Disease-specific IgG Fc N-glycosylation as personalized biomarkers to differentiate gastric cancer from benign gastric diseases

Dan Zhang,Peng Xia,Yanmin Wang,Chengyan He,Zhili Li,Bingchao Chen,Mo Zhang,Yujie Liu,Ruiqing Zhang

doi:10.1038/srep25957

Abstract

Interest in the pathophysiological role of IgG fragment crystallizable (Fc) N-linked glycosylation arose from changes in humoral immune responses. In this study, circulating disease-specific IgG (DSIgG) derived from serum immunoinflammation-related protein complexes was isolated from 846 serum samples of 443 patients with benign gastric diseases (BGDs) and 403 patients with gastric cancer (GC), and DSIgG glycopeptides attached to IgG Fc region at the site of Asn297 were analyzed using matrix-assisted laser desorption/ionization- Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR MS). A total of 22 glycopeptides were detected. Statistical analysis indicated that DSIgG1 G1S, DSIgG2 G0F, G1, G2F, and G2FS as well as DSIgG2 galactosylation and sialylation are significantly associated with sex in BGD patients and that the age-specific glycoforms and glycosylation features from DSIgG between BGD patients and GC patients have similar change trends. In addition, significant changes in galactosylation, sialylation, and bisecting N-acetylglucosamine (GlcNAc) from DSIgG were also observed between two pathophysiological states. Receiver operating characteristic (ROC) analysis indicated that the G2FN/G1FN (from DSIgG2) ratio has an excellent capability to distinguish female BGD patients from female GC patients over the age range of 20–79 years, with the sensitivity of 82.6%, the specificity of 82.6%, and the area under curve (AUC) of 0.872.

Highlights

Gastric cancer (GC) is one of the leading cause of cancer-related death worldwide, contributing to 8.8% of the cancer mortality[1]
Representative mass spectra of the glycoforms derived from disease-specific IgG (DSIgG) are shown in Fig. 1, and the corresponding m/z values of the detected glycopeptides of DSIgG and their individual peptide sequences are listed in Supplementary Information Table S1
Relative standard deviations (RSDs) of the glycoforms distributed in almost equal interval of m/z value in mass spectra with middle intensity (i.e., G0F at m/z 2602.0561, G1F at m/z 2764.1089, G0FN at m/z 2805.1355, G2F at m/z 2926.1617, G1FN at m/z 2967.1883, and G1FS at m/z 3055.2043) from DSIgG were calculated to evaluate the experimental precision during the whole experiment

Summary

Introduction

Gastric cancer (GC) is one of the leading cause of cancer-related death worldwide, contributing to 8.8% of the cancer mortality[1]. Effector cells or complement components to eliminate non-self invaders and abnormal cells such as cancer cells[20] This interaction can mediate pro- and anti-inflammatory activities via the Fc N-linked glycans attached at the site of Asn[297]. Our previous studies have found that serum immunoinflammation-related protein complexes (IIRPCs) are closely associated with disease states, disease types, and the progression of lung cancer[26,27,28]. Their major components are complements, haptoglobin, immunoglobulin A, and IgG. Changes in the levels of DSIgG glycoforms between benign gastric diseases (BGDs) and GC were statistically analyzed, and receiver operating characteristic (ROC) analysis indicated that glycoform ratio (G2FN/G1FN from DSIgG2) has a powerful capability to distinguish female BGD patients from female GC patients over the age range of 20–79 years, with the sensitivity of 82.6%, the specificity of 82.6%, and the area under curve (AUC) of 0.872

Methods

Results

Discussion

Conclusion