Abstract
Epithelial ovarian cancer (EOC) is a rather rare but lethal disease that is usually diagnosed at an advanced stage; this is due to a lack of early diagnostic markers. At the time being, less than a quarter of patients are diagnosed when the tumor has not metastasized yet. In previous work, we demonstrated that antennarity, fucosylation, and sialylation increased in EOC patients and built a glycan-based score that was able to diagnose EOC better than CA125, the routine diagnostic marker, does. To date, little attention had been paid to the sialic acid linkages of N-glycans in the context of blood biomarker research. In this work, the sialic acid linkages of the serum glycome of ovarian cancer patients were investigated for the first time by MALDI-TOF-MS. To this end, we released N-glycans, derivatized sialic acids solely in a linkage-specific way and measured glycome profiles by MALDI-TOF mass spectrometry. A statistically significant decrease was observed between late stage patients and controls or early stage patients for high-mannose, hybrid-type, complex-type asialylated, bi, tri- and tetraantennary sialylated structures. A significant decrease of monosialylated monoantennary N-glycan structures was observed in early and late stage EOC when compared to healthy controls. Statistically significant increases were observed in early and late stage patients compared to controls for tri, tetraantennary fucosylated structures, afucosylated, and fucosylated triantennary structures taken as α-2,3-linked/α-2,6-linked sialic acid ratio. Moreover, all afucosylated and fucosylated structures taken as α-2,3-linked/α-2,6-linked sialic acid ratio and the α-2,3-linked/α-2,6-linked sialic acid ratio of all sialylated structures were increased significantly for early and late stage EOC patients when compared to healthy controls. Finally, ROC curves were built for the most significant glycan combinations and we were able to show that the serum glycome sialic acid ratio could enhance ovarian cancer diagnosis as sialic acid linkage modulations arise even in early stage ovarian cancer.
Highlights
Ovarian cancer was among five leading cancer types in cancer deaths in women in United States in 2017 [1] with estimated 14,800 ovarian cancer deaths and 22,440 new cases
The sialic acid linkages of the serum glycome of ovarian cancer patients were investigated for the first time by MALDI-TOF-MS
We focused on the analysis of sialic acid linkages from primary serous ovarian cancer patients in early (FIGO I + II) and late stages (FIGO III + IV) of the disease to age-matched healthy controls
Summary
Ovarian cancer was among five leading cancer types in cancer deaths in women in United States in 2017 [1] with estimated 14,800 ovarian cancer deaths and 22,440 new cases. Sialic Acids in Ovarian Cancer Glycomics for the long-term survival rate, 60% of cases in United States between 2006 and 20012 were of late stage [1]. The routinely used tumor marker for ovarian cancer CA125 shows specificity of 94–98.5%, but low sensitivity (50–62% for early stages of epithelial ovarian cancer) [4]. Newer biomarkers have been proposed and used, such as HE4, which shows better sensitivity than CA125 in terms of distinguishing benign disease from malignant tumor [6]. Alternative methods for early ovarian cancer diagnosis have been proposed in the last decade, such as microRNA [9], protein panel screening [10, 11] and bioinformatic tools [12]
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