OS) for prevention of EOC is being implemented into clinical routine in several countries worldwide. Taking the opportunity of a gynecological surgery in women at average cancer risk, extramural fallopian tubes are completely resected preserving the ovaries with their infundibulopelvic blood supply. Until recently, only 13 of the 130 national partner societies of the International Federation of Obstetrics and Gynecology (FIGO) have published a statement on OS. This study aimed to analyze the acceptance of OS in Germany.Methods(1) Survey of German gynecologists in 2015 and 2022 by the Department of Gynecology of the Jena University Hospital in co-operation with the Department of Gynecology at Charité-University Medicine Berlin with support of NOGGO e. V. and AGO e. V. (2) Salpingectomy numbers in Germany for years 2005–2020 as retrieved from the Federal Statistical Office of Germany (Destatis).Results(1) Survey: Number of participants was 203 in 2015 and 166 in 2022, respectively. Nearly all respondents (2015: 92%, 2022: 98%) have already performed bilateral salpingectomy without oophorectomy in combination with benign hysterectomy with the intention to reduce the risk for malignant (2015: 96%, 2022: 97%) and benign (2015: 47%, 2022: 38%) disorders. Compared to 2015 (56.6%), considerably more survey participants performed OS in > 50% or in all cases in 2022 (89.0%). Recommendation of OS for all women with completed family planning at benign pelvic surgery was approved by 68% in 2015 and 74% in 2022. (2) Case number analysis: In 2020, four times more cases of salpingectomy were reported by German public hospitals compared to 2005 (n = 50,398 vs. n = 12,286). Of all inpatient hysterectomies in German hospitals in 2020, 45% were combined with salpingectomy, and more than 65% in women at the age of 35 to 49 years.ConclusionMounting scientific plausibility regarding involvement of fallopian tubes in the pathogenesis of EOC led to change of clinical acceptance of OS in many countries including in Germany. Case number data and widespread expert judgment demonstrate that OS has become a routine procedure in Germany and a de facto standard for primary prevention of EOC.

Preoperative serum microRNAs as potential prognostic biomarkers in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian carcinoma with poor prognosis. However, no effective biomarkers have been established for predicting unfavorable events, including recurrence and poor prognoses. Serum microRNAs (miRNAs) have been increasingly reported to be useful in predicting a patient's condition and have been recognized as a potentially less-invasive source for liquid biopsy in cancer. Therefore, this study aimed to evaluate serum miRNA profiles from patients with OCCC and to establish biomarker for predicting the prognoses. The GSE106817, which included preoperative serum miRNA profiles of patients with ovarian tumors, was used, and clinical information was investigated. In all, 66 patients with OCCC were included, excluding those with other histological subtypes or insufficient prognostic information. Moreover, miRNA profiles of OCCC tissues were also examined. The median follow-up period was 64.3 (8.0-153.3) months. Based on multivariable Cox regression analyses and the expression of miRNAs in OCCC tissues, miR-150-3p, miR-3195, and miR-7704 were selected as miRNA candidates associated with both progression-free survival (PFS) and overall survival (OS). Then, the prognostic index was calculated based on expression values of 3 serum miRNAs. Kaplan-Meier survival analysis indicated that the prognostic index was significantly predictive of PFS and OS (p=0.004 and p=0.012, respectively). Preoperative serum miRNA profiles of miR-150-3p, miR-3195, and miR-7704 can be used to potentially predict the prognosis of patients with OCCC.

