Differential exoprotease activities confer tumor-specific serum peptidome patterns Journal Article

Authors: Villanueva, J.; Shaffer, D. R.; Philip, J.; Chaparro, C. A.; Erdjument-Bromage, H.; Olshen, A. B.; Fleisher, M.; Lilja, H.; Brogi, E.; Boyd, J.; Sanchez Carbayo, M.; Holland, E. C.; Cordon-Cardo, C.; Scher, H. I.; Tempst, P.
Article 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.
Keywords: controlled study; major clinical study; sequence analysis; solid tumor; validation process; cancer patient; neoplasms; biological marker; accuracy; proteome; protein degradation; neoplasm proteins; enzyme activity; peptide; tumor marker; prostate cancer; amino acid sequence; molecular sequence data; peptide fragments; reference values; ex vivo study; matrix assisted laser desorption ionization time of flight mass spectrometry; serum; sample; complement; blood clotting; spectrometry, mass, matrix-assisted laser desorption-ionization; extraction; exopeptidase; exopeptidases
Journal Title: Journal of Clinical Investigation
Volume: 116
Issue: 1
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2006-01-01
Start Page: 271
End Page: 284
Language: English
DOI: 10.1172/jci26022
PUBMED: 16395409
PROVIDER: scopus
PMCID: PMC1323259
Notes: --- - "Cited By (since 1996): 373" - "Export Date: 4 June 2012" - "CODEN: JCINA" - "Source: Scopus"
Citation Impact