Screening of Glycan Markers in Serum for Early Detection of HCC in Different Etiologies of Disease

筛选血清中的聚糖标记物以早期检测不同病因的 HCC

• 批准号: 9893836
• 负责人: David M. Lubman
• 金额: $ 49.36万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-09 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893836
• 关键词: Adherence; Alcohol-Related Hepatocellular Carcinoma; Alcohols; Bioinformatics; Biological Assay; Biological Markers; Cancer Etiology; Carbon; Cessation of life; Cirrhosis; Complex; Computer software; Coupled; Databases; Development; Diagnosis; Disease; Early Diagnosis; Etiology; Europe; Evaluation; Frequencies; Glycopeptides; Glycoproteins; Guidelines; Hepatitis B Virus; Hepatitis C virus; Incidence; Isomerism; Japan; Lectin; Liver Cirrhosis; Liver diseases; Machine Learning; Malignant Neoplasms; Malignant neoplasm of liver; Mass Spectrum Analysis; Measurement; Methods; Minor; Monitor; Natural graphite; Patients; Pattern; Peptides; Performance; Polysaccharides; Preparation; Primary carcinoma of the liver cells; Protein Glycosylation; Protein Isoforms; Proteins; Proteome; Recommendation; Risk; Sampling; Screening for cancer; Serum; Serum Markers; Site; Software Tools; Specificity; Statistical Data Interpretation; Structure; Survival Rate; Testing; Time; Tumor Markers; Ultrasonography; Work; alpha-Fetoproteins; base; carbohydrate structure; curative treatments; diagnostic screening; early detection biomarkers; early onset; glycoproteomics; glycosylation; improved; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; patient screening; patient stratification; precision medicine; screening; sialylation; tandem mass spectrometry; tumor

Abstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide and is rising in incidence in the US. 90% of patients in the US with liver cancer have underlying cirrhosis, thus guideline recommendations recommend surveillance in all patients with cirrhosis to facilitate early detection. Unfortunately, only 20-30% of patients are detected with early detection and are thus eligible for potentially curative treatments. There is an unmet need for reliable biomarkers for HCC to facilitate adherence to screening and for early detection. In the proposed work we will develop early detection strategies for HCC based on glycoproteomic profiles. Unique changes in glycosylation in proteins, which involve structural changes in glycan groups, have been shown to be important serum biomarkers for early cancer detection. Importantly, the subtle changes may only involve minor structures but they can be very specific in differentiating cirrhosis versus early versus late stage HCC. In addition, these changes may be specific to the etiology of liver disease. These glycan structural changes will be detected and monitored quantitatively using a mass spectrometry approach which has proven to be an accurate way to characterize even minor changes in structure which may be significant as biomarkers based on our previous mass analysis, tandem mass spectrometry measurements and databases which have been developed for glycan and glycopeptide analysis. This will be demonstrated for both glycan and glycopeptide screening from serum using novel extraction and separation methods coupled to mass spectrometry which can ultimately be used to distinguish early stage HCC from cirrhosis. The proposed work will deliver separations and mass spec methods enabling isomeric separation of glycans and glycopeptides, permitting unequivocal assignment of protein glycosylation related to disease state. We will be able to distinguish different isomeric forms of fucosylation and sialylation which may contain important disease related markers. Novel software will be developed and used to assign these glycan structures. The markers will be discovered for specific etiologies of HCV-related, alcohol-related and NAFLD-related etiologies of HCC. This will be a multisite study to include all components required for a tumor biomarker lab including samples and sample preparation, separations and mass spec analysis, bioinformatics evaluation and statistical analysis. Ultimately, we will develop methods for discovery of glycan/glycopeptide markers from patient serum, the identification of potential markers and the development of new assays to provide a limited confirmation of these markers.

摘要：肝细胞癌（HCC）是癌症相关死亡的第三大常见原因 在世界范围内，美国的发病率正在上升。在美国，90%的肝癌患者有潜在的 肝硬化，因此指南建议对所有肝硬化患者进行监测，以促进早期 侦测不幸的是，只有20-30%的患者被早期发现，因此有资格接受治疗。 潜在的治愈性治疗。对于HCC的可靠生物标志物的需求尚未得到满足，以促进 坚持筛查和早期发现。在拟议的工作中，我们将开发早期检测 基于糖蛋白组学谱的HCC治疗策略。蛋白质中糖基化的独特变化， 涉及聚糖基团结构变化，已被证明是早期糖尿病的重要血清生物标志物。 癌症检测重要的是，细微的变化可能只涉及微小的结构，但它们可能非常重要。 特异性区分肝硬化与早期与晚期HCC。此外，这些变化可能是 具体到肝脏疾病的病因。这些聚糖结构变化将被检测和监测 定量使用质谱法，这已被证明是一种准确的方式来表征 即使是微小的结构变化，根据我们以前的质量， 已开发的聚糖分析、串联质谱测量和数据库 和糖肽分析。这将通过从血清中筛选聚糖和糖肽来证明 使用与质谱联用的新型提取和分离方法，最终可用于 区分早期HCC和肝硬化。拟议的工作将提供分离和质谱 能够异构分离聚糖和糖肽的方法， 与疾病状态相关的蛋白质糖基化。我们将能够区分不同的异构形式的 岩藻糖基化和唾液酸化，其可能含有重要的疾病相关标志物。新软件将成为 开发并用于分配这些聚糖结构。这些标记物将被发现用于特定的病因学 HCV相关、酒精相关和NAFLD相关的HCC病因。这将是一项多中心研究，包括 肿瘤生物标志物实验室所需的所有组件，包括样品和样品制备、分离 和质谱分析、生物信息学评价和统计分析。最终，我们将开发 从患者血清中发现聚糖/糖肽标记物的方法， 标记物和新的检测方法的开发，以提供这些标记物的有限确认。