Prognostic Biomarker For Ovarian Cancer Research Articles

Clinicopathological and Prognostic Significance of Cancer Stem Cell Markers in Ovarian Cancer Patients: Evidence from 52 Studies

Background/Aims: Relevant markers of cancer stem cells (CSCs) may serve as commonly used biomarkers of ovarian cancer (OC). However, their actual clinicopathological and prognostic significance remains inconclusive. Thus, we conducted a meta-analysis to quantitatively evaluate the association between the expression of CSC-relevant markers (ALDH1, CD117, CD133, and CD44) and OC. Methods: We used an odds ratio (OR) and a hazard ratio (HR) with a 95% confidence interval (CI) to estimate the effects by analyzing 52 studies from a literature search. Heterogeneity and sensitivity were evaluated, as well. Publication bias was assessed using funnel plots and Egger tests. Results: ALDH1 expression was statistically associated with FIGO stage (OR=1.872, 95%CI=1.14-3.076, P=0.013) and lymph invasion (OR=2.78, 95%CI=1.08-7.152, P=0.034). CD117 expression was significantly associated with FIGO stage (OR=2.01, 95%CI=1.35-2.98, P=0.001). CD133 expression was correlated with FIGO stage (OR=3.410, 95%CI=2.196-5.294, P< 0.001) and differentiation grade (OR=2.672, 95%CI=1.354-5.272, P=0.005). CD44s was related to chemotherapy resistance (OR=3.218, 95%CI=1.148-9.016, P=0.026). Furthermore, overexpression of ALDH1 (HR=1.494, 95%CI=1.207-1.849, P< 0.001), CD117 (HR=1.395, 95%CI=1.025-1.898, P=0.034) or CD44s (HR=1.725, 95%CI=1.135-2.623, P=0.011) was associated with poor OS. Further, overexpression of both ALDH1 (HR=1.524, 95%CI=1.158-2.007, P=0.003) and CD44s (HR=2.12, 95%CI=1.692-2.657, P< 0.001) was correlated with worse DFS. Conclusion: CSC markers are useful predictive or prognostic biomarkers for OC in clinical assessments. Combined detection of CSC marker expression may be a powerful tool for prognostic predictions in clinical practice for patients with OC.

14-3-3ζ Overexpression is Associated with Poor Prognosis in Ovarian Cancer.

Purpose14-3-3ζ regulates cell signaling, cell cycle progression, and apoptosis, and its overexpression is associated with disease recurrence and poor clinical outcomes in some solid tumors. However, its clinicopathological role in ovarian cancer is unknown. Our goal was to investigate whether 14-3-3ζ is associated with ovarian cancer prognosis.Materials and MethodsWe examined 14-3-3ζ expression by immunohistochemistry in ovarian cancer tissues obtained from 88 ovarian cancer patients. The examined tissues were of various histologies and stages. 14-3-3ζ expression was also analyzed by western blot in seven ovarian cancer cell lines and a primary ovary epithelial cell line. Cell viability was measured using an MTS-based assay following cisplatin treatment.ResultsAmong the ovarian cancer samples, 53.4% (47/88) showed high 14-3-3ζ expression, and 14-3-3ζ overexpression was positively correlated with more advanced pathologic stages and grades. 14-3-3ζ overexpression was also significantly associated with poor disease-free survival (DFS) and overall survival (OS) of ovarian cancer patients. Median DFS and OS were 1088 and 3905 days, respectively, in the high 14-3-3ζ expression group, but not reached in the low 14-3-3ζ expression group (p=0.004 and p=0.033, log-rank test, respectively). Downregulating 14-3-3ζ by RNA interference in ovarian cancer cells led to enhanced sensitivity to cisplatin-induced cell death.Conclusion14-3-3ζ overexpression might be a potential prognostic biomarker for ovarian cancer, and the inhibition of 14-3-3ζ could be a therapeutic option that enhances the antitumor activity of cisplatin.

