Glycopathology of HCC: identification of the source cells of serum fucosylation

摘要： 在国家癌症状况年度报告中，肝细胞癌的死亡率 肝癌（HCC）在男性中以2.8%的年增长率增加，在女性中以2.2%的年增长率增加， 使其成为美国死亡率增加最多的癌症（美国） 在过去的十年里肝癌的发病率预计将继续上升， 到2021年将超过50，000例。大多数HCC发生在 肝纤维化和肝硬化的背景，通常与慢性病毒感染有关 （乙型肝炎B和丙型肝炎病毒）或非酒精性脂肪肝/非酒精性 与肥胖相关的脂肪性肝炎（NAFLD/NASH）。 我们的实验室已经显示了在核心和外臂岩藻糖基化的改变， HCC。这些聚糖修饰有希望作为癌症的生物标志物，并且被积极地用于治疗癌症。 被一些团体（包括我们）商业化。我们有发达的 诊断面板，由临床数据沿着一个额外的新 生物标志物，岩藻糖基化激肽原，显着提高了HCC的检测， 特别是早期HCC患者的鉴别。 为了鉴定岩藻糖基化血清糖蛋白的来源，我们 开发了一种基于组织的聚糖分析的新方法。在对145例HCC的分析中， 组织和112个相邻对照或异位组织对照样品，我们已经确定了两个 与HCC相关的N-连接聚糖家族的主要变化。第一 观察到的变化是岩藻糖基化水平增加，这种修饰也经常 在HCC患者的血清中观察到。然而，约50%的组织样本 分析的岩藻糖没有增加。通常这些肿瘤没有增加岩藻糖基化 四触角聚糖增加。我们假设遗传异质性 可能对组织中的聚糖异质性产生影响， 血清的因此，聚糖不仅可以用作早期肿瘤的生物标志物， 检测癌症，但提供信息到特定的遗传学的癌症。在这 应用中，我们将在组织和血清中观察到的糖组学变化与 潜在的基因变化因为我们有匹配的组织和血清，我们就能 以确定我们目前的生物标志物小组是否能够识别岩藻糖阴性 HCC。最后，我们将利用几种蛋白质组学和糖组学方法来鉴定 癌症的生物标志物，而岩藻糖基化水平没有增加。

Abstract: In the Annual Report to the Nation on the Status of Cancer, mortality from Hepatocellular carcinoma (HCC) increased at an annual rate of 2.8% in men and 2.2% in women, making it the cancer with the greatest increase in mortality in the United States (USA) over the last 10 years. The occurrence of liver cancer is predicted to continue rising in the USA and will exceed 50,000 cases by 2021. The majority of HCC arises in the background of liver fibrosis and cirrhosis, usually associated with chronic viral infection (hepatitis B and hepatitis C virus) or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) associated with obesity. Our laboratory has shown alterations in both core and outer-arm fucosylation in HCC. These glycan modifications have promise as biomarkers of cancer and are actively being commercialized by a number of groups (including us). We have a developed a diagnostic panel that is comprised of clinical data along with one additional novel biomarker, fucosylated kininogen, that dramatically improves upon the detection of HCC, and in particular, the identification of those with early stage HCC. In an effort to identify the source of fucosylated serum glycoprotein, we have developed a novel method for tissue-based glycan analysis. In an analysis of 145 HCC tissue and 112 adjacent control or cirrhotic tissue control samples, we have identified two major changes in the N-linked glycan family that are associated with HCC. The first change observed was increased levels of fucosylation, a modification also often observed in serum of patients with HCC. However, ~50% of the tissue samples analyzed had no increase in fucose. Often these tumors without increased fucosylation had increases in tetra-antennary glycan. We hypothesize that the genetic heterogeneity of the tumor might have an impact upon the glycan heterogeneity in the tissue and serum. Consequently, the glycans may not only be used as biomarkers for the early detection of cancer but offer information into the specific genetics of the cancer. In this application, we will link the glycomic changes observed in both tissue and serum with the underlying genetic changes. As we will have matching tissue and serum, we will be able to determine if our current biomarker panel is capable of identifying fucose negative HCC. Lastly, we will utilize several proteomic and glycomic methods to identify biomarkers for cancer without increased levels of fucosylation.