title: Differential exoprotease activities confer tumor-specific serum peptidome patterns.
abstract: Recent studies have established distinctive serum polypeptide patterns through mass spectrometry (MS) that reportedly correlate with clinically relevant outcomes. Wider acceptance of these signatures as valid biomarkers for disease may follow sequence characterization of the components and elucidation of the mechanisms by which they are generated. Using a highly optimized peptide extraction and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS-based approach, we now show that a limited subset of serum peptides (a signature) provides accurate class discrimination between patients with 3 types of solid tumors and controls without cancer. Targeted sequence identification of 61 signature peptides revealed that they fall into several tight clusters and that most are generated by exopeptidase activities that confer cancer type-specific differences superimposed on the proteolytic events of the ex vivo coagulation and complement degradation pathways. This small but robust set of marker peptides then enabled highly accurate class prediction for an external validation set of prostate cancer samples. In sum, this study provides a direct link between peptide marker profiles of disease and differential protease activity, and the patterns we describe may have clinical utility as surrogate markers for detection and classification of cancer. Our findings also have important implications for future peptide biomarker discovery efforts.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Josep
authors.initials: J
authors.lastname: Villanueva
authors.forename: David R
authors.initials: DR
authors.lastname: Shaffer
authors.forename: John
authors.initials: J
authors.lastname: Philip
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Chaparro
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.forename: Martin
authors.initials: M
authors.lastname: Fleisher
authors.forename: Hans
authors.initials: H
authors.lastname: Lilja
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.forename: Jeff
authors.initials: J
authors.lastname: Boyd
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Carbayo
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
mesh_terms: D000595:Amino Acid Sequence; D020689:Exopeptidases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics*; D020543:Proteome; D012016:Reference Values; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
chemical_list: D009363:Neoplasm Proteins; D010446:Peptide Fragments; D020543:Proteome; D020689:Exopeptidases