Abstract 2315: Overcoming treatment resistance in cisplatin-resistant ovarian carcinoma cells by tissue-specific miRNAs

Abstract Ovarian cancer is a common human cancer with a poor outcome and a high risk of death. Due to resistances to current standard therapies (carboplatin and paclitaxel for 3 to 6 cycles) additional therapeutic approaches are required and novel specific biomarkers for ovarian cancer patients are necessary. MicroRNAs (miRNA) are conserved, small noncoding RNAs regulating gene expression by binding to their target mRNA which have been shown to regulate biological processes including apoptosis. Apoptosis is a conserved, irreversible process that allows cells to undergo a highly regulated form of cell death. However, the final role of miRNAs in apoptotic signaling has not yet been fully determined. Modulating the expression of key molecular components of the cell death machinery is an attractive strategy for cancer therapy overcoming chemo drug resistance. To extend the pool of potential miRNA as anticancer agents and biomarkers, we transferred a high content miRNA screening for pro-apoptotic miRNAs to human cancer cell lines. Based on the high recovery rate of apoptosis inducing miRNAs in SKOV3 cells analyses were extended to multiple ovarian carcinoma cell lines with different genetic background. After transfection of miR-1912-5p the apoptosis rate increased strongly in cisplatin-resistant cells. In combination treatment with carboplatin the apoptotic effect increased after transfection of miR-1912-5p in the cisplatin-resistant A2780 cells. Furthermore, miR-1912-5p, miR-147b and miR-3073a showed significant apoptosis induction in the various ovarian cancer cell lines alone and in combined therapy with carboplatin. Western Blot analysis revealed an enhanced expression of the pro-apoptotic proteins Bak1 and Bax and a decrease inBcl2 and Bcl-xL. We characterized the miRNAs in regard to their endogenous expression and detected an enhanced expression after apoptosis induction by chemotherapeutic drugs. Finally, analysis of The Cancer Genome Atlas data showed an influence on the median survival of ovarian cancer patients (&amp;gt; 69 years). Our data indicate a potential benefit of tissue specific pro-apoptotic miRNAs in regard to cisplatin-resistant cells. Furthermore the study identified novel pro-apoptotic miRNAs with their potential use as novel therapeutic entities or prognostic biomarkers for ovarian cancer. Citation Format: Michael Kleemann, Jeremias Bereuther, Simon Fischer, Kim Marquart, Simon Hänle, Kristian Unger, Verena Jendrossek, Christian U. Riedel, René Handrick, Kerstin Otte. Overcoming treatment resistance in cisplatin-resistant ovarian carcinoma cells by tissue-specific miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2315. doi:10.1158/1538-7445.AM2017-2315

Abstract 2249: Integrated multi-level omics-based biomarker models for ovarian cancer survival

Abstract Background: Although a number of prognostic biomarkers for ovarian cancer have been proposed, the pool of clinically useful biomarkers remains small. While the predictive power of individual biomarkers may be weak, the advent of more affordable high-throughput technologies and readily available “omics” level data point toward the possibility of high performance biomarker panels. In this study, we used tumor-based somatic mutation, mRNA and miRNA expression, and DNA methylation data from The Cancer Genome Atlas (TCGA) to construct integrated biomarker models for overall and progression-free survival. Methods: The somatic mutations, mRNA expression, and DNA methylation of 451 candidate genes, as well as the expression of the miRNAs targeting them, were individually analyzed for association with overall and progression-free survival in 488 TCGA serous cystadenocarcinoma patients of predominantly Caucasian descent. Following correction for multiple comparisons, molecular variations associated with survival were combined to construct integrated cross-validated prediction models for overall and progression-free survival. The discriminative power of these models was then evaluated for 1-, 3-, and 5-year overall and progression-free survival using ROC analysis. Results: Our cross-validated integrated molecular models were demonstrated to predict 5-year overall survival in the total patient pool with a ROC AUC of 0.801 and 5-year overall and progression-free survival in Caucasian patients with ROC AUCs of 0.866 and 0.809, respectively. Conclusions: Our findings suggest the potential utility of our multi-omics-based biomarker models in helping to inform clinical decisions following ovarian cancer diagnosis. Although extensive efforts were made to maximize the predictive potential of our models, further retrospective and prospective validation efforts are necessary before their clinical utility can be accurately assessed. Citation Format: Alan Fu, Shen-Chih Chang, Aileen Baecker, Helena R. Chang, Zuo-Feng Zhang. Integrated multi-level omics-based biomarker models for ovarian cancer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2249. doi:10.1158/1538-7445.AM2017-2249

Panel of seven long noncoding RNA as a candidate prognostic biomarker for ovarian cancer.

