Pre-transplant Changes in Serum Protein Glycosylation Relates to Risk of Hepatocellular Carcinoma Recurrence After Liver Transplantation and Provide a Potential Prognostic Biomarker: A Proof-of-Concept Study - European Medical Journal

Pre-transplant Changes in Serum Protein Glycosylation Relates to Risk of Hepatocellular Carcinoma Recurrence After Liver Transplantation and Provide a Potential Prognostic Biomarker: A Proof-of-Concept Study

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EMJ Hepatology 10.1 Feature Image
*Xavier Verhelst,1,2 Heleen Engels,1 Anja Geerts,1,2 Aude Vanlander,3 Luis Abreu de Carvalho,3 Helena Degroote,1,2 Leander Meuris,4,5 Frederik Berrevoet,3 Nico Callewaert,4,5 Hans Van Vlierberghe1,2

Verhelst and Van Vlierberghe declare that they have a patent licensed as WO2021191372A1. The other authors have declared no conflicts of interest.

EMJ Hepatol. ;10[1]:36-37. DOI/10.33590/emjhepatol/10020546..
Glycan, glycomics, hepatocellular carcinoma (HCC), liver transplantation (LT), precision medicine, prediction, recurrence.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.


Hepatocellular carcinoma (HCC) recurs after liver transplantation (LT) in approximately 10% of patients. Changes in protein glycosylation have been described during the development of HCC and are associated with progressive disease and early mortality.1 The authors’ study goal was to assess the risk of HCC recurrence after LT, according to changes in serum protein glycosylation before LT.


A prospective study was performed in patients receiving LT between July 2011 and September 2018 at the Liver Transplant Unit of Ghent University Hospital, Belgium. A whole serum protein N-glycan profile was assessed using a DNA sequencer assisted by fluorophore and capillary electrophoresis, and validated high-throughput protocol.2 For every sample, 13 glycans were quantified. Patients were followed until HCC recurrence or death. Specific changes in serum protein glycosylation profiles were analysed in patients with HCC recurrence compared with patients without.


Amongst 225 consecutive patients with LTs, 76 patients had a diagnosis of HCC before LT. The main indications were related to alcoholic cirrhosis (47.4%), hepatitis C virus infection (21.1%), and non-alcoholic steatohepatitis (15.8%). Eight patients (10.5%) developed HCC recurrence after a median follow-up time of 9.5 months after LT. Seventy-four patients (97.0%) fulfilled the Milan criteria. Significant differences in the relative abundance of five serum glycans were present in patients with HCC recurrence compared with patients without (through Cox regression analysis).

Based on these changes, a composite biomarker was developed (Glyco HCC Recurrence Score). This score integrates an increased presence of tri-antennary glycans (NA3) with and without branch and core fucosylation (NA3Fc and NA3Fbc), and a decreased presence of under-galactosylated glycans (NGA2F and NGA2FB) in patients with HCC recurrence. This biomarker panel showed an area under the curve of 0.855 (p=0.001; 95% confidence interval: 0.731–0.979) for association with HCC recurrence. Using an optimised cut-off (-4.24), sensitivity was 87.5% and specificity 67.6%. Only 2.1% of patients with a value below this cut-off showed HCC recurrence compared with 24.1% of patients with values above this cut-off (p=0.011). The positive predictive value was 72.98% and negative predictive value was 84.39%.


A glycomics-based serum biomarker panel is strongly associated with tumour recurrence in a cohort of patients who have had a LT with HCC, even if adhering to Milan criteria. In a multivariate analysis, this biomarker was the only pre-transplant discriminative parameter of HCC recurrence in this cohort. The biomarker could potentially increase the prediction of HCC recurrence and improve allocation strategies in LT candidates with HCC. A prospective validation study will start soon.

Verhelst X et al. Protein glycosylation as a diagnostic and prognostic marker of chronic inflammatory gastrointestinal and liver diseases. Gastroenterology. 2020;158(1):95-110. Laroy W. Glycome mapping on DNA sequencing equipment. Nat Protoc. 2006;1(1):397-405.

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