Computed Tomographic Radiomics in Differentiating Histologic Subtypes of Epithelial Ovarian Carcinoma

Epithelial ovarian carcinoma is heterogeneous and classified according to the World Health Organization Tumour Classification, which is based on histologic features and molecular alterations. Preoperative prediction of the histologic subtypes could aid in clinical management and disease prognostication. To assess the value of radiomics based on contrast-enhanced computed tomography (CT) in differentiating histologic subtypes of epithelial ovarian carcinoma in multicenter data sets. In this diagnostic study, 665 patients with histologically confirmed epithelial ovarian carcinoma were retrospectively recruited from 4 centers (Hong Kong, Guangdong Province of China, and Seoul, South Korea) between January 1, 2012, and February 28, 2022. The patients were randomly divided into a training cohort (n = 532) and a testing cohort (n = 133) with a ratio of 8:2. This process was repeated 100 times. Tumor segmentation was manually delineated on each section of contrast-enhanced CT images to encompass the entire tumor. The Mann-Whitney U test and voted least absolute shrinkage and selection operator were performed for feature reduction and selection. Selected features were used to build the logistic regression model for differentiating high-grade serous carcinoma and non-high-grade serous carcinoma. Contrast-enhanced CT-based radiomics. Intraobserver and interobserver reproducibility of tumor segmentation were measured by Dice similarity coefficients. The diagnostic efficiency of the model was assessed by receiver operating characteristic curve and area under the curve. In this study, 665 female patients (mean [SD] age, 53.6 [10.9] years) with epithelial ovarian carcinoma were enrolled and analyzed. The Dice similarity coefficients of intraobserver and interobserver were all greater than 0.80. Twenty radiomic features were selected for modeling. The areas under the curve of the logistic regression model in differentiating high-grade serous carcinoma and non-high-grade serous carcinoma were 0.837 (95% CI, 0.835-0.838) for the training cohort and 0.836 (95% CI, 0.833-0.840) for the testing cohort. In this diagnostic study, radiomic features extracted from contrast-enhanced CT were useful in the classification of histologic subtypes in epithelial ovarian carcinoma. Intraobserver and interobserver reproducibility of tumor segmentation was excellent. The proposed logistic regression model offered excellent discriminative ability among histologic subtypes.

Antibody therapeutics for epithelial ovarian cancer

ABSTRACT Introduction High-grade serous ovarian carcinoma (HGSC) is an aggressive subtype of epithelial ovarian carcinoma (EOC) and remains the most lethal gynecologic cancer. A lack of effective and tolerable therapeutic options and nonspecific symptoms at presentation with advanced stage of disease are among the challenges in the management of the disease. Areas covered An overview of ovarian cancer, followed by a discussion of the current therapeutic regimes and challenges that arise during and after the treatment of EOC. We discuss different formats of antibody therapeutics and their usage in targeting validated targets implicated in ovarian cancer, as well as three emerging novel proteins as examples recently implicated in their contribution to adaptive resistance in ovarian cancer. Expert opinion Antibody therapeutics allow for a unique and effective way to target proteins implicated in cancer and other diseases, and have the potential to radically change the outcomes of patients suffering from ovarian cancer. The vast array of targets that have been implicated in ovarian cancer and yet the lack of effective therapeutic options for patients further stresses the importance of discovering novel proteins that can be targeted, as well as predictive biomarkers that can inform the stratification of patients into treatment-specific populations.

The proteome of clear cell ovarian carcinoma.

Clear cell ovarian carcinoma (CCOC) is the second most common subtype of epithelial ovarian carcinoma. Late-stage CCOC is not responsive to gold-standard chemotherapy and results in suboptimal outcomes for patients. In-depth molecular insight is urgently needed to stratify the disease and drive therapeutic development. We conducted global proteomics for 192 cases of CCOC and compared these with other epithelial ovarian carcinoma subtypes. Our results showed distinct proteomic differences in CCOC compared with other epithelial ovarian cancer subtypes including alterations in lipid and purine metabolism pathways. Furthermore, we report potential clinically significant proteomic subgroups within CCOC, suggesting the biologic plausibility of stratified treatment for this cancer. Taken together, our results provide a comprehensive understanding of the CCOC proteomic landscape to facilitate future understanding and research of this disease. © 2022 The Pathological Society of Great Britain and Ireland.

