Types Of Epithelial Ovarian Carcinoma Research Articles

Differentiation of ovarian serous carcinoma from ovarian clear cell carcinoma using a 10-gene signature selected by comprehensive gene expression analysis.

Ovarian serous carcinoma (OSC) and ovarian clear cell carcinoma (OCCC) are two major histological types of epithelial ovarian carcinoma (EOC), each with different biological features and clinical behaviors. Although immunostaining is commonly used for differential diagnosis between OSC and OCCC, correct identification of EOC with mixed-type histology is sometimes a diagnostic challenge. The aim of the present study was to explore candidate genes as potential diagnostic biomarkers that distinguish OSC from OCCC. A total of 57 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery. Total RNAs were extracted from fresh-frozen tissues of EOC patients, and were used for comprehensive gene expression analysis using DNA microarray technology. Ten candidate genes, FXYD2, TMEM101, GABARAPL1, ARG2, GLRX, RBPMS, GDF15, PPP1R3B, TOB1, and GSTM3 were up-regulated in OCCC compared to OSC. All EOC patients were divided into two groups according to hierarchical clustering using a 10-gene signature. Our data suggest that the 10 candidate genes would be an excellent marker for distinguishing OSC from OCCC. Furthermore, the molecular signatures of the 10 genes may enlighten us on the differences in carcinogenesis, and provide a theoretical basis for OCCC's resistance to chemotherapy in the future.

CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer

Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is associated with poor prognosis, while the presence of CD8 + tumor-infiltrating lymphocytes (TIL) is positively prognostic. We employed [18F]EF5-PET/CT imaging, transcriptome profiling, and spatially-resolved histological analysis to evaluate relationships between CAIX, CD8, and survival in CCOC. Tissue microarrays (TMAs) were evaluated for 218 cases in the Canadian COEUR study. Non-spatial relationships between CAIX and CD8 were investigated using Spearman rank correlation, negative binomial regression and gene set enrichment analysis. Spatial relationships at the cell level were investigated using the cross K-function. Survival analysis was used to assess the relationship of CAIX and CD8 with patient survival for 154 cases. CD8 + T cell infiltration positively predicted survival with estimated hazard ratio 0.974 (95% CI 0.950, 1000). The negative binomial regression analysis found a strong TMA effect (p-value < 0.0001). It also indicated a negative association between CD8 and CAIX overall (p-value = 0.0171) and in stroma (p-value = 0.0050) but not in tumor (p-value = 0.173). Examination of the spatial association between the locations of CD8 + T cells and CAIX cells found a significant amount of heterogeneity in the first TMA, while in the second TMA there was a clear signal indicating negative spatial association in stromal regions. These results suggest that hypoxia may contribute to immune exclusion, primarily mediated by effects in stroma.

A DNA Damage Response Gene Panel for Different Histologic Types of Epithelial Ovarian Carcinomas and Their Outcomes.

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p < 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma.

A DNA Damage Response Gene Panel for Different Histologic types of Epithelial Ovarian Carcinomas and their Outcomes

A DNA Damage Response Gene Panel for Different Histologic types of Epithelial Ovarian Carcinomas and their Outcomes

Napsin-A, a Possible Diagnostic Marker for Differentiating Clear Cell Ovarian Carcinoma From Other High-grade Ovarian Carcinomas

Ovarian clear cell carcinoma (CCC) is divergent from other types of epithelial ovarian carcinoma in terms of clinicopathologic and molecular features. It should be separated from other high-grade carcinomas of the ovary for appropriate treatment. Napsin A is a reliable marker for adenocarcinoma of the lungs, but its role in ovarian epithelial carcinomas is vague. We investigated the expression of a panel of TTF-1, paired box 8, estrogen receptor, Wilms tumor 1, and Napsin A in 100 cases of high-grade ovarian carcinomas. All the examined cases were TTF-1 negative and paired box 8 positive. The 2 biomarkers estrogen receptor together with Wilms tumor 1 can separate CCC from endometriod carcinoma, yet this cannot be carried out in the case of serous and mucinous carcinomas of high grade. Napsin A can differentiate CCC with high sensitivity and specificity. It can be concluded that Napsin A is a sensitive and specific marker for CCC of the ovary. However, an entire marker panel may be useful for distinguishing ovarian CCC from other mimics.

