Serum IgA1 shows increased levels ofα2,6-linked sialic acid in breast cancer

Abstract

The lectin Helix pomatia agglutinin (HPA) recognizes altered glycosylation in solid cancers and the identification of HPA binding partners in tumour tissue and serum is an important aim. Among the many HPA binding proteins, IgA1 has been reported to be the most abundant in liver metastases. In this study, the glycosylation of IgA1 was evaluated using serum samples from patients with breast cancer (BCa) and the utility of IgA1 glycosylation as a biomarker was assessed. Detailed mass spectrometric structural analysis showed an increase in disialo-biantennary N- linked glycans on IgA1 from BCa patients ( p < 0.0001: non-core fucosylated; p = 0.0345: core fucosylated) and increased asialo-Thomsen–Friedenreich antigen (TF) and disialo-TF antigens in the O- linked glycan preparations from IgA1 of cancer patients compared with healthy control individuals. An increase in Sambucus nigra binding was observed, suggestive of increased α 2,6-linked sialic acid on IgA1 in BCa. Logistic regression analysis showed HPA binding to IgA1 and tumour size to be significant independent predictors of distant metastases ( χ 2 13.359; n = 114; p = 0.020) with positive and negative predictive values of 65.7% and 64.6%, respectively. Immunohistochemical analysis of tumour tissue samples showed IgA1 to be detectable in BCa tissue. This report provides a detailed analysis of serum IgA1 glycosylation in BCa and illustrates the potential utility of IgA1 glycosylation as a biomarker for BCa prognostication.

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

“…In clinical studies, sialylation in human serum or saliva can be accurately detected using quantification methods. Notably, specific proteins, such as IgA1 with sialylation, were proved to relate to certain tumor occurrences [159]. Enhanced levels of sialic acids in clinical serum provided a promising biomarker and a reliable predictor for prostate cancer and its bone metastases [160].…”

Profiling of Naturally Occurring Antibodies to the Thomsen-Friedenreich Antigen in Health and Cancer: The Diversity and Clinical Potential

“…The expression of TF was found to be associated with a distinct molecular subtype of gastric cancer and may be used as a new marker of microsatellite instability [52]. Interestingly, an increased TF as well as disialo-TF antigen structure was recently observed in Olinked glycan preparations of IgA1 from patients with breast cancer [53]. A high proportion of cancer cells coexpresses TF and CD44 as a marker of cancer-initiating or stem cells [54,55].…”

“…It is to be noted that in contrast to the TF expression via the desialylation of O-glycans, the increased sialylation of many glycoproteins and gangliosides is also one of the main characteristics of malignant transformation [7,64]. In addition, the increased level of free and conjugated forms of sialic acids appears to be a frequent phenomenon in cancer, for instance, the increased α2-3-linked sialylation of prostatespecific antigen in prostate cancer [65], the increased serum glycoprotein sialylation in multiple myeloma [66], or an increase in disialobiantennary N-linked glycans on serum IgA1 in breast cancer [53]. However, the mechanisms behind the sialylation-related changes in different cancers remain poorly understood, and in many cancers, these changes show the lack of cancer specificity.…”

“…However, less is known about the glycosylation patterns of total serum IgM, obviously due to limitations in technology and the complexity of IgM glycans. The serum IgG glycosylation profiling has shown cancerspecific changes in multiple cancer types [53,64,109,110,113,117] and a diagnostic and prognostic potential in various malignancies [107,113,118,119]. The distinct tIgG profile (a higher agalactosylation and a lower sialylation ratio of IgG1) has shown a high diagnostic accuracy (>90%) at discrimination of patients with autoimmune pancreatitis and pancreatic cancer [113].…”

Synthetic glycobiology

“…The composition of the glycocalyx also changes when cells become cancerous. Lomax-Browne et al present a recent study that shows that the IgA1 in the serum of BCa patients has variations of their O-glycosylation repertoire and that these alterations could be useful as cancer biomarkers [10]. Their study used several validated commercial lectins with detailed analysis of serum IgA1 glycosylation in breast cancer and illustrates the potential utility of IgA1 glycosylation as a biomarker for breast cancer prognostication.…”