Elevated core-fucosylated IgG is a new marker for hepatitis B virus-related hepatocellular carcinoma

Abstract

Immunoglubulin G (IgG) and its abnormal glycosylations are associated with carcinogenesis. The present study investigates the relationship between cancer-derived IgG and clinicopathological characteristics in hepatocellular carcinoma (HCC) and assesses the value of serum N-glycosylated IgG in diagnosing and monitoring hepatitis B virus (HBV)-related HCC. Tissue microarray analysis of 90 HCC tissues showed that HCC patients with IgG immunopositivity had higher levels of core-fucosylated a fetoprotein (AFP-L3), larger tumors, and a higher incidence of portal vein tumor thrombus. HCC-derived IgG stimulated the growth of liver cancer cells in vitro. HCC patients presented a significantly increased fraction of Lens culinaris agglutinin binding IgG (core-fucosylated IgG, IgG-L3) among total serum IgG. The clinical diagnostic performance of serum IgG-L3% was evaluated in 3 case-control studies (1 training set and 2 validation cohorts), including 293 patients with HCC, 131 with liver cirrhosis, 132 HBV carriers, and 151 healthy controls. IgG-L3% had better general diagnostic performance than AFP in the training set and validation cohort 1 (accuracy: 81.33-85.11% versus 63.33-78.61%). In validation cohort 2, where we aimed to assess the efficiency of IgG-L3% in patients with AFP-negative HCC, the diagnostic accuracy of IgG-L3% was 72.54-73.60%. Finally, a longitudinal evaluation based on 31 HCC patients demonstrated that IgG-L3% decreased in 24 patients after curative surgery. The remaining 7 patients showed elevated IgG-L3% and post-operative recurrence. HCC patients with higher IgG-L3% had poor survival during a 3-year follow up. We conclude that HCC-derived IgG is correlated with progressive behavior of HCC. Therefore, elevated core-fucosylated IgG is a new diagnostic and prognostic marker in HBV-related HCC.

New Blood Biomarkers for the Diagnosis of AFP-Negative Hepatocellular Carcinoma

“…HCC-derived immunoglobulin G (IgG) and its abnormal glycosylations are related to carcinogenesis. The fraction of Lens culinaris agglutinin binding IgG (IgG-L3) among total serum IgG (IgG-L3%) was found to gradually increase from healthy volunteers, HBV carriers, and patients with LC to HCC patients, including ANHC patients, and to be more valuable than AFP for the diagnosis of HBV-related HCC (157), with an AUROC 0.835 vs. 0.718, accuracy 81.3 vs. 78.0%, sensitivity 86.7 vs. 66.7%, and specificity 77.8 vs. 85.6%, and also to be valuable for distinguishing ANHC (n = 123) from non-HCC (n = 234) (AUROC of 0.795, sensitivity of 80.5%, specificity of 70.0%) and from LC (n = 71) (AUROC of 0.711, sensitivity of 80.5%, specificity of 58.6%). In addition, patients with a high IgG-L3% value had a significantly lower overall survival rate than patients with low IgG-L3% value, and serum IgG-L3% values reduced after surgery and increased with recurrence.…”

Aberrant glycosylation and cancer biomarker discovery: a promising and thorny journey

“…Fortunately, lectins have been considered as an extremely useful tool for glycomic and glycoproteomic study that can be used alone or in conjunction with other methods such as MS and CE because of the wide availability, affinity and relative specificity [93]. Several approaches based on lectins including lectin blot [94,95], lectin histochemistry/cytochemisty [29,96], lectin-antibody sandwich enzyme-linked immunosorbent assay (ELISA) [33,44,97], lectin affinity chromatography [98,99], lectin microarray [100][101][102] and lectin microfluidics [103] have been applied to capture the specific glycan of the glycoproteins [102,[104][105][106], enhancing the understanding of aberrant glycosylation and carcinogenesis, accelerating biomarkers recognition and quantitative detection. The Gao group has investigated the diagnostic and prognostic value of fucosylated fetuin A in HCC patients by AAL-based ELISA [107].…”

“…Hepatic Core-fucosylation [18,19] Diagnosis, prognosis CA19-9 (used in clinic) Pancreatic Sialyl-Lewis A structure [20,21] Diagnosis, prognosis Total serum/plasma profiles Hepatic Increased multi-antennary glycans with fucose residues [22] Diagnosis Gastric Decreased core-fucosylated glycans [23,24]; increased hybrid and multi-branched structures and decreased monoantennary, galactose, bisecting type and core fucose structures [25] Diagnosis; monitoring progression Pancreatic Increased core-fucose residues [26] Diagnosis Breast Increased sialylation, branching, and outer-arm fucosylation and decreased high-mannosylated and biantennary core-fucosylated glycans [27] Diagnosis Immunoglobulin G (IgG) Hepatic Decreased galactosylation [28]; increased core-fucosylation [29] Diagnosis; prognosis Colorectal Decreased galactosylation [28]; decreased galactosylation and sialylation; increased core-fucosylation of neutral glycans and decreased core-fucosylation of sialylated glycans [ [35,44] Diagnosis; prognosis Cholangio Increased fucosylation [45] Diagnosis…”

Distribution of IgG galactosylation as a promising biomarker for cancer screening in multiple cancer types

“…There has been an increasing interest in the analysis of the N -glycan profile of human IgG in healthy and disease states, such as autoimmune diseases and cancer 3 . Several studies recently showed that the glycosylation profiles of total serum IgG exhibited significant differences between non-malignant controls and cancer patients, such as gastric, liver and ovarian cancers 4 , 5 , 6 , 7 . We have previously demonstrated significant decrease in serum level of terminally galactosylated N -glycans of IgG in 32 patients with ovarian cancer compared with 26 patients with benign gynecological conditions 7 .…”