Analysis of preoperative blood platelet parameters in terms of diversity of epithelial ovarian cancer.

Smouldering inflammation, thrombocytosis, and platelet hyper-reactivity are linked to malignancy. The relationships between preoperative diagnostic blood morphology parameters and cancer have been the focus of much interest, because some of these parameters are correlated with advanced cancer stages and poor patient survival rates. This study aimed to perform an observational, retrospective analysis of the intradiversity of blood platelet parameters in patients with different International Federation of Gynaecology and Obstetrics (FIGO) stages and different histological types of epithelial ovarian carcinomas (EOC), and also an analysis of the overall survival rate.In all, 94 EOC patients were included in this analysis (23 mucinous, 33 serous, 20 undifferentiated, 14 endometrioid, and 4 clear cell carcinoma cases). Peripheral blood samples were collected and analyzed before drug or surgical treatment.The platelet-to-neutrophil ratio (PNR) was related to the histological type of EOC, particularly mucinous carcinoma. In patients with mucinous cancer, the PNR was significantly lower compared with patients with nonmucinous cancer, and this parameter distinguished between mucinous and nonmucinous groups of patients (area under receiver-operating characteristic [ROC] curve 0.721 ± .056; sensitivity 82.6%; specificity 61%; P < .001; ROC analysis), regardless of the FIGO stage. Moreover, elevated PNR values were correlated with lower survival rate of EOC patients.The reduced PNR, similar to the lower level of cancer antigen 125, is characteristic for mucinous ovarian carcinoma patients. Moreover, elevated PNR index might correlate with poor survival of patients.

Preoperative serum levels of cancer antigen 125 and carcinoembryonic antigen ratio can improve differentiation between mucinous ovarian carcinoma and other epithelial ovarian carcinomas.

ObjectiveThe main aim of this study was to evaluate cancer antigen 125 (CA125)/carcinoembryonic antigen (CEA) ratio (CCR), as a reliable marker to differentiate ovarian mucinous carcinoma from other epithelial ovarian carcinomas (EOCs), namely serous, clear cell, and endometrioid carcinomas.MethodsFemale patients suffering from different kinds of EOCs whom were subjected to elective surgery at the Gangnam Severance Hospital between January 2008 and December 2016, were included in this study. The serum levels of CA125 and CEA were assayed using commercially available kits per the manufacturer's instructions.ResultsThe CCR in mucinous carcinoma (mean 32.1) was significantly lower than that of clear cell (mean 235.0) and endometrioid carcinoma (mean 427.0) in stage I (all P<0.05). In stage II–IV, CCR in mucinous carcinoma (mean 37.6) was significantly lower than that of serous carcinoma (mean 148.0) (P<0.01). The sensitivity and specificity of CCR in detecting mucinous carcinoma from other types of EOC was 75.0% and 77.5%, respectively in stage I and 100.0% and 84.4%, respectively in stage II–IV (both cut-off value <90.7).ConclusionThe present results suggest that pretreatment CCR might provide higher specificity and clinically relevant information as a criterion for the differentiation between ovarian mucinous carcinoma and other types of EOC.

