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Differential exoprotease activities confer tumor-specific serum peptidome patterns
Josep Villanueva, … , Howard I. Scher, Paul Tempst
Josep Villanueva, … , Howard I. Scher, Paul Tempst
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):271-284. https://doi.org/10.1172/JCI26022.
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Research Article Oncology Article has an altmetric score of 19

Differential exoprotease activities confer tumor-specific serum peptidome patterns

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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

Josep Villanueva, David R. Shaffer, John Philip, Carlos A. Chaparro, Hediye Erdjument-Bromage, Adam B. Olshen, Martin Fleisher, Hans Lilja, Edi Brogi, Jeff Boyd, Marta Sanchez-Carbayo, Eric C. Holland, Carlos Cordon-Cardo, Howard I. Scher, Paul Tempst

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Figure 4

MALDI-TOF/TOF MS/MS identification of serum peptide 2305.

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MALDI-TOF/TOF MS/MS identification of serum peptide 2305.
0 as a fragmen...
0 as a fragment of complement C4a. Peptides from a serum sample of a breast cancer patient were extracted and analyzed by MS and the ion of choice selected for MS/MS analysis, as described in Supplemental Methods. The fragment ion spectrum shown here was taken for a Mascot MS/MS ion search of the human segment of the NR database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein) and retrieved a sequence, GLEEELQFSLGSKINVKVGGNS ([MH]+ = 2305.19; Δ = 4 ppm), with a Mascot score of 38. b and y fragment ion series are indicated together with the limited sequences (arrows at top). Note that y ions originate at the C terminus and that the sequence therefore reads backwards (see direction of the arrows).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 31 patents
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