Purpose: A better understanding of the molecular pathways underlying the development of epithelial ovarian cancer (EOC) is critical to identify ovarian tumor markers for use in diagnostic or therapeutic applications. The aims of this study were to integrate the results from 14 transcript profiling studies of EOC to identify novel biomarkers and to examine their expression in early and late stages of the disease.Experimental Design: A database incorporating genes identified as being highly up-regulated in each study was constructed. Candidate tumor markers were selected from genes that overlapped between studies and by evidence of surface membrane or secreted expression. The expression patterns of three integral membrane proteins, discoidin domain receptor 1 (DDR1), claudin 3 (CLDN3), and epithelial cell adhesion molecule, all of which are involved in cell adhesion, were evaluated in a cohort of 158 primary EOC using immunohistochemistry.Results: We confirmed that these genes are highly overexpressed in all histological subtypes of EOC compared with normal ovarian surface epithelium, identifying DDR1 and CLDN3 as new biomarkers of EOC. Furthermore, we determined that these genes are also expressed in ovarian epithelial inclusion cysts, a site of metaplastic changes within the normal ovary, in borderline tumors and in low-grade and stage cancer. A trend toward an association between low CLDN3 expression and poor patient outcome was also observed.Conclusions: These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease.
Purpose: Dysregulation of cell cycle control, in particular G 1 -S-phase transition, is implicated in the pathogenesis of most human cancers, including epithelial ovarian cancer (EOC). However, the prognostic significance of aberrant cell cycle gene expression in EOC remains unclear.Experimental Design: The expression of selected genes from the pRb pathway that regulates G 1 -S-phase progression, including cyclin D1, p16Ink4a , cyclin E, p27 Kip1 , p21Waf1/Cip1 , and p53, was examined in a consecutive series of 134 serous EOC using immunohistochemistry and the results correlated to disease outcome.Results: Molecular markers predictive of reduced overall survival in univariate analysis were overexpression of cyclin D1 (P ؍ 0.03) and p53 (P ؍ 0.03) and reduced expression of p27 Kip1 (P ؍ 0.05) and p21 Waf1/Cip1 (P ؍ 0.02), with the latter three also being prognostic for a shorter progression-free interval. In addition, patients displaying overexpression of p53 with concurrent loss of p21 Waf1/Cip1 had a significantly shorter overall (P ؍ 0.0008) and progression-free survival (P ؍ 0.0001). On multivariate analysis, overexpression of cyclin D1 and combined loss of p21 Waf1/Cip1 in the presence of p53 overexpression were independent predictors of overall survival. Similarly, the combination of p21 Waf1/Cip1 loss and p53 overexpression was independently predictive of a shorter progression-free interval. Overexpression of p53 and cyclin E and reduced expression of p27Kip1 and p21 Waf1/Cip1 were significantly associated with increasing tumor grade.Conclusions: This study confirms that dysregulation of cell cycle genes is common in EOC, and that aberrant expression of critical cell cycle regulatory proteins can predict patient outcome in serous EOC.
Ovarian cancer is associated with high mortality due to asymptomatic nature of the disease and advance stage at presentation. In advanced stages, it is associated with cachexia and ascites leading to malnutrition. Nutritional status of a patient with cancer has been well known to be associated with survival and can be assessed by level of albumin in blood. Therefore, in this study, we sought to determine preoperative serum albumin as prognostic predictor of survival in patients with ovarian cancer. Preoperative serum albumin was determined in 235 patients undergoing surgery for ovarian cancer at Royal Derby Hospital. The prognostic predictive value of serum albumin, along with other prognostic markers was then analysed using univariate and multivariate analyses. Low serum albumin was associated with poor survival (P < 0.001) in patients with ovarian cancer. There was an inverse correlation between serum albumin levels and survival with lower levels having poor survival. Patients with serum albumin levels of <25 g/l had a median survival of 4.8 months (95% CI 0-13.1 months), whilst levels >35 g/l were associated with median survival of 43.2 months (95% CI 11.6-20.9). Serum albumin (P < 0.001) retained its significance as an independent predictor of poor survival on Cox's multivariate regression analysis along with Age (P < 0.001) and FIGO stage (P < 0.001). Serum albumin can be used as an independent prognostic predictor of survival in patients with ovarian cancer.
Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing 459 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT -PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.
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Voltage gated potassium channels have been extensively studied in relation to cancer. In this review, we will focus on the role of two potassium channels, Ether à-go-go (Eag), Human ether à-go-go related gene (HERG), in cancer and their potential therapeutic utility in the treatment of cancer. Eag and HERG are expressed in cancers of various organs and have been implicated in cell cycle progression and proliferation of cancer cells. Inhibition of these channels has been shown to reduce proliferation both in vitro and vivo studies identifying potassium channel modulators as putative inhibitors of tumour progression. Eag channels in view of their restricted expression in normal tissue may emerge as novel tumour biomarkers.
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