Pretransplant changes in serum protein glycosylation relate to risk of HCC recurrence after liver transplantation and provide a potential prognostic biomarker: a proof-of-concept study

Abstract

Background and aims: Hepatocellular carcinoma (HCC) recurs after liver transplantation (LT) in 10% of patients. Changes in protein glycosylation have been described during the development of HCC. Study goal was to assess the risk of HCC recurrence after LT, according to changes in serum protein glycosylation before LT. Method(s): A prospective study was performed in patients receiving LT between July 2011 and September 2018. A whole serum protein Nglycan profile was assessed using DNA sequencer assisted fluorophore assisted capillary electrophoresis, using a validated highthroughput protocol. 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 to patients without. Result(s): Amongst 225 consecutive liver transplant patients, 76 patients suffered from HCC before LT. Main indications were related to alcoholic cirrhosis (47.4%), HCV infection (21.1%) and NASH (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%) fulfilled Milan criteria. Significant differences in the relative abundance of 5 serum glycans were present in patients with HCC recurrence compared to patients without (Cox regression analysis). Based on these changes, a composite biomarker was developed (GlycoHCCRecurrenceScore). This score integrates an increased presence of triantennary glycans with and without branch and core fucosylation (NA3, NA3Fc and NA3Fbc) and a decreased presence of undergalactosylated glycans NGA2F and NGA2FB in patients with HCC recurrence. This biomarker panel shows an AUC of 0.855 (p = 0.001; 95% CI 0.731-0.979) for association with HCC recurrence. Using an optimized cut-off (-4.24), sensitivity fwas 87.5% and specificity 67.6%. Only 2.1% of patients with a value belowthis cut-off showed HCC recurrence, compared to 24.1% of patients with values above this cut-off (p = 0.011). PPV was 72.98% and NPV 84.39%. Figure 1 illustrates the discriminative value of this biomarker. In a univariate cox regression analysis other factors related to HCC recurrence in this cohort were diameter of the largest lesion before LT and the presence of perineural or lymphovascular invasion in the explant liver. In a multivariate analysis, the biomarker showed an independent relation with HCC recurrence (HR 1.931; p = 0.008:1.184-3.149).(Figure Presented)Conclusion: A glycomics based serum biomarker panel is strongly associated with tumor recurrence in a cohort of LT patients with HCC, even if adhering to Milan criteria. In a multivariate analysis, this biomarker was the only pretransplant 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 Copyright © 2022 European Association for the Study of the Liver