Ovarian cancer is one of the most common and lethal gynecological malignancies. The diagnosis of ovarian cancer is often at an advanced stage. Accumulated evidence suggests that long noncoding RNAs (lncRNAs) play important roles during ovarian tumorigenesis. In this study, using the lncRNA-mining approach, we analyzed lncRNA expression profiles of 493 ovarian cancer patients from Gene Expression Omnibus datasets, and identified a signature group of seven lncRNAs (BC037530, AK021924, AK094536, AK094536, BC062365, BC004123 and BC007937) associated with patient survival in the training dataset GSE9891. We also formulated a risk score model to divide patients into low-risk and high-risk groups based on the expression of these seven lncRNAs. We further validated the predictive power of our risk score model in two other datasets, GSE26193 and GSE63885. Our analysis showed that the seven-lncRNA signature can serve as an independent predictor apart from Federation of Gynecology and Obstetrics (FIGO) stage and patient age. Further investigation revealed the seven-lncRNA signature correlated with few critical signaling pathways involved in cancer. Combined, all these findings strongly support that the seven-lncRNA signature can serve as a strong prognosis biomarker.

Single-gene prognostic biomarkers in ovarian cancer: Vetting associations by survival-determining clinical confounders

Single-gene prognostic biomarkers in ovarian cancer: Vetting associations by survival-determining clinical confounders

Primary and metastatic ovarian cancer: Characterization by 3.0T diffusion-weighted MRI

ObjectivesWe aimed to investigate whether apparent diffusion coefficients (ADCs) measured by 3.0T diffusion-weighted magnetic resonance imaging (DWI) associate with histological aggressiveness of ovarian cancer (OC) or predict the clinical outcome. This prospective study enrolled 40 patients with primary OC, treated 2011-2014.MethodsDWI was performed prior to surgery. Two observers used whole lesion single plane region of interest (WLsp-ROI) and five small ROIs (S-ROI) to analyze ADCs. Samples from tumours and metastases were collected during surgery. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to measure the expression of vascular endothelial growth factor (VEGF) and its receptors.ResultsThe interobserver reliability of ADC measurements was excellent for primary tumours ICC 0.912 (WLsp-ROI). Low ADCs significantly associated with poorly differentiated OC (WLsp-ROI P = 0.035). In primary tumours, lower ADCs significantly associated with high Ki-67 (P = 0.001) and low VEGF (P = 0.001) expression. In metastases, lower ADCs (WLsp-ROI) significantly correlated with low VEGF receptors mRNA levels. ADCs had predictive value; 3-year overall survival was poorer in patients with lower ADCs (WLsp-ROI P = 0.023, S-ROI P = 0.038).ConclusionReduced ADCs are associated with histological severity and worse outcome in OC. ADCs measured with WLsp-ROI may serve as a prognostic biomarker of OC.Key Points• Reduced ADCs correlate with prognostic markers: poor differentiation and high Ki-67 expression• ADCs also significantly correlated with VEGF protein expression in primary tumours• Lower ADC values are associated with poorer survival in ovarian cancer• Whole lesion single plane-ROI ADCs may be used as a prognostic biomarker in OC

Overexpression of miRNA-221 promotes cell proliferation by targeting the apoptotic protease activating factor-1 and indicates a poor prognosis in ovarian cancer.

MicroRNAs are a class of small non-coding, endogenous RNAs involved in cancer development and progression. MicroRNA-221 (mir-221) has been reported to have both an oncogenic and tumor-suppressive role in human tumors, but the role of miR-221 in ovarian cancer is poorly understood. In the present study, the expression levels of miR-221 and the apoptosis protease activating factor 1 (APAF1) protein in 63 samples of ovarian cancer tissues and the cell lines, IOSE25, A2780, OVCAR3, SKOV3 and 3AO were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Cell proliferation was measured using Cell Counting kit-8 (CCK-8); cell migration and invasion were detected using a Transwell assay; cell apoptosis was evaluated by flow cytometry and Hoechst staining, and a luciferase assay was performed to verify a putative target site of miR-221 in the 3′-UTR of APAF1 mRNA. Expression of miR-221 was upregulated in ovarian cancer tissues. Patients with increased miR-221 expression levels had a reduced disease-free survival (P=0.0014) and overall survival (P=0.0058) compared with those with low miR-221 expression. Transfection of SKOV3 and A2780 cell lines with miR-221 inhibitor induced APAF1 protein expression, suppressed cell proliferation and migration and promoted tumor cell apoptosis. In conclusion, the APAF1 gene was confirmed as a direct target of miR-221 and overexpression of APAF1 suppressed ovarian cancer cell proliferation and induced cell apoptosis in vitro. These findings indicate that miR-221-APAF1 should be studied further as a potential new diagnostic or prognostic biomarker for ovarian cancer.

