Serum N-glycan profiling as a diagnostic biomarker for the identification of hepatitis B virus-associated hepatocellular carcinoma

Abstract

Background: Changes in N-glycosylation of proteins are thought to play a key role in cancer. This study aims to investigate the changes in the serum N-glycan profiles of patients with hepatitis B virus (HBV)-related liver disease, and to evaluate the role of N-glycan markers in the noninvasive diagnosis of hepatocellular carcinoma (HCC).Methods: Serum samples were available for 21 patients with HCC, 20 patients with liver cirrhosis (LC), 20 patients with chronic hepatitis B (CHB), and 20 healthy subjects. Serum N-glycans were released and analyzed using DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Serum AFP was determined by electrochemiluminescence (ECL) (AFP reference value range: <10 ng/mL).Results: There were characteristic changes in the serum N-glycan profiles of patients with HBV-related liver disease, including NA2FB, NA3, and NA3Fb. NA2FB was the most abundant in LC patients, while NA3Fb abundance was the highest in HCC patients. For HCC screening in patients, especially in patients with LC, the sensitive of Log peak 9 (94.4%) and Log (peak 9/peak 7) (88.9%) were better than alphafetoprotein (AFP) (33.3-61.1%), and their specificity was similar to that of AFP. The receiver operating characteristic (ROC) curve showed that the accuracy of Log peak 9 (AUC: 0.81±0.07) and Log (peak 9/peak 7) (AUC: 0.87±0.06) was better than that of AFP (AUC: 0.72±0.09), while the accuracy of AFP combined with the above 2 indexes was better than that of a single index. Moreover, Log (peak 9/peak 7) combined with AFP (AUC: 0.89±0.06) had the best accuracy in the diagnosis of HCC.Conclusions: Our research indicates that N-glycan may serve a new, valuable, and noninvasive alternative method for diagnosing HCC, and it may be a supplement to AFP in the diagnosis of HCC in patients with HBV-related liver disease.

Systematic review: Glycomics as diagnostic markers for hepatocellular carcinoma

“…Two studies compared the logarithm of the ratio NA3Fb to NA2FB, AFP, and their combination in diagnosing HCC in HBV‐related cirrhosis. They concluded that the combination of log(NA3Fb/NA2FB) and AFP provided the most accurate diagnostic test performances with AUC values of 0.89 and 0.92 23,24 . Similarly, the logarithm of the ratio of NA3Fb to NG1A2F (single agalacto core‐α‐1,6‐fucosylated bi‐antennary glycan) was able to discriminate between HBV‐infected patients with liver fibrosis and HCC.…”

“…Since GnT‐V is competing with N‐acetylglucosaminyltransferase III (GnT‐III) for its substrate, the abundance of bisecting GlcNAc structures, as a product of GnT‐III activity, is downregulated in HCC. Whereas GnT‐V is recognised as pro‐oncogenic glycosyltransferase in several cancer types, GnT‐III mostly presents as tumour suppressor glycosyltransferase 22,23,79,80 …”

“…They concluded that the combination of log(NA3Fb/NA2FB) and AFP provided the most accurate diagnostic test performances with AUC values of 0.89 and 0.92. 23,24 Similarly, the logarithm of the ratio of NA3Fb to NG1A2F (single agalacto coreα-1,6-fucosylated bi-antennary…”

“…Whereas GnT-V is recognised as pro-oncogenic glycosyltransferase in several cancer types, GnT-III mostly presents as tumour suppressor glycosyltransferase. 22,23,79,80 Fucosylation, or the attachment of a fucose residue to glycans, is among the most prevalent post-translational modifications of glycoproteins associated with various types of cancer. 81 Accordingly, multiple fucosylated glycoproteins have been described in HCC, such as GP73, Hpx, Hp, and AFP.…”

Machine Learning Reveals Serum Glycopatterns as Potential Biomarkers for the Diagnosis of Nonalcoholic Fatty Liver Disease (NAFLD)

“…8 The liver synthesizes most of the glycosylated serum proteins, and studies have indicated that changes in serum glycopatterns can serve as indicators of liver damage. 9,10 For instance, abnormalities in fucosylation, mannosylation, and sialylation have been observed in cases of liver fibrosis, cirrhosis, and hepatocellular carcinoma. 11−13 While changes in serum glycopatterns have been extensively documented in various liver diseases, there is a lack of systematic studies on the glycopatterns of serum in NAFLD patients.…”