Molecular Mechanisms of Carcinogenesis of Epithelial Ovarian Cancers

Epithelial ovarian carcinomas are one of the most common causes of death among gynecologic malignancies in the Czech population. This group of tumors is characterized by considerable heterogeneity in terms of its pathogenesis and response to therapy. It is questionable whether advances in the elucidation of molecular pathogenesis of various types of epithelial ovarian carcinomas can contribute to application of personalized targeted therapy.This work aims to summarize current knowledge on carcinogenesis and molecular basis of epithelial ovarian cancers and point out their potential applications in clinical practice. The characterization of the epithelial ovarian carcinomas is based on a dualistic model, which divides these tumors into two groups based on their different origins and mechanisms of carcinogenesis. Type I includes low-grade serous carcinomas, endometrioid carcinomas, mucinous carcinomas and Brenner tumor. Type II then comprises high-grade serous carcinomas.The new findings acquired by next generation sequencing revealed major differences in the genetic alterations in both groups of tumors. Differences in genetic instability between the two groups of tumors determine the mechanisms of their carcinogenesis and show new ways for application of targeted therapy. Deficient homologous recombination and high genetic instability in type II tumors is a prerequisite for efficient application of platinum cytostatics and PARP (poly-ADP ribose polymerase) inhibitors. On the other hand, carcinogenesis of the less aggressive, but often resistant type I tumous is dependent on the activation of signaling pathways PI3K/AKT and RAS/BRAF/MEK/ERK pathway. Targeted inhibition of these pathways could efficiently improve therapy of type I tumors and decrease serious adverse side effects.Key words: ovarian cancer - high-grade serous ovarian carcinoma - low-grade ovarian carcinoma - endometrioid carcinoma - mucinous carcinoma - malignant transformation - genetic instabilityWe would like to thank M.Sc. Eva Michalova for critical reading of the manuscript.This work was supported by the project MEYS - NPS I - LO1413.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 7. 8. 2016Accepted: 29. 8. 2016.

Novel biomarker candidates for the diagnosis of ovarian clear cell carcinoma.

Ovarian clear cell carcinoma can arise from endometriosis; however, it is distinct from other types of epithelial ovarian carcinoma in terms of its clinicopathological and molecular features. Cancer antigen 125 lacks the sensitivity and specificity required for accurate clinical diagnosis of clear cell carcinoma. Therefore, the aim of the current review was to identify novel biomarker candidates for the immunohistochemical and serological diagnosis of clear cell carcinoma. A search of the relevant English language literature published between 1966 and 2014 was conducted using the PubMed MEDLINE online database. High-throughput tissue microarray technology and proteomic screening combined with mass spectrometry may provide additional information regarding diagnostic biomarker candidates for ovarian clear cell carcinoma. The present review summarizes the characteristics of potential genomic alterations that activate cancer signaling pathways and, thus, contribute to carcinogenesis. The major signaling pathways activated in clear cell carcinoma are associated with cell cycle regulation (hepatitis A virus cellular receptor 1 and tumor protein D52), growth factor signaling (insulin-like growth factor binding protein 1; KiSS-1 metastasis-suppressor; erb-b2 receptor tyrosine kinase 2; and fibroblast growth factor receptor 2), anti-apoptosis and survival pathways [sialidase 3 (membrane sialidase)], metabolism (γ-glutamyltransferase 1), chemoresistance (napsin A aspartic peptidase, glutathione peroxidase 3; and aldehyde dehydrogenase 1 family, member A1), coagulation [coagulation factor III (thromboplastin, tissue factor); and tissue factor pathway inhibitor 2], signaling (lectin, galactoside-binding and soluble, 3), and adhesion and the extracellular matrix [cadherin 1, type 1, E-cadherin (epithelial); versican; and laminin, α 5]. The present review of the relevant literature may provide a basis for additional clinical investigation of the ovarian clear cell carcinoma serum biomarker candidate proteins identified herein.

Different Patterns of Disease Spread between Advanced-Stage Type I and II Epithelial Ovarian Cancer

Background and Aims: Two types of epithelial ovarian carcinoma (EOC) have been recently distinguished. Type I comprises low-grade serous, endometrioid and clear-cell tumors. High-grade endometrioid and serous tumors belong to type II. The aim of this study was to compare patterns of disease spread in advanced-stage type I and II EOCs at primary surgery. Methods: Surgical and pathological data of 233 patients with advanced-stage EOCs were collected, 42 with type I and 191 with type II. The two groups were compared for tumor localization at primary surgery. Intraoperative mapping of ovarian cancer (IMO) was used to assess tumor dissemination. Results: Tumor involvement was significantly higher in the type II group for the following: peritoneum (68.1 vs. 40.5%, p < 0.001), pouch of Douglas (60.2 vs. 40.5%, p = 0.06), vesicouterine ligament (40.8 vs. 19%, p = 0.027), diaphragm (45.0 vs. 11.9%, p < 0.001), serosa of liver (17.2 vs. 4.8%, p = 0.05), omentum (81.1 vs. 59.5%, p = 0.007), mesentery (42.9 vs. 16.7%, p = 0.005), pleural effusions (19.4 vs. 4.6%, p = 0.01) and ascites (60.7 vs. 21.4%, p < 0.001). IMO levels were different between the two groups (p = 0.001). Conclusions: This study provides clinical evidence in favor of the dualistic model of carcinogenesis, since types I and II are characterized by different findings at primary surgery.