Proteomics Analysis of Ovarian Cancer Cell Lines and Tissues Reveals Drug Resistance-associated Proteins.

Carboplatin and paclitaxel form the cornerstone of chemotherapy for epithelial ovarian cancer, however, drug resistance to these agents continues to present challenges. Despite extensive research, the mechanisms underlying this resistance remain unclear. A 2D-gel proteomics method was used to analyze protein expression levels of three human ovarian cancer cell lines and five biopsy samples. Representative proteins identified were validated via western immunoblotting. Ingenuity pathway analysis revealed metabolomic pathway changes. A total of 189 proteins were identified with restricted criteria. Combined treatment targeting the proteasome-ubiquitin pathway resulted in re-sensitisation of drug-resistant cells. In addition, examination of five surgical biopsies of ovarian tissues revealed α-enolase (ENOA), elongation factor Tu, mitochondrial (EFTU), glyceraldehyde-3-phosphate dehydrogenase (G3P), stress-70 protein, mitochondrial (GRP75), apolipoprotein A-1 (APOA1), peroxiredoxin (PRDX2) and annexin A (ANXA) as candidate biomarkers of drug-resistant disease. Proteomics combined with pathway analysis provided information for an effective combined treatment approach overcoming drug resistance. Analysis of cell lines and tissues revealed potential prognostic biomarkers for ovarian cancer.

MiR-376a promotion of proliferation and metastases in ovarian cancer: Potential role as a biomarker

AimsOvarian cancer is the fifth most deadly cancer in women, and is usually diagnosed too late. Exploring specific and sensitive biomarkers will be helpful to early detection and will improve the survival rates of ovarian cancer patients. Main methodsRealtime PCR was used to detect the expression of miR-376a. Wound healing and transwell assays were used to examined the migration and invasion abilities of ovarian cancer cells. Tumor xenograft experiments were employed to test the in vivo malignancy of ovarian cancer cells. Western Blotting and luciferase report assays were conducted for the target genes analysis. Key findingsUsing a cohort of 32 cases of ovarian cancer and 10 cases of healthy control samples, we found that miR-376 expression is increased in ovarian cancer tissues. The serum level of miR-376a is significantly higher in ovarian cancer patients and is associated with the clinical stages of ovarian cancer. Over expression of miR-376a stimulated the proliferation, migration, and invasion of ovarian cancer cells, while inhibition of miR-376a expression blocked the proliferation, migration, and invasion. Data from nude mice further demonstrated the stimulatory role of miR-376a in ovarian cancer progression. Mechanically, miR-376a played its role by targeting KLF15 and Caspase-8. SignificanceOur findings enrich the knowledge of miR-376a in ovarian cancer formation and progression, providing a possibility of using miR-376a as a diagnostic and prognostic biomarker for ovarian cancer.

Differential role of microRNAs in prognosis, diagnosis, and therapy of ovarian cancer

Ovarian cancer (OC) is the most lethal of malignant gynecological cancers, and has a very poor prognosis, frequently, attributable to late diagnosis and responsiveness to chemotherapy. In spite of the technological and medical approaches over the past four decades, involving the progression of several biological markers (mRNA and proteins biomarkers), the mortality rate of OC remains a challenge due to its late diagnosis, which is expressly ascribed to low specificities and sensitivities. Consequently, there is a crucial need for novel diagnostic and prognostic markers that can advance and initiate more individualized treatment, finally increasing survival of the patients. MiRNAs are non-coding RNAs that control target genes post transcriptionally. They are included in tumorigenesis, apoptosis, proliferation, invasion, metastasis, and chemoresistance. Several studies have within the last decade demonstrated that miRNAs are dysregulated in OC and have possibilities as diagnostic and prognostic biomarkers for OC. Additionally; recent studies have also focused on miRNAs as predictors of chemotherapy sensitivities and their potential as therapeutic targets. In this review, we discuss the current data involving the accumulating evidence of the altered expression of miRNAs in OC, their role in diagnosis, prognosis, and forecast of response to therapy. Given the heterogeneity of this disease, it is likely that advances in long-term survival might be also attained by translating the recent insights of miRNAs participation in OC into new targeted therapies that will have a crucial effect on the management of ovarian cancer.

