title: Analysis of MALDI-TOF mass spectrometry data for discovery of peptide and glycan biomarkers of hepatocellular carcinoma.
abstract: This paper presents computational methods to analyze MALDI-TOF mass spectrometry data for quantitative comparison of peptides and glycans in serum. The methods are applied to identify candidate biomarkers in serum samples of 203 participants from Egypt; 73 hepatocellular carcinoma (HCC) cases, 52 patients with chronic liver disease (CLD) consisting of cirrhosis and fibrosis cases, and 78 population controls. Two complementary sample preparation methods were applied prior to generating mass spectra: (1) low molecular weight (LMW) enrichment of each serum sample was carried out for MALDI-TOF quantification of peptides, and (2) glycans were enzymatically released from proteins in each serum sample and permethylated for MALDI-TOF quantification of glycans. A peak selection algorithm was applied to identify the most useful peptide and glycan peaks for accurate detection of HCC cases from high-risk population of patients with CLD. In addition to global peaks selected by the whole population based approach, where identically labeled patients are treated as a single group, subgroup-specific peaks were identified by searching for peaks that are differentially abundant in a subgroup of patients only. The peak selection process was preceded by peak screening, where we eliminated peaks that have significant association with covariates such as age, gender, and viral infection based on the peptide and glycan spectra from population controls. The performance of the selected peptide and glycan peaks was evaluated in terms of their ability in detecting HCC cases from patients with CLD in a blinded validation set and through the cross-validation method. Finally, we investigated the possibility of using both peptides and glycans in a panel to enhance the diagnostic capability of these candidate markers. Further evaluation is needed to examine the potential clinical utility of the candidate peptide and glycan markers identified in this study.
authors.affiliation: Georgetown University, Lombardi Comprehensive Cancer Center, Washington, DC, USA. hwr@georgetown.edu
authors.forename: Habtom W
authors.initials: HW
authors.lastname: Ressom
authors.forename: Rency S
authors.initials: RS
authors.lastname: Varghese
authors.forename: Lenka
authors.initials: L
authors.lastname: Goldman
authors.forename: Yanming
authors.initials: Y
authors.lastname: An
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Loffredo
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Hamid
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kyselova
authors.forename: Yehia
authors.initials: Y
authors.lastname: Mechref
authors.forename: Milos
authors.initials: M
authors.lastname: Novotny
authors.forename: Steven K
authors.initials: SK
authors.lastname: Drake
authors.forename: Radoslav
authors.initials: R
authors.lastname: Goldman
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000595:Amino Acid Sequence; D014408:Biomarkers, Tumor / Q000097:blood / Q000302:isolation & purification*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000737:chemistry*; D019694:Hepatitis B, Chronic / Q000097:blood; D019698:Hepatitis C, Chronic / Q000097:blood; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000737:chemistry*; D008969:Molecular Sequence Data; D010455:Peptides / Q000097:blood / Q000302:isolation & purification*; D011134:Polysaccharides / Q000097:blood / Q000302:isolation & purification*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D014408:Biomarkers, Tumor; D010455:Peptides; D011134:Polysaccharides