Original Article
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World J Gastroenterol. Jun 21, 2013; 19(23): 3573-3582
Published online Jun 21, 2013. doi: 10.3748/wjg.v19.i23.3573
Aberrant glycosylation of the anti-Thomsen-Friedenreich glycotope immunoglobulin G in gastric cancer patients
Kristel Kodar, Jelena Izotova, Kersti Klaamas, Boris Sergeyev, Lilian Järvekülg, Oleg Kurtenkov
Kristel Kodar, Jelena Izotova, Kersti Klaamas, Boris Sergeyev, Oleg Kurtenkov, Department of Oncology and Immunology, National Institute for Health Development, 11619 Tallinn, Estonia
Kristel Kodar, Jelena Izotova, Lilian Järvekülg, Tallinn University of Technology, Institute of Gene Technology, 12618 Tallinn, Estonia
Author contributions: Kurtenkov O and Järvekülg L designed the research and drafted the manuscript; Kodar K, Izotova J and Klaamas K performed the study, analyzed the data and helped draft the manuscript; Sergeyev B performed the statistical analysis; all authors read and approved the manuscript.
Supported by The Estonian Science foundation, No. 7317 and 8399
Correspondence to: Oleg Kurtenkov, MD, PhD, ScD, Department of Oncology and Immunology, National Institute for Health Development, Hiiu 42, 11619 Tallinn, Estonia. oleg.kurtenkov@tai.ee
Telephone: +372-6-593932 Fax: +372-6-593901
Received: May 18, 2012
Revised: November 19, 2012
Accepted: December 5, 2012
Published online: June 21, 2013

AIM: To study whether alterations in the glycosylation of immunoglobulin G (IgG) specific to the Thomsen-Friedenreich glycotope (TF) have diagnostic and prognostic potential in gastric cancer.

METHODS: Serum samples were obtained from patients with histologically verified gastric carcinoma (n = 89), healthy blood donors (n = 40), and patients with benign stomach diseases (n = 22). The lectin-enzyme-linked immunosorbent assay-based glycoprofiling of TF-specific IgG (anti-TF IgG) was performed using synthetic TF-polyacrylamide conjugate as antigen, total IgG purified by affinity chromatography on protein G sepharose, and lectins of various sugar specificities: mannose-specific concanavalin A (ConA), fucose-specific Aleuria aurantia lectin (AAL) and sialic acid-specific Sambucus nigra agglutinin (SNA). The sensitivity and specificity of the differences between cancer patients and controls were evaluated by receiver operator characteristic (ROC) curve analysis. Overall survival was analyzed by the Kaplan-Meier method. Time-dependent ROC curve statistics were applied to determine cut-off values for survival analysis. All calculations and comparisons were performed using the GraphPad Prism 5 and SPSS 15.0 software.

RESULTS: The level of TF-specific IgG was significantly increased in cancer patients compared with non-cancer controls (P < 0.001). This increase was pronounced mostly in stage 1 of the disease. Cancer patients showed a higher level of ConA binding to anti-TF-IgG (P < 0.05) and a very low level of SNA lectin binding (P = 0.0001). No appreciable stage-dependency of the binding of any lectin to anti-TF IgG was found. A strong positive correlation between the binding of AAL and SNA was found in all groups studied (r = 0.71-0.72; P < 0.0001). The changes in ConA reactivity were not related to those of the fucose- or sialic acid-specific lectin. Changes in the SNA binding index and the ConA/SNA binding ratio demonstrated good sensitivity and specificity for stomach cancer: sensitivity 78.79% (95%CI: 61.09-91.02) and 72.73% (95%CI: 57.21-85.04); specificity 79.17 (95%CI: 65.01-89.53) and 88.64% (95%CI: 71.8-96.6), for the SNA binding index and the ConA/SNA binding ratio, respectively. The other combinations of lectins did not improve the accuracy of the assay. The low level of ConA-positive anti-TF IgG was associated with a survival benefit in cancer patients (HR = 1.56; 95%CI: 0.78-3.09; P = 0.19), especially in stages 3-4 of the disease (HR = 2.17; 95%CI: 0.98-4.79; P = 0.048). A significantly better survival rate was found in all cancer patients with a low reactivity of anti-TF IgG to the fucose-specific AAL lectin (HR = 2.39; 95%CI: 1.0-5.7; P = 0.038).

CONCLUSION: The changes in the TF-specific IgG glycosylation pattern can be used as a biomarker for stomach cancer detection, and to predict patient survival.

Keywords: Thomsen-Friedenreich antigen, Anticarbohydrate antibodies, Stomach cancer, IgG glycosylation, Survival, Lectins