Lymphocyte infiltration in histologic subtypes of epithelial ovarian carcinoma and its effect on survival (229)

Lymphocyte infiltration in histologic subtypes of epithelial ovarian carcinoma and its effect on survival (229)

Low-Grade Serous Carcinoma of the Ovary: The Current Status.

Low-grade serous carcinoma (LGSC) of the ovary is a rare histological subtype of epithelial ovarian carcinoma. It has distinct clinical behavior and a specific molecular profile. Compared with high-grade serous carcinoma, this tumor presents at a younger age, has an indolent course, and is associated with prolonged survival. LGSC can arise de novo or originate following a serous borderline tumor (SBT). Pathological differentiation between LGSC and other ovarian carcinoma histological subtypes is fundamental. Several factors might influence the overall outcome, such as the age at diagnosis, current smoking, elevated body mass index, mutational status, hormonal receptors’ expression, and Ki-67 proliferation index. Surgery is the main treatment option in LGSC, and efforts must be maximized to achieve a microscopic residual in metastatic disease. Despite being relatively chemo-resistant, adjuvant platinum-based chemotherapy remains the standard of care in LGSC. Hormonal maintenance therapy after adjuvant chemotherapy results in improved outcomes. Treatment options for disease recurrence include secondary cytoreductive surgery, chemotherapy, hormonal therapy, targeted therapy, and clinical trials. Advancements in genomic studies and targeted therapies are expected to change the treatment landscape in LGSC.

Outcomes of comprehensive lymphadenectomy for patients with advanced stage ovarian carcinoma and rare histologic sub-types

ObjectiveTo investigate the prognostic significance of comprehensive lymphadenectomy at the time of primary debulking surgery for patients with rare histologic sub-types of epithelial ovarian carcinoma and clinically advanced stage disease...

CT texture analysis in histological classification of epithelial ovarian carcinoma.

The study aimed to compare the ability of morphological and texture features derived from contrast-enhanced CT in histological subtyping of epithelial ovarian carcinoma (EOC). Consecutive 205 patients with newly diagnosed EOC who underwent contrast-enhanced CT were included and dichotomised into high-grade serous carcinoma (HGSC) and non-HGSC. Clinical information including age and cancer antigen 125 (CA-125) was documented. The pre-treatment images were analysed using commercial software, TexRAD, by two independent radiologists. Eight qualitative CT morphological features were evaluated, and 36 CT texture features at 6 spatial scale factors (SSFs) were extracted per patient. Features' reduction was based on kappa score, intra-class correlation coefficient (ICC), univariate ROC analysis and Pearson's correlation test. Texture features with ICC ≥ 0.8 were compared by histological subtypes. Patients were randomly divided into training and testing sets by 8:2. Two random forest classifiers were determined and compared: model 1 incorporating selected morphological and clinical features and model 2 incorporating selected texture and clinical features. HGSC showed specifically higher texture features than non-HGSC (p< 0.05). Both models performed highly in predicting histological subtypes of EOC (model 1: AUC 0.891 and model 2: AUC 0.937), and no statistical significance was found between the two models (p= 0.464). CT texture analysis provides objective and quantitative metrics on tumour characteristics with HGSC demonstrating specifically high texture features. The model incorporating texture analysis could classify histology subtypes of EOC with high accuracy and performed as well as morphological features. • A number of CT morphological and texture features showed good inter- and intra-observer agreements. • High-grade serous ovarian carcinoma showed specifically higher CT texture features than non-high-grade serous ovarian carcinoma. • CT texture analysis could differentiate histological subtypes of epithelial ovarian carcinoma with high accuracy.

