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

摘要： 在提交给全国的癌症状况年度报告中，肝细胞癌死亡率 癌症(HCC)以每年2.8%的男性和2.2%的女性增长， 使其成为美国死亡率上升幅度最大的癌症 在过去的10年里。预计#年肝癌发病率将继续上升。 美国，到2021年将超过5万例。大多数肝细胞癌发生在 肝纤维化和肝硬变背景，通常与慢性病毒感染有关 (乙肝和丙型肝炎病毒)或非酒精性脂肪性肝病/非酒精性脂肪性肝病 与肥胖相关的脂肪性肝炎(NAFLD/NASH)。 我们的实验室已经显示出核心和外臂岩藻糖基化的变化。 肝细胞癌。这些糖链修饰有望成为癌症的生物标记物，并且是积极的 被许多团体(包括我们)商业化。我们已经开发了一个 由临床数据和一项额外的新书组成的诊断小组 生物标记物岩藻糖化激肽原，显著提高了对肝癌的检测， 尤其是那些患有早期肝癌的人的识别。 为了确定岩藻糖化血清糖蛋白的来源，我们已经 开发了一种新的基于组织的多糖分析方法。145例肝细胞癌临床分析 组织和112个邻近的对照或肝硬变组织对照样本，我们已经鉴定了两个 与肝细胞癌相关的N-连接糖链家族的主要变化。第一 观察到的变化是岩藻糖化水平增加，这也是一种修饰 在肝细胞癌患者血清中观察。然而，约50%的组织样本 分析表明，岩藻糖含量没有增加。通常这些肿瘤没有增加岩藻糖基化 四触角多聚糖含量增加。我们假设基因的异质性 可能会对组织中的糖链异质性产生影响 血清。因此，葡聚糖不仅可以作为早期的生物标志物 检测癌症，但提供有关癌症特定遗传学的信息。在这 应用，我们将在组织和血清中观察到的血糖变化与 潜在的基因变化。由于我们将有匹配的组织和血清，我们将能够 以确定我们目前的生物标记物小组是否能够识别岩藻糖阴性 肝细胞癌。最后，我们将利用几种蛋白质组学和糖学方法来鉴定 不增加岩藻糖化水平的癌症生物标记物。

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.