Abstract 5080: Amylase overexpression promotes ovarian cancer invasion

Abstract Introduction: Hyperamylasemia is an overexpression of amylase. Hyperamylasemia is associated with poor clinical outcome in ovarian cancer and reportedly serves as a prognostic biomarker for ovarian cancer. However, the function of hyperamylasemia in ovarian cancer is thus far unknown. Since amylase cleaves α1, 4-glycosidic bonds in carbohydrates, hyperamylasemia may play an active role in the etiology of ovarian cancer. Purpose: The purpose of this study was to characterize amylase expression in ovarian cancer cell lines and establish an active role for hyperamylasemia in ovarian cancer. Hypothesis: We hypothesized that secreted amylase enzymes cleave α1, 4-glycosidic bonds found in the carbohydrate shell which may result in a modified glycocalyx structure facilitating ovarian cancer cell invasion. Consequently, inhibiting amylase expression could abrogate ovarian cancer cell invasion/metastasis. Methods: To characterize amylase isozyme expression, we assayed amylase expression in normal and cancerous ovarian epithelial cell lines by western immunoblot, qPCR, amylase assays and computational analyses. We measured the ability of amylase to promote cellular proliferation by MTS assays. We assayed invasive capacity of cultured cells using collagen coated Boyden chambers and abrogated amylase expression with either amylase siRNA or treatment with the blue-green algae, Spriulina. Results: It was found that the amylase genes have identical or similar biochemical and bioinformatics properties: similar molecular weights, theoretical isoelectric points, disorder and hydropathy profiles, secondary structure and posttranslational modifications. In contrast to normal cell lines, ovarian cancer cell lines overexpress amylase at the messenger and protein levels and secrete high levels of metabolically active amylase. Amylase isozymes 1 and 2B were preferentially overexpressed in ovarian cancer cell lines. Inhibition of amylase abrogated ovarian cancer cell migration/invasion through collagen coated Boyden chambers which was associated with amylase-dependent alteration of extracellular carbohydrates. Further, the blue-green algae, Spirulina, was found to be a novel inhibitor of amylase. Conclusion: Herein, we describe for the first time an active function of amylase to promote ovarian cancer cell invasion potentially mediated by amylase-dependent alteration of extracellular carbohydrates. Further, transcriptional inhibition of amylase by Spirulina demonstrates its clinical potential as an adjuvant nutraceutical therapy. Citation Format: Mai Mohamed, Patricia Kruk. Amylase overexpression promotes ovarian cancer invasion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5080.

Current status on microRNAs as biomarkers for ovarian cancer.

Ovarian cancer (OC) is the most lethal gynecological malignancy in the Western world, and has a very poor prognosis, often due to late diagnosis and emergence of chemotherapy resistance. Therefore, there is an essential need for new diagnostic and prognostic markers that can improve and initiate more personalized treatment, eventually improving survival of the patients. MicroRNAs are small, non-coding RNA molecules, that post-transcriptionally regulate gene expression. Several studies have within the last decade shown that microRNAs are deregulated in OC and have potential as diagnostic and prognostic biomarkers for OC. Recently studies have also focused on microRNAs as predictors of chemotherapy responses and their potential as therapeutic targets. However, many of the published studies are difficult to interpret as a whole due to various methods of analysis. Future focus should be aimed at developing a general standardized analytical method, which can limit differences between studies thus allowing easier comparison across them. In addition, validation of studies in independent series that ideally should be histotype-specific is essential to determine the clinical role of microRNAs in different types of OC. In this review we summarize the current knowledge of microRNAs as potential biomarkers for OC, with focus on their clinical relevance.