UNILATERAL EXUDATIVE PLEURAL EFFUSION AS THE SOLE PRESENTING FEATURE OF A CLEAR CELL OVARIAN CARCINOMA

SESSION TITLE: Medical Student/Resident Disorders of the Pleura Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pleural effusions are usually a manifestation of a pleuropulmonary or systemic disease. Pleural fluid analysis often provides insight into the underlying etiology, however, a thorough extrathoracic evaluation is needed in some cases for a definitive diagnosis. CASE PRESENTATION: We present the case of a 48-year-old female with a multinodular goiter who presented with exertional shortness of breath and cough over a 8-week duration. Chest radiograph showed complete opacification of the right hemithorax. Computed tomography of the chest revealed a large right-sided pleural effusion with complete collapse of the right lower and middle lobes, partial collapse of the right upper lobe and mediastinal shift to the left. Also noted was a heterogeneous enlargement of the left thyroid gland, with significant retrosternal extension into the superior mediastinum. A small-bore chest tube was inserted and 3 liters of serosanguinous pleural fluid was drained. Pleural fluid studies were consistent with an exudative effusion with lymphocytic predominance. Infectious workup including tuberculosis was negative. Fluid cytology was negative for malignant cells. Given the significant retrosternal extension of her goiter, the possibility of chylothorax was raised, which was rebutted by the pleural fluid appearance and normal triglycerides levels. Thyroid function tests and autoimmune markers were negative. An abdomino-pelvic ultrasound was performed, with the clinical possibility of an occult malignancy, as a possible etiology. This showed a left adnexal lesion, which prompted further characterization, by magnetic resonance imaging. The findings were compatible with epithelial ovarian/fallopian tube neoplasm. Laparoscopic left salpingo-oophorectomy was performed and pathology confirmed clear cell ovarian carcinoma. DISCUSSION: Clear cell ovarian carcinoma is a subtype of epithelial ovarian carcinoma, the most common type of malignant ovarian neoplasms. It often presents in perimenopausal women in their fifth or sixth decade of life. Epithelial ovarian cancer frequently presents with subacute pelvic or abdominal symptoms; however, it may present acutely with nonpelvic manifestations including bowel obstruction, venous thromboembolism, or malignant pleural effusion. Given the absence of abdominal and pelvic symptoms on clinical presentation, this case would have been missed if pelvic ultrasound was not performed. CONCLUSIONS: In conclusion, an unexplained exudative pleural effusion in a young female should warrant a high degree of clinical suspicion and further evaluation to rule out an abdominal or gynecological malignancy. Reference #1: Stéphane Beaudoin and Anne V. Gonzalez. Evaluation of the patient with pleural effusion. CMAJ March 12, 2018 190 (10) E291-E295 Reference #2: Rubins JB, Colice GL. Evaluating pleural effusions. How should you go about finding the cause? Postgrad Med. 1999 May 1;105(5):39-42, 45-8 Reference #3: Xavier Matias-Guiu and Colin J R Stewart. Endometriosis-associated Ovarian Neoplasia. Pathology, 2018-02-01, Volume 50, Issue 2, Pages 190-204 DISCLOSURES: No relevant relationships by Abdulaziz Alonazi, source=Web Response No relevant relationships by Shine Raju, source=Web Response No relevant relationships by Nadine Zahar, source=Web Response

Immunological functions of complement system involved in evolution of ovarian clear cell carcinoma discovered by the gene ontology-based immunofunctionome analysis

Objective: Ovarian clear cell carcinoma (OCCC) is the second most common among the four subtypes of epithelial ovarian carcinoma (EOC), especially in Asia, and refractory to chemotherapy is accompanied with worse prognosis after the preliminary optimal debulking operation. OCCC may evolve from endometriosis, a chronic immune-related disease, and immunotherapy seems to be a potential alternative solution for OCCC. This study investigated the whole picture of immunological functions of OCCC during disease progression.

