Serum Glyco-Markers of Early Hepatocellular Carcinoma Using a Mass Spec Approach

使用质谱方法检测早期肝细胞癌的血清糖标记物

• 批准号: 10657544
• 负责人: David M. Lubman
• 金额: $ 35.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657544
• 关键词: Abdomen; Address; Archives; Biological Assay; Biological Markers; Blinded; Cancer Etiology; Cessation of life; Characteristics; Cirrhosis; Clinical; Clinical Data; Clinical Treatment; Complex; Computer software; Coupled; Data; Databases; Detection; Disease; Early Detection Research Network; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Etiology; Glycopeptides; Glycoproteins; Goals; Guidelines; Haptoglobins; Incidence; Isomerism; Laboratories; Lectin; Liver diseases; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Methods; Minor; Monitor; Patients; Peptides; Performance; Phase; Polysaccharides; Primary carcinoma of the liver cells; Professional Organizations; Proteins; Publishing; Race; Reaction; Recommendation; Sampling; Screening for cancer; Serum; Site; Specificity; Structure; Survival Rate; Techniques; Testing; Validation; Work; alpha-Fetoproteins; bioinformatics tool; biomarker performance; biomarker validation; carbohydrate structure; curative treatments; detection sensitivity; early detection biomarkers; glycoproteomics; glycosylation; high risk; improved; innovation; multiplex assay; novel; screening; sex; sialylation; success; surveillance strategy; tandem mass spectrometry; ultrasound

Abstract: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide and is rising in incidence in the US. Over 80% of patients in the US with HCC have underlying cirrhosis, and professional societies guidelines recommend surveillance in all patients with cirrhosis to facilitate early detection. Unfortunately, only 20-30% of patients are detected at an early stage when potentially curative treatments are possible. Our proposal, based on our strong preliminary data evaluating glycoproteomic profiles, addresses the clear unmet need for accurate early HCC detection biomarkers. Unique changes in glycosylation in proteins, which involve structural changes in glycan groups, have been shown to be important serum biomarkers for early HCC detection. Importantly, even subtle changes involving minor structures can be very specific in differentiating cirrhosis versus early stage HCC. In this study, we will use a mass spectrometry approach, which has proven to be a highly sensitive and accurate way to detect and quantitatively monitor glycan structural changes. Our published mass analysis discovery work, tandem mass spectrometry measurements, and novel bioinformatic tools for glycan and glycopeptide analysis demonstrate these minor changes in structure can act as promising early HCC detection biomarkers. In aim 1 these methods will be demonstrated for glycopeptide screening from serum using novel mass spec assays using parallel reaction monitoring (PRM) analysis based on a stepped HCD fragmentation method which can ultimately be used to distinguish early stage HCC from cirrhosis. The PRM method is a targeted assay which can distinguish small changes in glycan structure and can be multiplexed to monitor large numbers of markers simultaneously. In addition, using separations coupled to the PRM strategy, we will be able to distinguish different isomeric forms of fucosylation and sialylation in glycan structures which may contain important disease related markers. In aim 2 the methods developed herein will be optimized and then applied to a large confirmation set of 300 early stage HCC and cirrhosis samples for 20 target glycopeptides from Haptoglobin and to several other potential glycopeptide markers discovered and evaluated in our prior work. In aim 3 we will then validate the biomarker performance in a blinded phase II biomarker study using a large set of 800-1000 early stage HCC and cirrhosis patients, diverse with regard to sex, race/ethnicity, and liver disease etiology. Through these aims, we will identify a panel of glycopeptides that can serve as highly accurate biomarkers for early HCC detection.

摘要：肝细胞癌（HCC）是全球癌症相关死亡的第四大常见原因

项目成果

GlycoSLASH: Concurrent Glycopeptide Identification from Multiple Related LC-MS/MS Data Sets by Using Spectral Clustering and Library Searching.

• DOI: 10.1021/acs.jproteome.3c00066
• 发表时间: 2023-05-05
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Li, Sujun;Zhu, Jianhui;Lubman, David M.;Zhou, He;Tang, Haixu
• 通讯作者: Tang, Haixu

Large Scale Screening and Quantitative Analysis of Site-Specific N-Glycopeptides from Human Serum in Early Alzheimer's Disease Using LC-HCD-PRM-MS.

• DOI: pii: 587
• 发表时间: 2022
• 期刊: Journal of proteomics & bioinformatics
• 作者: Pan L;Lin Y;Zhu J;Zhang J;Tan Z;Lubman DM
• 通讯作者: Lubman DM

The analysis of alpha-1-antitrypsin glycosylation with direct LC-MS/MS.

使用直接 LC-MS/MS 分析 Alpha-1-抗胰蛋白酶糖基化

• DOI: 10.1002/elps.201700426
• 发表时间: 2018-09
• 期刊: Electrophoresis
• 影响因子: 2.9
• 作者: Yin H;An M;So PK;Wong MY;Lubman DM;Yao Z
• 通讯作者: Yao Z

David M. Lubman-The University of Michigan-A retrospective in research.

• DOI: 10.1002/mas.21718
• 发表时间: 2023-03
• 期刊: Mass spectrometry reviews
• 影响因子: 6.6
• 作者: Lubman DM

Glycopeptides with Sialyl Lewis Antigen in Serum Haptoglobin as Candidate Biomarkers for Nonalcoholic Steatohepatitis Hepatocellular Carcinoma Using a Higher-Energy Collision-Induced Dissociation Parallel Reaction Monitoring-Mass Spectrometry Method.

• DOI: 10.1021/acsomega.2c02600
• 发表时间: 2022-07-05
• 期刊: ACS omega
• 影响因子: 4.1