Origin and molecular pathogenesis of ovarian high-grade serous carcinoma

A new paradigm for the pathogenesis of ovarian cancer has recently been proposed which helps to explain persistent problems in describing the development and diverse morphology of these neoplasms. The paradigm incorporates recent advances in our understanding of the molecular pathogenesis of epithelial ‘ovarian’ cancer with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies led to the development of a dualistic model that divides all the various histologic types of epithelial ovarian carcinomas into two broad categories designated ‘type I’ and ‘type II’. The prototypic type I tumor is low-grade serous carcinoma and the prototypic type II tumor is high-grade serous carcinomas (HGSCs). As the serous tumors comprise ∼70% of all epithelial ovarian tumors and account for the majority of deaths, the serous tumors will be the subject of this review. There are marked differences between the low-grade and high-grade serous tumors. Briefly, the former are indolent, present in stage I (tumor confined to the ovary) and develop from well-established precursors, so-called ‘atypical proliferative (borderline) tumors,’ which are characterized by specific mutations, including KRAS, BRAF and ERBB2; they are relatively genetically stable. In contrast, HGSCs are aggressive, present in the advanced stage, and develop from intraepithelial carcinomas in the fallopian tube. They harbor TP53 mutations in over 95% of cases, but rarely harbor the mutations detected in the low-grade serous tumors. At the time of diagnosis they demonstrate marked chromosomal aberrations but over the course of the disease these changes remain relatively stable. Along with the recent advances in understanding the molecular pathogenesis of these tumors, studies have demonstrated that the long sought for precursor of ovarian HGSC appears to develop from an occult intraepithelial carcinoma in the fimbrial region of the fallopian tube designated ‘serous tubal intraepithelial carcinoma (STIC)’ and involves the ovary secondarily. Another possible mechanism for the development of ‘‘ovarian’' HGSC is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs. We speculate that this tubal epithelium can result in the formation of a cortical inclusion cyst (CICs) that can then undergo malignant transformation. Thus, serous tumors may develop from inclusion cysts, as has been previously proposed, but by a process of implantation of tubal (müllerian-type) tissue rather than by a process of metaplasia from ovarian surface epithelium (OSE, mesothelial). The dualistic model serves as a framework for studying ovarian cancer and can assist investigators in organizing this complex group of neoplasms. In conjunction with the recognition that the majority of ‘ovarian’ carcinomas originate outside the ovary, this model also facilitates the development of new and novel approaches to prevention, screening and treatment of this devastating disease.

Mammaglobin B (SCGB2A1)-specific CD8 + cytotoxic T lymphocytes (CTL) are highly effective in killing autologous chemotherapy resistant ovarian cancer cells: Implications for SCGB2A1 dendritic cell-based therapeutic vaccines

Objective: Objective: To evaluate the potential of SCGB2A1, a top differentially expressed gene in various histological types of epithelial ovarian carcinomas, as a novel tumor antigen for ovarian cancer immunotherapy.

Metabolomic Characterization of Ovarian Epithelial Carcinomas by HRMAS-NMR Spectroscopy

Objectives. The objectives of the present study are to determine if a metabolomic study by HRMAS-NMR can (i) discriminate between different histological types of epithelial ovarian carcinomas and healthy ovarian tissue, (ii) generate statistical models capable of classifying borderline tumors and (iii) establish a potential relationship with patient's survival or response to chemotherapy. Methods. 36 human epithelial ovarian tumor biopsies and 3 healthy ovarian tissues were studied using 1H HRMAS NMR spectroscopy and multivariate statistical analysis. Results. The results presented in this study demonstrate that the three histological types of epithelial ovarian carcinomas present an effective metabolic pattern difference. Furthermore, a metabolic signature specific of serous (N-acetyl-aspartate) and mucinous (N-acetyl-lysine) carcinomas was found. The statistical models generated in this study are able to predict borderline tumors characterized by an intermediate metabolic pattern similar to the normal ovarian tissue. Finally and importantly, the statistical model of serous carcinomas provided good predictions of both patient's survival rates and the patient's response to chemotherapy. Conclusions. Despite the small number of samples used in this study, the results indicate that metabolomic analysis of intact tissues by HRMAS-NMR is a promising technique which might be applicable to the therapeutic management of patients.