Plasticity in Ovarian Cancer: The Molecular Underpinnings and Phenotypic Heterogeneity

Cellular plasticity, by large, is the ability through which cells morph into new phenotypic identity by trading-off with the previous one. This phenomenon has been observed in the normal and tumor cells in a very similar fashion. Occurrence of cellular plasticity, in malignancies like epithelial ovarian carcinoma (EOC) are well known but highly debated in terms of origin of the tumor for the inherent heterogeneity across subtypes. EOC has been termed as a clinically challenging malady for its subversive nature against chemotherapy. The management of ovarian cancer is mostly hindered by relapse with recalcitrance towards primary chemotherapy regimen e.g. platinum–taxol combination. Also, late detection preceded by peritoneal metastasis poses another challenge to the treatment. Underlying both these aspects of the disease, tumor heterogeneity turns out as the most critical factor. In the light of heterogeneity that can be across patients (inter-tumoral) and/or within a tumor (intra-tumoral), ovarian carcinoma is a multifactorial ailment. The governing factors behind this heterogeneity are—diverse genetic landscape among subtypes of EOC; the presence of cancer stem cell (CSC) niche and inherent plasticity of the cancer cells themselves. Apart from the well-studied mechanisms of plasticity, there are several emerging molecular players like lncRNAs, Hippo pathway and also phenomena like dedifferentiation of non-CSC neoplastic cells ,and transdifferentiation of CSCs. Here, we present an overview of the current knowledge on the evolution of EOC through cellular plasticity with emphasis on the three major aspects namely, subtype-specific genetic diversity; ovarian CSC and cancer cell duality between epithelial and mesenchymal lineages.

Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer

ObjectivesWnt pathway mutations are a hallmark of endometrioid and clear cell subtypes of epithelial ovarian carcinoma (EOC). However, no drugs targeting the Wnt pathway in EOC are FDA-approved. Dickkopf-related protein 1 (DKK1), a modulator of the Wnt pathway, has emerged as a promising therapeutic target. We aimed to examine the role of DKK1 and the effects of a monoclonal antibody against DKK1 (DKN-01) in vivo and in a murine model of ovarian cancer. MethodsWe examined in vitro the role of DKK1 and the effects of DKK1 inhibition in EOC cell lines. We then studied in vivo the role of DKN-01 and DKK1 overexpression on tumor burden and anti-tumor immune cell populations using the ID8 syngeneic mouse model. ResultsDKN-01 did not phenotypically alter ES2 cells in vitro; however, DKK1 inhibition promoted Wnt signaling. Tumor burden and immune populations were unchanged in ID8 challenged mice treated with mDKN01. Mice challenged with ID8 cells overexpressing DKK1 had tumor burden similar to controls (p = 0.175). However, the overexpression of DKK1 decreased CD45+ leukocyte infiltration into the peritoneum (p = 0.008) and omentum (p = 0.032), reducing both natural killer (NK) and CD8 T cells, and reducing interferon-gamma (IFNγ) expression on activated CD8 T cells. ConclusionsOur results suggest that DKK1 inhibition does not affect tumor growth in the ID8 ovarian cancer model. DKK1 overexpression alters anti-tumor immune populations within the tumor microenvironment. Thus, our findings confirm DKK1 as a new therapeutic target in EOC and suggest that DKK1 inhibition may function best in a combinatorial, immune-modulatory therapy.

