Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina.
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
Cancer Res Commun. 2023 Mar 6;3(3):383-394. doi: 10.1158/2767-9764.CRC-22-0422. eCollection 2023 Mar.
There is an urgent need for the identification of reliable prognostic biomarkers for patients with intrahepatic cholangiocarcinoma (iCCA) and alterations in N-glycosylation have demonstrated an immense potential to be used as diagnostic strategies for many cancers, including hepatocellular carcinoma (HCC). N-glycosylation is one of the most common post-translational modifications known to be altered based on the status of the cell. N-glycan structures on glycoproteins can be modified based on the addition or removal of specific N-glycan residues, some of which have been linked to liver diseases. However, little is known concerning the N-glycan alterations that are associated with iCCA. We characterized the N-glycan modifications quantitatively and qualitatively in three cohorts, consisting of two tissue cohorts: a discovery cohort ( = 104 cases) and a validation cohort ( = 75), and one independent serum cohort consisting of patients with iCCA, HCC, or benign chronic liver disease ( = 67). N-glycan analysis was correlated to tumor regions annotated on histopathology and revealed that bisected fucosylated N-glycan structures were specific to iCCA tumor regions. These same N-glycan modifications were significantly upregulated in iCCA tissue and serum relative to HCC and bile duct disease, including primary sclerosing cholangitis (PSC) ( < 0.0001). N-glycan modifications identified in iCCA tissue and serum were used to generate an algorithm that could be used as a biomarker of iCCA. We demonstrate that this biomarker algorithm quadrupled the sensitivity (at 90% specificity) of iCCA detection as compared with carbohydrate antigen 19-9, the current "gold standard" biomarker of CCA.
This work elucidates the N-glycan alterations that occur directly in iCCA tissue and utilizes this information to discover serum biomarkers that can be used for the noninvasive detection of iCCA.
对于肝内胆管癌（iCCA）患者，迫切需要鉴定可靠的预后生物标志物，并且 N-糖基化的改变已经证明具有巨大的潜力，可以作为许多癌症（包括肝细胞癌（HCC））的诊断策略。N-糖基化是最常见的翻译后修饰之一，已知根据细胞状态而改变。糖蛋白上的 N-聚糖结构可以根据特定 N-聚糖残基的添加或去除而改变，其中一些与肝脏疾病有关。但是，关于与 iCCA 相关的 N-聚糖改变知之甚少。我们在三个队列中对 N-糖基化修饰进行了定量和定性分析，包括两个组织队列：一个发现队列（= 104 例）和一个验证队列（= 75 例），以及一个由患有 iCCA、HCC 或良性慢性肝脏疾病的患者组成的独立血清队列（= 67 例）。N-糖基化分析与组织病理学上注释的肿瘤区域相关，结果表明双分叉岩藻糖基化 N-聚糖结构是 iCCA 肿瘤区域特有的。与 HCC 和胆管疾病（包括原发性硬化性胆管炎（PSC））相比，这些相同的 N-糖基化修饰在 iCCA 组织和血清中均显著上调（<0.0001）。在 iCCA 组织和血清中鉴定出的 N-糖基化修饰被用于生成算法，该算法可用作 iCCA 的生物标志物。我们证明，与当前的“金标准”CCA 标志物 CA19-9 相比，该生物标志物算法可将 iCCA 的检测灵敏度提高四倍（特异性为 90%）。
这项工作阐明了直接在 iCCA 组织中发生的 N-聚糖改变，并利用这些信息发现了可用于无创检测 iCCA 的血清生物标志物。