Lysophosphatidic Acid in Patients With Ovarian Cancer

Purpose: We seek to compare lysophosphatidic acid (LPA) plasma levels (all subtypes) in patients with ovarian cancer and patients without this disease. Patients and Methods: Capillary electrophoresis with indirect ultraviolet detection was used to analyze the plasma LPA levels (with all subtypes) of 133 patients (60 patients with ovarian cancer, 43 patients without ovarian pathology, and 30 patients with benign ovarian tumors) during a 3-year period. The Kolmogorov-Smirnov test and Mann-Whitney U test were used for statistical analysis. Results: Patients with ovarian cancer had a significantly higher plasma LPA level (all subtypes; n = 60; median, 6.99 μmol/L; range, 4.53-43.21 μmol/L) compared with controls with no ovarian pathology (n = 43, median, 2.92 μmol/L; range, 0.94-22.93 μmol/L) and patients with benign ovarian tumor (n = 30; median, 7.73 μmol/L; range, 1.12-28.84 μmol/L; P < .001). We found that plasma LPA levels were associated with the International Federation of Gynecology and Obstetrics stage and ovarian cancer histologic type. Patients with endometrial ovarian cancer had significantly higher plasma LPA levels in comparison with other histologic types of epithelial ovarian carcinoma. Conclusion: The plasma LPA level can be a useful marker for ovarian cancer, particularly in the early stages of the disease.

Claudin-7 expression in human epithelial ovarian cancer

Claudin-7 (CLDN-7) is a tight junction protein recently found highly differentially expressed in ovarian carcinoma. To evaluate its potential as a novel biomarker, in this study, we quantified and compared claudin-7 expression at messenger RNA and protein level in 110 patients harboring various histologic types of epithelial ovarian carcinomas (EOC). CLDN-7 transcript was found significantly overexpressed in both primary and metastatic EOCs compared to normal human ovarian surface epithelium cell lines (fold change = 111.4, P < 0.001) by reverse transcription-polymerase chain reaction. At the protein level, CLDN-7 expression was found significantly higher in tumors of primary and metastatic origin when compared to normal ovaries (P < 0.001), regardless of the histologic type, the grade of differentiation, and the pathologic stage of the disease (P = 0.12). Moreover, a strong immunoreactivity for CLDN-7 was detected in EOC cells present in ascites fluids, whereas ascites-derived inflammatory cells, histiocytes, and reactive mesothelial cells were negative. Finally, immunohistochemical expression of CLDN-7 was observed in several human normal epithelial control tissues analyzed. CLDN-7 is significantly overexpressed in all main histologic types of EOC and in single neoplastic cells disseminated in peritoneal cavity and pleural effusions, suggesting its potential role as novel diagnostic marker in ovarian cancer. Despite widespread expression of CLDN-7 in several human normal tissues, the high density of CLDN-7 molecules, their membranous localization on EOC cells, and their lack of expression on the celomic epithelium in the peritoneal cavity suggest that this target could be potentially suitable for antibody-mediated localized therapies of ovarian adenocarcinoma.

Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma

Objective. Unlike other histological types of epithelial ovarian carcinoma, ovarian clear cell carcinoma is known to have very poor response to therapy even when discovered in its early stages. Since tumor hypoxia has been shown to be strongly associated with poor prognosis, deregulation of the representative factor of tissue hypoxia; hypoxia-inducible factor 1 alpha (HIF-1α) and related protein; Von Hippel-Lindau (VHL) may be associated with poor prognosis of ovarian clear cell carcinoma. Methods. Immunolocalization of both HIF-1α and VHL was performed on 56 cases of paraffin-embedded tissue sections of four different histological types of epithelial ovarian carcinoma and 5 cases of benign ovarian tumors as a control. Quantitative RT-PCR analysis of both HIF1A and VHL was performed on RNA isolated from 61 microdissected frozen tissues of four different histological types of epithelial ovarian carcinoma and 6 cases of normal ovarian epithelial cells. Expression levels of HIF-1α and VHL in different histological types and correlation between HIF-1α and VHL were determined by nonparametric analysis by Kruskal–Wallis and Spearman’s test. Results. HIF-1α expression levels were significantly higher in ovarian clear cell carcinoma than in other histological types ( P = 0.001). We found no correlation between mRNA and protein expression level in any type of carcinoma specimens. Among endometrioid, serous, and mucinous carcinoma, there were no differences in HIF-1α expression ( P = 0.643). There was a negative correlation between HIF-1α and VHL in serous ( r = − 0.661, P = 0.027) and in endometrioid carcinoma ( r = − 0.657 P = 0.039), but no correlation was found between HIF-1α and VHL expression levels in ovarian clear cell carcinoma ( P = 0.60). Conclusions. The results suggest that the role of hypoxia may change according to the histological type of ovarian carcinoma. High expression of HIF-1α and its independence from VHL in ovarian clear cell carcinoma may confer chemoresistance in this histological type.

Overexpression of mammaglobin B in epithelial ovarian carcinomas

Objective Mammaglobin B is a uteroglobin gene family member recently found highly differentially expressed in serous papillary ovarian cancer by gene expression profiling. In order to evaluate its potential as a novel ovarian cancer biomarker, in this study we quantified and compared Mammaglobin B expression in various histologic types of epithelial ovarian carcinomas (EOC). Methods Mammaglobin B expression was evaluated by real-time PCR and/or immunohistochemistry in fresh-frozen biopsies and paraffin-embedded tissues derived from a total of 137 patients including 69 primary EOC with different histologies, 28 serous papillary omental metastasis, 8 borderline tumors, 26 benign cystadenomas and 14 normal ovaries. Results High levels of Mammaglobin B gene expression were detected in 100% (68 out of 68) of the ovarian cancer biopsies tested by real-time PCR. In contrast, normal human ovarian surface epithelium (HOSE) expressed negligible levels of Mammaglobin B mRNA (EOC versus HOSE, p < 0.01). Although Mammaglobin B gene expression levels were higher in endometrioid, mucinous and undifferentiated tumors when compared to serous papillary tumors, clear cell tumors and those with mixed histology, these differences were not statistically significant. In agreement with real-time PCR results, EOC were found to express significantly higher levels of Mammaglobin B protein when compared to normal ovaries and benign cystadenomas ( p < 0.01). However, only 29 out of 68 (42%) of the EOC samples found positive for Mammaglobin B by real-time PCR showed immunoreactivity by IHC. Conclusions Mammaglobin B gene is highly expressed in EOC and may represent a novel molecular marker for multiple histological types of ovarian cancer. Additional studies to evaluate the clinical utility of Mammaglobin B as a diagnostic and/or therapeutic target in ovarian cancer are warranted.

Human Epididymis Protein 4 (HE4) Is a Secreted Glycoprotein that Is Overexpressed by Serous and Endometrioid Ovarian Carcinomas

Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4). To ascertain its clinical utility, we did a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and nonovarian tissues by immunohistochemistry. In comparison with normal surface epithelium, which does not express HE4, we found that cortical inclusion cysts lined by metaplastic Mullerian epithelium abundantly express the protein. Its expression in tumors was restricted to certain histologic subtype: 93% of serous and 100% of endometrioid EOCs expressed HE4, whereas only 50% and 0% of clear cell carcinomas and mucinous tumors, respectively, were positive. Tissue microarrays revealed that the majority of nonovarian carcinomas do not express HE4, consistent with our observation that HE4 protein expression is highly restricted in normal tissue to the reproductive tracts and respiratory epithelium. HE4 is predicted to encode a secreted protein. Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4. Cultured medium from these cells revealed a secreted form of HE4 that is N-glycosylated. This observation is consistent with the recent report that HE4 circulates in the bloodstream of patients with EOC. Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs. Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs.