Profiling of Glycans in Serum for the Discovery of Potential Biomarkers for Ovarian Cancer

An, Hyun Joo; Miyamoto, Suzanne; Lancaster, Katherine S.; Kirmiz, Crystal; Li, Bensheng; Lam, Kit S.; Leiserowitz, Gary S.; Lebrilla, Carlito B.

doi:10.1021/pr060010k

Cited by 206 publications

(267 citation statements)

References 27 publications

(45 reference statements)

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“…Indeed, the profiling of serum glycans has been performed previously as a screen for distinct potential glycan biomarkers of ovarian cancer and breast cancer. 18,19 Hence, we surmised that highly specific glycoprotein markers of HCC should be detected by monitoring the serum glycosylation profile in these patients. In glycan structure, both G2890 and G3560 are multiply branched (G2890 is tri-antennary and G3560 is tetra-antennary) glycans with a core fucose.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, some glycoproteins have been suggested as biomarkers of human carcinomas such as ovarian cancer, breast cancer, and HCC. [16][17][18][19] Of note, changes to the N-linked glycan modification of glycoproteins occur during the tumorigenesis and progression of HCC lesions. However, the correlation between the N-glycan profile and tumorassociated characteristics such as the degree of malignancy and prognosis has not been previously evaluated in HCC.…”

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Identification of novel serum biomarkers of hepatocellular carcinoma using glycomic analysis

et al. 2013

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The altered N-glycosylation of glycoproteins has been suggested to play an important role in the behavior of malignant cells. Using glycomics technology, we attempted to determine the specific and detailed N-glycan profile for hepatocellular carcinoma (HCC) and investigate the prognostic capabilities. From 1999 to 2011, 369 patients underwent primary curative hepatectomy in our facility and were followed up for a median of 60.7 months. As normal controls, 26 living Japanese related liver transplantation donors were selected not infected by hepatitis B and C virus. Their mean age was 40.0 and 15 (57.7%) were male. We used a glycoblotting method to purify N-glycans from preoperative blood samples from this cohort (10 lL serum) which were then identified and quantified using mass spectrometry (MS). Correlations between the N-glycan levels and the clinicopathologic characteristics and outcomes for these patients were evaluated. Our analysis of the relative areas of all the sugar peaks identified by MS, totaling 67 N-glycans, revealed that a proportion had higher relative areas in the HCC cases compared with the normal controls. Fourteen of these molecules had an area under the curve of greater than 0.80. Analysis of the correlation between these 14 N-glycans and surgical outcomes by univariate and multivariate analysis identified G2890 (m/z value, 2890.052) as a significant recurrence factor and G3560 (m/z value, 3560.295) as a significant prognostic factor. G2890 and G3560 were found to be strongly correlated with tumor number, size, and vascular invasion. Conclusion: Quantitative glycoblotting based on whole serum N-glycan profiling is an effective approach to screening for new biomarkers. The G2890 and G3560 N-glycans determined by tumor glycomics appear to be promising biomarkers for malignant behavior in HCCs. (HEPATOLOGY 2013;57:2314-2325 H epatocellular carcinoma (HCC) is a common and fatal malignancy with a worldwide occurrence.1 Liver resection has shown the highest level of control among the local treatments for HCC and is associated with a good survival rate.2,3 However, the recurrence rates for HCC are still high even when a curative hepatectomy is performed. 4 Many factors associated with the prognosis and recurrence of HCC have now been reported. Vascular invasion of the portal vein and/or hepatic vein and tumor differentiation are important factors affecting survival and recurrence in HCC cases after a hepatectomy. 5,6 However, microvascular invasion and differentiation can only be detected by pathological examination just after a hepatectomy, and cannot be diagnosed preoperatively, and thus cannot be identified preoperatively either. Hence, the serum biomarkers alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II) are used as prognostic markers 7,8 and also as surrogate markers for microvascular invasion and tumor differentiation.9,10 AFP is associated with grade differentiation, 11 whereas PIVKA-II is related to vascularAbbreviations: AFP, alpha-fetoprotein; AFP-L3, lens cul...

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Section: Discussionmentioning

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Identification of novel serum biomarkers of hepatocellular carcinoma using glycomic analysis

et al. 2013

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“…Proposed mechanism for high levels of sialic acid could be the change in sialylation that occurs before cancer development. Recently, An et al [31] developed the glycomic approach to identify oligosaccharide markers for ovarian cancer. Globally released oligosaccharides from O-linked glycoproteins can be harvested and could serve as biomarkers for ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Serum Levels of Glycoproteins are Elevated in Patients with Ovarian Cancer

et al. 2013

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Identification of reliable biomarkers for detection and staging of cancer and monitoring the outcome of anticancer therapy has been considered to be of high importance. We aimed to estimate the levels of serum glycoproteins, protein bound-hexose, protein bound hexosamine, protein bound fucose, protein bound sialic acid and protein bound carbohydrate in 32 ovarian cancer patients and compared them with the levels that found in 25 normal subjects. As compared to the normal subjects, all the four fractions of glycoproteins level were significantly elevated in ovarian cancer patients (p \ 0.05). Chemotherapy in these patients significantly decreased the levels of serum glycoproteins (p \ 0.05). Thus, high levels of serum glycoproteins in ovarian cancer patients could be due to abnormal protein glycosylation indicating malignant transformation of the cells.

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“…In a study on human pancreatic cancer, serum samples contained N-glycans with increased fucosylation and sialylation relative to those from healthy individuals [24]. Samples in the study of ovarian cancer patients also showed a number of neutral oligosaccharides that appeared related to cancer [25]. Despite intense research efforts, many times the findings are relevant only to the particular biological material on which the analysis was performed.…”

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Mass spectrometric profiling of N-linked oligosaccharides and uncommon glycoform in mouse serum with head and neck tumor

Lattová

Varma

Bezabeh

et al. 2008

J. Am. Soc. Mass Spectrom.

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N-linked oligosaccharides obtained from total serum of mice with implanted head and neck tumors were analyzed and compared with those from control samples of healthy mice. Methods used include a combination of a derivatization procedure with phenylhydrazine (PHN) and analysis by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Oligosaccharides were enzymatically released from total serum with PNGaseF and purified by high-performance liquid chromatography (HPLC) on a reversed-phase column. Mass spectra contained ion peaks of labeled oligosaccharides and MS/MS experiments provided useful data for the structural elucidation of these compounds. More than 40 N-glycans with compositions characteristic of high-mannose, hybrid, complex, neutral, and sialylated structures were identified in the serum of tumoral mice. Significant differences between samples were observed with respect to the abundances of high mannose and hybrid glycans. These oligosaccharides showed higher relative intensities in the spectra obtained from the cancer sera. Complex sialylated oligosaccharides had similar abundances in both types of sera, with the exception of fucosylated biantennary disialylated oligosaccharide, which was mostly detected with lower abundance in control samples. In the MALDI spectra, several minor species corresponded to uncommon carbohydrates. These structures have been investigated in detail by MS/MS. Among these novel glycoforms, a few sialylated oligosaccharides without a free reducing end were identified. Also, glycans with an extra 60 u were observed and likely feature the presence of a 2-acetamido-2-deoxyoctose residue attached on antennae of 3-or 6-linked mannose. . It has been recognized that altered glycosylation is an universal feature of living cells and several studies have demonstrated that the changes in cellular glycosylation profiles can be also related to aggressive cancer cell behavior, such as tumor cell invasion and metastasis [2][3][4][5][6][7][8]. As cancer cells can produce oligosaccharides that are significantly different from those in normal cells, comparative studies between glycoprotein carbohydrates produced by malignant cells and normal cells may provide useful information for diagnosis, prognosis, and immunotherapy of tumors [9].Mass spectrometry (MS) has been used extensively as the most sensitive method for the analysis of carbohydrate molecules [10 -14]. Moreover, modern MS instruments allow the measurement of unseparated mixtures, and make possible the identification of trace amounts of glycans in biological materials [15]. Nonetheless, biochemical analysis of carbohydrates is generally complicated, not only because of their lower concentration relative to with proteins, but also because of the structural diversity of molecules, anomericity, linkage positions, and branching patterns of monosaccharides. Moreover, carboxylic groups cause sialylated oligosaccharides to ionize with less efficiency than neutral oligosaccharides, making MS analysis of glycans more difficu...

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Profiling of Glycans in Serum for the Discovery of Potential Biomarkers for Ovarian Cancer

Cited by 206 publications

References 27 publications

Identification of novel serum biomarkers of hepatocellular carcinoma using glycomic analysis

Identification of novel serum biomarkers of hepatocellular carcinoma using glycomic analysis

Serum Levels of Glycoproteins are Elevated in Patients with Ovarian Cancer

Mass spectrometric profiling of N-linked oligosaccharides and uncommon glycoform in mouse serum with head and neck tumor

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