Identification of Altered Glycan and Glycoproteins in Viral Induced Liver Cancer

描述（由申请人提供）：从我们过去的工作和其他人的工作中可以清楚地看出，一种特定类型的糖基化（岩藻糖基化）的升高与HCC相关。事实上，这种修饰是食品和药物管理局批准用于检测HCC的唯一生物标志物AFP-L3的基础。然而，在一些研究中，岩藻糖基化用于癌症检测的特异性受到质疑。也就是说，许多患有肝硬化而没有癌症的人也被证明岩藻糖升高。这种变化的性质是我们的母补助金和本修订申请的目标。观察到N-连接糖蛋白的岩藻糖基化有两种主要形式-α-1，6连接核心岩藻糖基化和外臂岩藻糖基化（α 1、2、3或4连接）。我们最近的研究表明，非HCC患者的血小板增加归因于α-1，3连接的外臂岩藻糖基化的增加，而不是α-1，6核心岩藻糖基化的增加。虽然这些是不同的聚糖修饰，但大多数岩藻糖结合凝集素不能区分这些细微的差异。因此，使用商业化的岩藻糖结合凝集素的测定具有较差的特异性。因此，我们最近制备了新型岩藻糖结合凝集素，其对核心岩藻糖修饰的特异性增强，对癌症更具特异性。因此，在本修订申请的母基金R 01 CA 120206中，我们将使用这些新型试剂和发现来支持一项合作性癌症成像研究，不仅可以在最早阶段检测癌症，还可以减少过度诊断。在具体目标1中，我们将确定核心岩藻糖基化蛋白增加成像特异性的能力，作为ACRIN方案6690的一部分。本试验的主要目的是比较CT和MRI对HCC放射学分期的准确性，并确定生物标志物是否可用于增加这些成像技术的特异性。在这种情况下，HCC的存在将通过接受肝移植治疗其肝病的受试者的外植体病理学来确定。在目标2中，我们将确定另一种聚糖 修饰，增加分支，可以与MRI和CT扫描组合用于HCC的特异性检测。在本补充材料的最后，我们将扩展母申请的目的，并表明糖基化的特定变化可用于辅助成像，以特异性识别HCC患者。

DESCRIPTION (provided by applicant): It has been clear from our past work and that of others, those elevations in one specific type of glycosylation, fucosylation, is associated with HCC. Indeed this modification is the basis of the only biomarker approved by the food and drug administration for the detection of HCC, AFP-L3. However, in several studies, the specificity of fucosylation for cancer detection has been questioned. That is, many people with cirrhosis, and without cancer, have been shown to have elevations in fucose as well. The nature of this change is the objective of our parent grant and this revision application. The fucosylation of N-linked glycoproteins is observed in two major forms- alpha-1, 6 linked core fucosylation and outer-arm fucosylation (alpha 1, 2, 3 or 4 linked). We have recently shown that the elevations in the cirrhotic, non-HCC patients are attributable to elevations in alpha-1, 3 linked outer arm fucosylation and not alpha-1, 6 core fucosylation. While these are distinct glycan modifications, most fucose-binding lectins cannot differentiate these subtle differences. As a result, assays using commercial fucose-binding lectins suffer from poor specificity. Hence, we have recently made novel fucose binding lectins with enhanced specificity towards the core fucose modification that is more specific for cancer. Therefore, in this revision application for parent grant R01 CA120206, we will use these novel reagents and findings to support a collaborative cancer imaging study to not only detect cancer at the earliest stages possible but to reduce over diagnosis. In specific aim 1, we will determine the ability of the core fucosylated proteins to increase the specificity of imaging as part of ACRIN protocol 6690. The main objective of this trial is to compare the accuracy of radiologic staging of HCC by CT and MRI and to determine if biomarkers can be used to increase the specificity of these imaging techniques. The presence of HCC in this case will be determined by explant pathology of participants who undergo liver transplantation for treatment of their liver disease. In aim 2, we will determine if another glycan modification, increased branching, can be used in combination with MRI and CT-Scan for the specific detection of HCC. At the end of this supplement we will have extended the aims of the parent application and shown that specific changes in glycosylation can be used to assist imaging to specifically identify those patients with HCC.