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Tissue and plasma levels of galectins in patients with high grade serous ovarian carcinoma as new predictive biomarkers.

ABSTRACT: Galectins are moving closer to center stage in detecting glycosylation aberration in cancer cells. Here, we have investigated the expression of galectins in ovarian cancer (OC) and examined their potential as biomarkers in tissues and blood plasma samples of high grade serous ovarian carcinoma (HGSC) patients. In tissues, we found that increased protein expression of stromal gal-1 and epithelial gal-8/9 was associated with a poor response to treatment of HGSC patients. Gal-8/9 were both independent predictors of chemoresistance and overall survival (OS), respectively. This galectin signature increased the predictive value of the cancer antigen 125 (CA125) on 5-year disease-free survival (DFS), post-chemotherapy treatment and 5-year OS. In CA125^LOW patients, epithelial gal-9 was associated with a lower 5-year OS while stromal gal-1 and epithelial gal-8 were both associated with a lower 5-year DFS. Such negative predictive value of gal-8 and gal-9 was also found using plasma samples. In both cases, high plasma levels of gal-8 and gal-9 was associated with a lower OS and DFS. Overall, these data suggest that galectins may be promising biomarkers to identify subgroups of HGSC patients with poorer prognosis. Our study also contributes to better define the heterogeneity of the disease.

SUBMITTER: Labrie M

PROVIDER: S-EPMC5643335 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Tissue and plasma levels of galectins in patients with high grade serous ovarian carcinoma as new predictive biomarkers.

Labrie Marilyne M De Araujo Lorenna Oliveira Fernandes LOF Communal Laudine L Mes-Masson Anne-Marie AM St-Pierre Yves Y

Scientific reports 20171016 1

Galectins are moving closer to center stage in detecting glycosylation aberration in cancer cells. Here, we have investigated the expression of galectins in ovarian cancer (OC) and examined their potential as biomarkers in tissues and blood plasma samples of high grade serous ovarian carcinoma (HGSC) patients. In tissues, we found that increased protein expression of stromal gal-1 and epithelial gal-8/9 was associated with a poor response to treatment of HGSC patients. Gal-8/9 were both independ ...[more]

PMID: 29038585

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Project description:Ovarian cancer is one of the most lethal female cancers. For accurate prognosis prediction, this study aimed to investigate novel, blood-based prognostic biomarkers for high-grade serous ovarian carcinoma (HGSOC) using mass spectrometry-based proteomics methods. We conducted label-free liquid chromatography-tandem mass spectrometry using frozen plasma samples obtained from patients with newly diagnosed HGSOC (n = 20). Based on progression-free survival (PFS), the samples were divided into two groups: good (PFS ≥18 months) and poor prognosis groups (PFS <18 months). Proteomic profiles were compared between the two groups. Referring to proteomics data that we previously obtained using frozen cancer tissues from chemotherapy-naïve patients with HGSOC, overlapping protein biomarkers were selected as candidate biomarkers. Biomarkers were validated using an independent set of HGSOC plasma samples (n = 202) via enzyme-linked immunosorbent assay (ELISA). To construct models predicting the 18-month PFS rate, we performed stepwise selection based on the area under the receiver operating characteristic curve (AUC) with 5-fold cross-validation. Analysis of differentially expressed proteins in plasma samples revealed that 35 and 61 proteins were upregulated in the good and poor prognosis groups, respectively. Through hierarchical clustering and bioinformatic analyses, GSN, VCAN, SND1, SIGLEC14, CD163, and PRMT1 were selected as candidate biomarkers and were subjected to ELISA. In multivariate analysis, plasma GSN was identified as an independent poor prognostic biomarker for PFS (adjusted hazard ratio, 1.556; 95% confidence interval, 1.073-2.256; p = 0.020). By combining clinical factors and ELISA results, we constructed several models to predict the 18-month PFS rate. A model consisting of four predictors (FIGO stage, residual tumor after surgery, and plasma levels of GSN and VCAN) showed the best predictive performance (mean validated AUC, 0.779). The newly developed model was converted to a nomogram for clinical use. Our study results provided insights into protein biomarkers, which might offer clues for developing therapeutic targets.

Project description:ObjectiveStudies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC.MethodsWomen with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre- and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated.ResultsA total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96-1.01 and 0.98; 95%CI 0.95-1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43-12.73) and OS (HR 1.69, 95%CI 0.56-5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36-5.81) and OS (HR 6.62, 95%CI 2.45-17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85).ConclusionAdvanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS.Highlights1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analyzed. 2. Although low-grade serous ovarian cancer is often considered indolent, the progression-free and overall survival are poor. 3. Elevated post-treatment CA-125 levels are independently associated with poor survival.

Project description:BackgroundInsulin-like growth factor binding protein 7 (IGFBP7) has been suggested to act as a tumour suppressor gene in various human cancers, yet its role in epithelial ovarian cancer (EOC) has not yet been investigated. We previously observed that IGFBP7 was one of several genes found significantly upregulated in an EOC cell line model rendered non-tumourigenic as consequence of genetic manipulation. The aim of the present study was to investigate the role of IGFBP7 in high-grade serous ovarian carcinomas (HGSC), the most common type of EOC.MethodsWe analysed IGFBP7 gene expression in 11 normal ovarian surface epithelial cells (NOSE), 79 high-grade serous ovarian carcinomas (HGSC), and seven EOC cell lines using a custom gene expression array platform. IGFBP7 mRNA expression profiles were also extracted from publicly available databases. Protein expression was assessed by immunohistochemistry of 175 HGSC and 10 normal fallopian tube samples using tissue microarray and related to disease outcome. We used EOC cells to investigate possible mechanisms of gene inactivation and describe various in vitro growth effects of exposing EOC cell lines to human recombinant IGFBP7 protein and conditioned media.ResultsAll HGSCs exhibited IGFBP7 expression levels that were significantly (p = 0.001) lower than the mean of the expression value of NOSE samples and that of a whole ovary sample. IGFBP7 gene and protein expression were lower in tumourigenic EOC cell lines relative to a non-tumourigenic EOC cell line. None of the EOC cell lines harboured a somatic mutation in IGFBP7, although loss of heterozygosity (LOH) of the IGFBP7 locus and epigenetic methylation silencing of the IGFBP7 promoter was observed in two of the cell lines exhibiting loss of gene/protein expression. In vitro functional assays revealed an alteration of the EOC cell migration capacity. Protein expression analysis of HGSC samples revealed that the large majority of tumour cores (72.6%) showed low or absence of IGFBP7 staining and revealed a significant correlation between IGFBP7 protein expression and a prolonged overall survival (p = 0.044).ConclusionThe low levels of IGFPB7 in HGSC relative to normal tissues, and association with survival are consistent with a purported role in tumour suppressor pathways.

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Tissue and plasma levels of galectins in patients with high grade serous ovarian carcinoma as new predictive biomarkers.

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Tissue and plasma levels of galectins in patients with high grade serous ovarian carcinoma as new predictive biomarkers.

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