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

HCC 糖病理学：血清岩藻糖基化来源细胞的鉴定

• 批准号: 10576851
• 负责人: RICHARD R. DRAKE
• 金额: $ 60.33万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-14 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576851
• 关键词: Annual Reports; Antibodies; Biological Markers; Blood; Cells; Choristoma; Chronic; Cirrhosis; Clinical Data; Communities; Detection; Development; Diagnostic; Early Diagnosis; Etiology; Family; Fucose; Galactose; Genetic; Genetic Heterogeneity; Glycoproteins; Grant; Hepatitis B; Hepatitis C virus; Heterogeneity; Image; Kininogens; Laboratories; Lectin; Link; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Methods; Modification; Mutation; Obesity; Patients; Pattern; Performance; Polysaccharides; Positioning Attribute; Primary carcinoma of the liver cells; Proteins; Proteomics; Sampling; Screening for cancer; Serum; Sialic Acids; Source; Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; Testing; Tissue Sample; Tissues; United States; Validation; Virus Diseases; Woman; alpha-Fetoproteins; arm; biomarker identification; biomarker panel; cancer biomarkers; cancer genetics; cancer heterogeneity; cancer prevention; cancer subtypes; commercialization; diagnostic panel; early detection biomarkers; falls; glycoproteomics; glycosylation; improved; interest; men; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel marker; sugar; tumor; tumor heterogeneity

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.

抽象的： 在向国家报告癌症状况的年度报告中，肝细胞质死亡率 男性癌（HCC）的年龄增长2.8％，女性为2.2％ 使其成为美国死亡率最大的癌症（美国） 在过去的十年中。预计肝癌的发生将继续增加 美国到2021年将超过50,000例。大多数HCC出现在 肝纤维化和肝硬化的背景，通常与慢性病毒感染有关 （丙型肝炎和乙型肝炎病毒）或非酒精性脂肪肝病/非酒精性 与肥胖相关的脂肪性肝炎（NAFLD/NASH）。 我们的实验室显示了核心和外臂岩藻糖基化的改变 HCC。这些聚糖的修饰有望作为癌症的生物标志物，并且正在积极地 由许多小组（包括我们）进行商业化。我们有一个开发的 由临床数据组成的诊断面板以及另一项新颖的小组 生物标志物，诱导型依诺原，可在检测HCC时显着改善 特别是，识别患有早期HCC的人。 为了确定岩藻糖基化的血清糖蛋白的来源，我们有 开发了一种基于组织的聚糖分析的新方法。在分析145 HCC中 组织和112个相邻的对照或肝硬化组织对照样品，我们已经确定了两个 与HCC相关的N连接聚糖家族的重大变化。第一个 观察到的变化是岩藻糖基化水平升高，经常修饰 在HCC患者的血清中观察到。但是，约50％的组织样品 被分析的岩藻糖没有增加。这些肿瘤通常不会增加岩藻糖基化 四年期聚糖增加了。我们假设遗传异质性 肿瘤可能对组织中的聚糖异质性有影响 血清。因此，聚糖不仅可以用作早期的生物标志物 检测癌症，但向癌症的特定遗传学提供了信息。在这个 应用，我们将在组织和血清中观察到的糖菌变化与 潜在的遗传变化。由于我们将拥有匹配的组织和血清，我们将能够 确定我们当前的生物标志物面板是否能够识别Fucose负面 HCC。最后，我们将利用几种蛋白质组学和糖基因方法来识别 癌症的生物标志物，没有造成糖基化水平的升高。