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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 5

Serum peptide signatures for advanced prostate, bladder, and breast cancer.

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Serum peptide signatures for advanced prostate, bladder, and breast canc...
Selected peptides identified by MALDI-TOF/TOF MS/MS are listed in clusters (ladders) of overlapping sequences, including 46 of the initial signature group of 68 (Figure 2 and Supplemental Table 2). m/z values are monoisotopic. Twenty-three additional peptides were positively matched to the existing clusters by hypothesis-driven, targeted MS/MS analysis. Overall, 61 entries had clear marker potential (adjusted P < 0.0002; Figure 6) for at least 1 cancer type and are color-coded blue (prostate cancer), green (bladder cancer), or red (breast cancer). Resulting signatures for the 3 cancers consist of 26 (prostate), 50 (bladder), and 25 (breast) peptide ions. Color-coded peptides have either higher (no filled circles) or lower (filled circles) differential ion intensities in a particular cohort of cancer samples compared with controls. C3f (m/z = 2021.05) and 1 member of the fibrinogen α cluster (m/z = 2553.01) gave comparable ion signals in all patient groups and control sera (see Figure 3, 2021, and Figure 6) and therefore represent effective internal standards (yellow). Six peptides (pink) were randomly observed. Residues in brackets were not experimentally observed but are shown to either indicate putative full-length sequences of the founder peptides and/or the positions of trypsin-like cleavage sites (Arg/Lys–Xaa).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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