Abstract B02: DNA promoter methylation of HIST1H2BB as a potential early detection biomarker to reduce ovarian cancer disparities in the United States

Abstract Background: Ovarian cancer disproportionately affects African American women in the United States (US) at all stages of the disease, from presentation through treatment, and ultimately leads to increased mortality and decreased survival, compared to non-Hispanic White women. Till recently, epithelial ovarian cancers were thought to arise from the ovarian surface epithelial cells. However, recent studies suggest that the majority of high-grade serous carcinomas (HGSCs) arise from lesions in the fallopian tubes. DNA promoter hypermethylation of certain genes is often an early event in tumorigenesis, and it can be detected in blood and other bodily fluids, making it a feasible biomarker strategy for early detection of tumors. Purpose of study: Therefore, we sought to determine the methylation profile of HGSCs as compared to fallopian tube epithelium. Using the Infinium HumanMethylation 450 Array, that permits to quantitatively assess over 450,000 methylation sites, within and outside of CpG islands and more than 20,000 genes per sample, at single-nucleotide resolution, we have obtained the genome-wide methylation profile of HGSC and fallopian tubal epithelium. We conducted a pilot study by comparing the global methylation status in 12 HGSC tissue samples to 15 fallopian tube epithelium samples. In addition, we compared the methylation profile among long-term survivors (more than 5 years) and short-term survivors (2-3 years) of HGSCs. Results: Our results identified the HIST1H2BB promoter as the most differentially methylated region when comparing HGSC with normal fallopian tube samples. Furthermore, we also found that HIST1H2BB is differentially methylated in HGSC patients with long-term survival when compared to patients with short-term survival. Conclusions: Taken together, these results support the potential use of HIST1H2BB promoter methylation as a diagnostic and prognostic biomarker for ovarian cancer. Our findings could lead to the development of a biomarker for the diagnosis and/or prognosis of ovarian cancer. An early detection biomarker for ovarian cancer could contribute to the reduction and eventual elimination of ovarian cancer health disparities in the US. Citation Format: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston. DNA promoter methylation of HIST1H2BB as a potential early detection biomarker to reduce ovarian cancer disparities in the United States. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B02.

Abstract AS15: DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer

Abstract Background: Until recently, epithelial ovarian cancers were thought to arise from the ovarian surface epithelial cells. However, recent studies suggest that the majority of high grade serous carcinomas (HGSCs) arise from lesions in the fallopian tubes. DNA promoter hypermethylation of certain genes is often an early event in tumorigenesis, and it can be detected in blood and other bodily fluids, making it a feasible biomarker strategy for early detection of tumors. Purpose of study: Therefore, we sought to determine the methylation profile of HGSCs as compared to fallopian tube epithelium. Using the Infinium HumanMethylation 450 Array, that permits to quantitatively assess over 450,000 methylation sites, within and outside of CpG islands and more than 20,000 genes per sample, at single-nucleotide resolution, we have obtained the genome-wide methylation profile of HGSC and fallopian tubal epithelium. We conducted a pilot study by comparing the global methylation in 12 HGSC tissue samples to 15 fallopian tube epithelium samples. In addition, we compared the methylation profile among long-term survivors (more than 5 years) and short-term survivors (2-3 years) of HGSCs. Results: Our results identified the HIST1H2BB promoter as the most differentially methylated region when comparing HGSC with normal fallopian tube samples. Furthermore, we also found that HIST1H2BB is differentially methylated in HGSC patients with long-term survival when compared to patients with short-term survival. Conclusions: Taken together, these results support the potential of HIST1H2BB promoter hypermethylation as a diagnostic and prognostic biomarker. Our findings could lead to the development of a biomarker for the diagnosis and/or prognosis of ovarian cancer and could contribute to the current understanding of the mechanisms of progression in ovarian cancer. Citation Format: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston. DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS15.

Abstract 2960: DNA promoter hypermethylation of genes as potential diagnostic and prognostic biomarkers for ovarian cancer

