Dataset Information

N-linked glycan structures and their expressions change in the blood sera of ovarian cancer patients.

ABSTRACT: Glycosylated proteins play important roles in a broad spectrum of biochemical and biological processes, and prior reports have suggested that changes in protein glycosylation occur during cancer initiation and progression. Ovarian cancer (OC) is a fatal malignancy, most commonly diagnosed after the development of metastases. Therefore, early detection of OC is key to improving survival. To this end, specific changes of the serum glycome have been proposed as possible biomarkers for different types of cancers. In this study, we extend this concept to OC. To characterize differences in total N-glycan levels, serum samples provided by 20 healthy control women were compared to those acquired from patients diagnosed with late-stage recurrent OC who were enrolled in an experimental treatment trial prior to receiving therapy (N=19) and one month later, prior to the second treatment cycle (N=11). Additionally, analyses of the N-glycans associated with IgG and characterization of the relative abundance levels of core vs outer-arm fucosylation were also performed. The N-linked glycomic profiles revealed increased abundances of tri- and tetra-branched structures with varying degrees of sialylation and fucosylation and an apparent decrease in the levels of "bisecting" glycans in OC samples compared to controls. Increased levels of a-galactosylation structures were observed on N-linked glycans derived from IgG, which were independent of the presence of fucose residues. Elevated levels of outer-arm fucosylation were also identified in the OC samples. These results allowed the control samples to be distinguished from the baseline ovarian cancer patients prior to receiving the experimental treatment. In some cases, the pre-treatment samples could be distinguished from the post-experimental treatment samples, as many of those patients showed a further progression of the disease.

SUBMITTER: Alley WR

PROVIDER: S-EPMC3321095 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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N-linked glycan structures and their expressions change in the blood sera of ovarian cancer patients.

Alley William R WR Vasseur Jacqueline A JA Goetz John A JA Svoboda Martin M Mann Benjamin F BF Matei Daniela E DE Menning Nancy N Hussein Ahmed A Mechref Yehia Y Novotny Milos V MV

Journal of proteome research 20120307 4

Glycosylated proteins play important roles in a broad spectrum of biochemical and biological processes, and prior reports have suggested that changes in protein glycosylation occur during cancer initiation and progression. Ovarian cancer (OC) is a fatal malignancy, most commonly diagnosed after the development of metastases. Therefore, early detection of OC is key to improving survival. To this end, specific changes of the serum glycome have been proposed as possible biomarkers for different typ ...[more]

PMID: 22304416

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Project description:Epithelial ovarian cancer is the fifth most common cause of cancer in women worldwide bearing the highest mortality rate among all gynecological cancers. Cell membrane glycans mediate various cellular processes such as cell signaling and become altered during carcinogenesis. The extent to which glycosylation changes are influenced by aberrant regulation of gene expression is nearly unknown for ovarian cancer and remains crucial in understanding the development and progression of this disease. To address this effect, we analyzed the membrane glycosylation of non-cancerous ovarian surface epithelial (HOSE 6.3 and HOSE 17.1) and serous ovarian cancer cell lines (SKOV 3, IGROV1, A2780, and OVCAR 3), the most common histotype among epithelial ovarian cancers. N-glycans were released from membrane glycoproteins by PNGase F and analyzed using nano-liquid chromatography on porous graphitized carbon and negative-ion electrospray ionization mass spectrometry (ESI-MS). Glycan structures were characterized based on their molecular masses and tandem MS fragmentation patterns. We identified characteristic glycan features that were unique to the ovarian cancer membrane proteins, namely the "bisecting N-acetyl-glucosamine" type N-glycans, increased levels of ? 2-6 sialylated N-glycans and "N,N'-diacetyl-lactosamine" type N-glycans. These N-glycan changes were verified by examining gene transcript levels of the enzymes specific for their synthesis (MGAT3, ST6GAL1, and B4GALNT3) using qRT-PCR. We further evaluated the potential epigenetic influence on MGAT3 expression by treating the cell lines with 5-azacytidine, a DNA methylation inhibitor. For the first time, we provide evidence that MGAT3 expression may be epigenetically regulated by DNA hypomethylation, leading to the synthesis of the unique "bisecting GlcNAc" type N-glycans on the membrane proteins of ovarian cancer cells. Linking the observation of specific N-glycan substructures and their complex association with epigenetic programming of their associated synthetic enzymes in ovarian cancer could potentially be used for the development of novel anti-glycan drug targets and clinical diagnostic tools.

Project description:Despite systemic therapy and cystectomy, bladder cancer is characterized by a high recurrence rate. Serum glycomics represents a promising source of prognostic markers for monitoring patients. Our approach, which we refer to as "glycan node analysis", constitutes the first example of molecularly "bottom-up" glycomics. It is based on a global glycan methylation analysis procedure that is applied to whole blood plasma/serum. The approach detects and quantifies partially methylated alditol acetates arising from unique glycan features such as α2-6 sialylation, β1-4 branching, and core fucosylation that have been pooled together from across all intact glycans within a sample into a single GC-MS chromatographic peak. We applied this method to 122 plasma samples from former and current bladder cancer patients (n = 72 former cancer patients with currently no evidence of disease (NED); n = 38 non-muscle invasive bladder cancer (NMIBC) patients; and n = 12 muscle invasive bladder cancer (MIBC) patients) along with plasma from 30 certifiably healthy living kidney donors. Markers for α2-6 sialylation, β1-4 branching, β1-6 branching, and outer-arm fucosylation were able to separate current and former (NED) cases from certifiably healthy controls (ROC curve c-statistics ~ 0.80); but NED, NMIBC, and MIBC were not distinguished from one another. Based on the unexpectedly high levels of these glycan nodes in the NED patients, we hypothesized that recurrence of this disease could be predicted by some of the elevated glycan features. Indeed, α2-6 sialylation and β1-6 branching were able to predict recurrence from the NED state using a Cox proportional hazards regression model adjusted for age, gender, and time from cancer. The levels of these two glycan features were correlated to C-reactive protein concentration, an inflammation marker and known prognostic indicator for bladder cancer, further strengthening the link between inflammation and abnormal plasma protein glycosylation.

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N-linked glycan structures and their expressions change in the blood sera of ovarian cancer patients.

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N-linked glycan structures and their expressions change in the blood sera of ovarian cancer patients.

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