Abstract
Altered levels of naturally occurring anti-glycan antibodies (AGA) circulating in human blood plasma are found in different pathologies including cancer. Here the levels of AGA directed against 22 negatively charged (sialylated and sulfated) glycans were assessed in high-grade serous ovarian cancer (HGSOC, n = 22) patients and benign controls (n = 31) using our previously developed suspension glycan array (SGA). Specifically, the ability of AGA to differentiate between controls and HGSOC, the most common and aggressive type of ovarian cancer with a poor outcome was determined. Results were compared to CA125, the commonly used ovarian cancer biomarker. AGA to seven glycans that significantly (P<0.05) differentiated between HGSOC and control were identified: AGA to top candidates SiaTn and 6-OSulfo-TF (both IgM) differentiated comparably to CA125. The area under the curve (AUC) of a panel of AGA to 5 glycans (SiaTn, 6-OSulfo-TF, 6-OSulfo-LN, SiaLea, and GM2) (0.878) was comparable to CA125 (0.864), but it markedly increased (0.985) when combined with CA125. AGA to SiaTn and 6-OSulfo-TF were also valuable predictors for HGSOC when CA125 values appeared inconclusive, i.e. were below a certain threshold. AGA-glycan binding was in some cases isotype-dependent and sensitive to glycosidic linkage switch (α2–6 vs. α2–3), to sialylation, and to sulfation of the glycans. In conclusion, plasma-derived AGA to sialylated and sulfated glycans including SiaTn and 6-OSulfo-TF detected by SGA present a valuable alternative to CA125 for differentiating controls from HGSOC patients and for predicting the likelihood of HGSOC, and may be potential HGSOC tumor markers.
Highlights
Ovarian cancer and in particular high-grade serous ovarian cancer (HGSOC) is the most deadly gynecologic cancer with an overall survival rate of less than 20% [1]
We and others have previously reported that human plasma contains a set of anti-glycan antibodies (AGA) directed against a variety glycans including known tumor- associated carbohydrate (glycan) antigens (TACA) [7, 13, 54,55,56]
We extended this panel of glycans and investigated whether human plasma contained AGA against closely related structural analogues and sialylated and sulfated glycans including some of which have not yet been associated with cancer
Summary
Ovarian cancer and in particular high-grade serous ovarian cancer (HGSOC) is the most deadly gynecologic cancer with an overall survival rate of less than 20% [1]. Though the commonly employed ovarian cancer biomarker CA125 is useful for monitoring response to chemotherapy and detecting disease recurrence, it lacks sufficient sensitivity and specificity, especially for detecting early FIGO stages of the disease [2,3,4]. Since the era of genomics and transcriptomics did not produced clinically used novel biomarkers that overcome the limitations of CA125 [5], the identification of new and reliable biomarkers for early diagnosis of ovarian cancer is urgently needed. A number of studies have proposed naturally occurring antibodies to tumor- associated carbohydrate (glycan) antigens (TACA) [6,7,8] or to glycopeptides [6, 9] as promising biomarkers for early detection and diagnosis of various malignancies. TACA are considered potential diagnostic markers since these glycan structures resemble molecular-level glycomic ‘fingerprints’ which facilitate the discrimination between healthy and diseased states or reflect tumor micro-heterogeneity: not surprising that most clinically used tumor markers are glycoproteins [10, 11]
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