Abstract Till recently, epithelial ovarian cancers were thought to arise from the ovarian surface epithelial cells. However, recent studies suggest that the majority of high grade serous carcinomas (HGSCs) arise from lesions in the fallopian tubes. DNA promoter hypermethylation of certain genes is often an early event in tumorigenesis, and it can be detected in blood and other bodily fluids, making it a feasible biomarker strategy for early detection of tumors. Therefore, we sought to determine the methylation profile of HGSCs as compared to fallopian tube epithelium, using the Infinium HumanMethylation 450 Array. We compared the methylation in 12 HGSC tissue samples to 15 fallopian tube epithelium samples. In addition, we compared the methylation profile among long-term survivors (more than 5 years) and short-term survivors (2-3 years) of HGSCs. Our results identified the promoter regions of HIST1H2BB, MAGI2, and EPSTI1 to be differentially methylated when comparing HGSC with normal fallopian tube samples. Furthermore, these genes were differentially methylated in HGSC patients with long-term survival when compared to patients with short-term survival. Quantitative methylation specific PCR analysis confirmed our results of differential methylation among short-term and long-term survivors, and show that these genes are also methylated in ovarian cancer cell lines. Taken together, we have identified genes that could have potential as diagnostic and prognostic biomarkers. Our findings could lead to the development of a biomarker panel for the diagnosis and/or prognosis of ovarian cancer. Citation Format: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston. DNA promoter hypermethylation of genes as potential diagnostic and prognostic biomarkers for ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2015-2960

MicroRNA-200c and microRNA-141 as potential diagnostic and prognostic biomarkers for ovarian cancer.

Ovarian cancer is the fifth leading cause of female death globally due to its low survival rates. Thus, improved approaches for ovarian cancer detection are urgently needed. MicroRNAs as a new class of biomarkers have been explored in recent studies. This study was trying to identify and validate the two kinds of serum microRNA (miR-200c and miR-141) as biomarkers for ovarian cancer. We extracted serum samples from 74 epithelial ovarian cancer patients, 19 borderline ovarian cancer, and 50 healthy controls. Relative expression of these miRNA markers were measured by quantificational real-time polymerase chain reaction assay (qRT-PCR). Receiver operating characteristics (ROC) and area under the ROC curve (AUC) were used to validate the diagnostic value of miR-200c and miR-141. Kaplan-Meier curve and the log-rank test were conducted to detect the prognostic value of miR-200c and miR-141. miR-200c and miR-141 were significantly elevated in the epithelial ovarian cancer patients compared to healthy controls. The relative expression level of miR-200c showed a descending trend from early stages to advanced stages, while the level of miR-141 displayed an escalating trend. Patients with high miR-200c level achieved significantly a higher 2-year survival rate compared with the other group (P < 0.001), while low miR-141 group showed a significantly higher survival rate. The results of the current study suggested that serum miR-200c and miR-141 were able to discriminate the ovarian cancer patients from healthy controls. In addition, miR-200c and miR-141 may be predictive biomarkers for ovarian cancer prognosis. Further large-scale studies are still needed to confirm our findings.

Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications.

Folate can be transported into the cell by the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), or the folate receptor (FR), of which various isoforms exist. While the RFC and PCFT are expressed by many normal cells, the FR is present only in a small proportion of normal tissues. In these tissues, the FR expression level is often low and restricted to the apical surface of polarized epithelial cells. In contrast, FR is expressed on the blood-accessible basal and lateral membranes of many types of epithelial cancer. Considering that FR is expressed in few nonmalignant cell types on luminal membranes generally not accessible for molecules transported in the blood, FR is considered a promising antitumor target. As FR expression seems associated with tumor progression and prognosis, anticancer therapies targeting FR are currently being developed, such as farletuzumab (Morphotek, Exton, PA, USA), IMGN853 (ImmunoGen, Waltham, MA, USA), vintafolide, and EC1456 (both Endocyte Inc., West Lafayette, IN, USA). FR expression could be used as a response-predictive biomarker for these treatments. The ability to identify patients and treat them with an effective therapy based on the known expression of the tumor marker would, indeed, be the next step in predictive medicine for these patients. This review summarizes the role of FR in ovarian cancer and the value of FR as a prognostic biomarker for ovarian cancer and a response-predictive biomarker for folate-targeted therapeutics.

WITHDRAWN: MicroRNA-200c and microRNA-141 as potential diagnostic and prognostic biomarkers for ovarian cancer

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Circulating MicroRNAs in gynecological malignancies: from detection to prediction.

MicroRNAs (miRNAs) have been demonstrated to play critical roles in many physiological and pathophysiological processes. The presence of altered miRNA profiles in human body fluids has been reported for a number of diseases including gynecological malignancies. In this review, we summarized the current progresses of circulating miRNAs associated with malignancies in gynecology, with an emphasizing on the circulating miRNAs as diagnostic and prognostic biomarkers in ovarian cancer, endometrial carcinoma and cervical cancer.