Kohansal-Nodehi Mahdokht, Swiatek-de Lange Magdalena, Kroeniger Konstantin, Rolny Vinzent, Tabarés Glòria, Piratvisuth Teerha, Tanwandee Tawesak, Thongsawat Satawat, Sukeepaisarnjaroen Wattana, Esteban Juan Ignacio, Bes Marta, Köhler Bruno, Chan Henry Lik-Yuen, Busskamp Holger
Roche Diagnostics GmbH, Research and Development Core Lab, Penzberg, Germany.
NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand.
Front Oncol. 2023 Oct 18;13:1213898. doi: 10.3389/fonc.2023.1213898. eCollection 2023.
There is a need for new serum biomarkers for early detection of hepatocellular carcinoma (HCC). Haptoglobin (Hp) N-glycosylation is altered in HCC, but the diagnostic value of site-specific Hp glycobiomarkers is rarely reported. We aimed to determine the site-specific glycosylation profile of Hp for early-stage HCC diagnosis.
Hp glycosylation was analyzed in the plasma of patients with liver diseases (n=57; controls), early-stage HCC (n=50) and late-stage HCC (n=32). Hp phenotype was determined by immunoblotting. Hp was immunoisolated and digested into peptides. N-glycopeptides were identified and quantified using liquid chromatography-mass spectrometry. Cohort samples were compared using Wilcoxon rank-sum (Mann-Whitney U) tests. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves and area under curve (AUC).
Significantly higher fucosylation, branching and sialylation of Hp glycans, and expression of high-mannose glycans, was observed as disease progressed from cirrhosis to early- and late-stage HCC. Several glycopeptides demonstrated high values for early diagnosis of HCC, with an AUC of 93% (n=1), >80% (n=3), >75% (n=13) and >70% (n=11), compared with alpha-fetoprotein (AFP; AUC of 79%). The diagnostic performance of the identified biomarkers was only slightly affected by Hp phenotype.
We identified a panel of Hp glycopeptides that are significantly differentially regulated in early- and late-stage HCC. Some glycobiomarkers exceeded the diagnostic value of AFP (the most commonly used biomarker for HCC diagnosis). Our findings provide evidence that glycobiomarkers can be effective in the diagnosis of early HCC - individually, as a panel of glycopeptides or combined with conventional serological biomarkers.
需要新的血清生物标志物用于肝细胞癌（HCC）的早期检测。肝癌中触珠蛋白（Hp）的N-糖基化发生改变，但位点特异性Hp糖生物标志物的诊断价值鲜有报道。我们旨在确定用于早期肝癌诊断的Hp位点特异性糖基化谱。
分析了肝病患者（n = 57；对照组）、早期肝癌（n = 50）和晚期肝癌（n = 32）患者血浆中的Hp糖基化情况。通过免疫印迹法确定Hp表型。免疫分离Hp并将其消化成肽段。使用液相色谱-质谱法鉴定和定量N-糖肽。使用Wilcoxon秩和（Mann-Whitney U）检验比较队列样本。使用受试者工作特征（ROC）曲线和曲线下面积（AUC）评估诊断性能。
随着疾病从肝硬化进展到早期和晚期肝癌，观察到Hp聚糖的岩藻糖基化、分支和唾液酸化显著增加，以及高甘露糖聚糖的表达增加。与甲胎蛋白（AFP；AUC为79%）相比，几种糖肽对肝癌早期诊断具有较高的价值，AUC分别为93%（n = 1）、>80%（n = 3）、>75%（n = 13）和>70%（n = 11）。所鉴定生物标志物的诊断性能仅受Hp表型的轻微影响。
我们鉴定出一组在早期和晚期肝癌中显著差异调节的Hp糖肽。一些糖生物标志物超过了AFP（肝癌诊断最常用的生物标志物）的诊断价值。我们的研究结果提供了证据，表明糖生物标志物可有效用于早期肝癌的诊断——单独使用、作为一组糖肽或与传统血清生物标志物联合使用。