An integrated molecular profile of endometrioid ovarian cancer

ObjectiveEndometrioid ovarian carcinoma (EOVC) is an uncommon subtype of epithelial ovarian carcinoma and its molecular characteristics have been incompletely described. Prior sequencing investigations have been limited to targeted gene panels. We performed whole-exome sequencing to build an unbiased genetic profile of molecular alterations in endometrioid ovarian tumors with a goal to better understand this disease in the context of epithelial ovarian cancer and endometrioid uterine cancers. MethodsWhole-exome sequencing was performed on EOVC samples (n = 26) and matched normals (n = 15). Gene mutations, mutational signatures and copy number variations (CNVs) informed a multi-dimensional regression classifier allowing for comparison to endometrial carcinoma (UCEC) and high grade serous ovarian carcinoma (HGSC). ResultsEOVC has a distinct and heterogeneous genomic profile. Identified significantly mutated genes in EOVC (PTEN, CTNNB1, PIK3CA, KMT2D, KMT2B, PIK3R1, ARID1A and TP53) occurred at similar frequencies in UCEC. Hypermutation, resulting from both mismatch repair deficiency (MMRd) and POLE mutation, was observed in EOVC at a frequency similar to UCEC. Like UCEC, a subset of EOVC cases closely resembled HGSC, harboring TP53 mutations, homologous recombination deficiency (HRd) mutation signatures and widespread CNVs. A machine-learning classifier confirmed the heterogeneous composition of EOVC. Potential therapeutic targets were identified in 62% of EOVC cases. We validated our findings in an orthogonal clinical sequencing registry of EOVC cases. ConclusionsWe identified that EOVC are a molecularly heterogeneous group of epithelial ovarian cancers with distinct mutational signatures. In an age of precision oncology, there is a pressing need to understand the unique molecular drivers in uncommon histologic subtypes to facilitate genomically driven oncologic treatments.

Evaluation of miR-22 and miR-21 as diagnostic biomarkers in patients with epithelial ovarian cancer.

Among the 11 most common cancers, ovarian cancer is the fifth leading cause of death after lung, breast, colorectal and pancreatic cancer. Although diagnosis of ovarian cancer in early stages is followed by various successful treatments, no accurate and reliable method is available at present. Currently microRNAs are being explored as signature biomarkers for early detection of various types of cancer. However little information is available on expression and correlation of microRNA in ovarian cancer. In this study, we have chosen two microRNA on the basis of their altered frequency in epithelial ovarian cancer cases. The main objective of this study is to evaluate the expression of microRNA-22 and microRNA-21 along with various clinicopathological parameters. Expression level of microRNA-22 and microRNA-21 in different stages and subtypes of epithelial ovarian carcinoma has been analyzed to find out its role as a potential diagnostic biomarker. Present study has been conducted in the serum of 80 epithelial ovarian cancer patients and 80 age matched healthy women. Quantitative real time PCR was used to compare the expression of miR-22 and miR-21 between the cases and control groups. Statistical analysis showed 7.85-fold increase in miR-21 expression and 2.1-fold reduction in miR-22 expression of ovarian cancer patients. Increased serum level of miR-21 in ovarian cancer patients and decreased level of miR-22 has been correlated with advanced international federation of gynecology and obstetrics (FIGO) stage and histological sub types of epithelial ovarian cancer. Serous ovarian carcinoma was the most common cancer in the present study. Calculated fold change value for miR-21 was 3.98 and - 2.86 for miR-22 in serous ovarian cancer. Fold change value in the miR-21 expression in advanced stage was 6.29 and 4.25 in early stage. Whereas lower calculated fold change was observed for miR-22 in advanced stage than in early stage (- 2.16). Present study revealed up-regulated expression of miR-21 and down regulated expression of miR-22 in the serum of epithelial ovarian cancer patients. Both of these could be validated as good diagnostic biomarkers for early detection of ovarian cancer.

Mucinous Cancer of the Ovary: Overview and Current Status.

Mucinous ovarian cancer (MOC) is a rare subtype of epithelial ovarian carcinoma (EOC). Whereas all EOC subtypes are addressed in the same way, MOC is a distinct entity. Appreciating the pathological features and genomic profile of MOC may result in the improvement in management and, hence, the prognosis. Distinguishing primary MOC from metastatic mucinous carcinoma can be challenging but is essential. Early-stage MOC carries an excellent prognosis, with advanced disease having a poor outcome. Surgical management plays an essential role in the early stage and in metastatic disease. Chemotherapy is usually administered for stage II MOC and beyond. The standard gynecology protocol is frequently used, but gastrointestinal regimens have also been administered. As MOC is associated with multiple molecular alterations, targeted therapy could be the answer to treat this disease.