Skip to main content
Molecular & Cellular Proteomics

Main menu

  • Home
  • Articles
    • Current Issue
    • Papers in Press
    • Reviews and Minireviews
    • Special Issues
    • Editorials
    • Archive
    • Letters to the Editor (eLetters)
  • Info for
    • Authors
      • Editorial Policies
      • How to Submit
      • Manuscript Contents & Organization
      • Data Reporting Requirements
      • Publication Charges
    • Reviewers
    • Librarians
    • Advertisers
    • Subscribers
  • Guidelines
    • Proteomic Identification
      • Checklist (PDF)
      • Instructions for Annotated Spectra
      • Tutorial (PDF)
    • Clinical Proteomics
      • Checklist (PDF)
    • Glycomic Identification
      • Checklist (PDF)
    • Targeted Proteomics
      • Checklist (PDF)
    • Data-Independent Acquisition
      • Checklist (PDF)
    • Frequently Asked Questions
  • About
    • Mission Statement and Scope
    • Editorial Policies
    • Editorial Board
    • MCP Lectureships
    • Permissions and Licensing
    • Partners
    • Alerts
    • Contact Us

Submit

  • Submit
  • Publications
    • ASBMB
    • Molecular & Cellular Proteomics
    • Journal of Biological Chemistry
    • Journal of Lipid Research

User menu

  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
  • Publications
    • ASBMB
    • Molecular & Cellular Proteomics
    • Journal of Biological Chemistry
    • Journal of Lipid Research
  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Molecular & Cellular Proteomics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Papers in Press
    • Reviews and Minireviews
    • Special Issues
    • Editorials
    • Archive
    • Letters to the Editor (eLetters)
  • Info for
    • Authors
      • Editorial Policies
      • How to Submit
      • Manuscript Contents & Organization
      • Data Reporting Requirements
      • Publication Charges
    • Reviewers
    • Librarians
    • Advertisers
    • Subscribers
  • Guidelines
    • Proteomic Identification
      • Checklist (PDF)
      • Instructions for Annotated Spectra
      • Tutorial (PDF)
    • Clinical Proteomics
      • Checklist (PDF)
    • Glycomic Identification
      • Checklist (PDF)
    • Targeted Proteomics
      • Checklist (PDF)
    • Data-Independent Acquisition
      • Checklist (PDF)
    • Frequently Asked Questions
  • About
    • Mission Statement and Scope
    • Editorial Policies
    • Editorial Board
    • MCP Lectureships
    • Permissions and Licensing
    • Partners
    • Alerts
    • Contact Us
  • Submit
Research

Multi-omics Biomarker Pipeline Reveals Elevated Levels of Protein-glutamine Gamma-glutamyltransferase 4 in Seminal Plasma of Prostate Cancer Patients

View ORCID ProfileAndrei P. Drabovich  Correspondence email, View ORCID ProfilePunit Saraon, Mikalai Drabovich, Theano D. Karakosta, Apostolos Dimitromanolakis, M. Eric Hyndman, Keith Jarvi  Correspondence email and View ORCID ProfileEleftherios P. Diamandis  Correspondence email
Molecular & Cellular Proteomics September 1, 2019, First published on June 27, 2019, 18 (9) 1807-1823; https://doi.org/10.1074/mcp.RA119.001612
Andrei P. Drabovich
‡Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5T 3L9 Canada §Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, M5T 3L9 Canada ¶Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, M5T 3L9 Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Andrei P. Drabovich
  • For correspondence: andrei.drabovich@ualberta.ca
Punit Saraon
‡Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5T 3L9 Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Punit Saraon
Mikalai Drabovich
‖Independent researcher, Palo Alto, California 94303
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Theano D. Karakosta
§Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, M5T 3L9 Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Apostolos Dimitromanolakis
§Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, M5T 3L9 Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Eric Hyndman
**Department of Surgery, Division of Urology, Southern Alberta Institute of Urology, University of Calgary, Calgary, AB T2V 1P9, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keith Jarvi
‡‡Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5T 3L9 Canada §§Department of Surgery, Division of Urology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, M5T 3L9 Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: keith.jarvi@sinaihealthsystem.ca
Eleftherios P. Diamandis
‡Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5T 3L9 Canada §Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, M5T 3L9 Canada ¶Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, M5T 3L9 Canada ‡‡Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5T 3L9 Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Eleftherios P. Diamandis
  • For correspondence: eleftherios.diamandis@sinaihealthsystem.ca
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Graphical Abstract

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Highlights

  • Seventy-six most promising proteins were qualified, and 19 proteins were verified by SRM in 219 seminal plasma samples of patients with prostate cancer and negative biopsies.

  • Prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4) was verified by SRM assay and an in-house immunoassay.

  • TGM4 detected prostate cancer on biopsy in seminal plasma (AUC=0.66), but not in blood serum.

Abstract

Seminal plasma, because of its proximity to prostate, is a promising fluid for biomarker discovery and noninvasive diagnostics. In this study, we investigated if seminal plasma proteins could increase diagnostic specificity of detecting primary prostate cancer and discriminate between high- and low-grade cancers. To select 147 most promising biomarker candidates, we combined proteins identified through five independent experimental or data mining approaches: tissue transcriptomics, seminal plasma proteomics, cell line secretomics, tissue specificity, and androgen regulation. A rigorous biomarker development pipeline based on selected reaction monitoring assays was designed to evaluate the most promising candidates. As a result, we qualified 76, and verified 19 proteins in seminal plasma of 67 negative biopsy and 152 prostate cancer patients. Verification revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which predicted prostate cancer on biopsy and outperformed age and serum Prostate-Specific Antigen (PSA). A machine-learning approach for data analysis provided improved multi-marker combinations for diagnosis and prognosis. In the independent verification set measured by an in-house immunoassay, TGM4 protein was upregulated 3.7-fold (p = 0.006) and revealed AUC = 0.66 for detecting prostate cancer on biopsy for patients with serum PSA ≥4 ng/ml and age ≥50. Very low levels of TGM4 (120 pg/ml) were detected in blood serum. Collectively, our study demonstrated rigorous evaluation of one of the remaining and not well-explored prostate-specific proteins within the medium-abundance proteome of seminal plasma. Performance of TGM4 warrants its further investigation within the distinct genomic subtypes and evaluation for the inclusion into emerging multi-biomarker panels.

  • Prostate cancer biomarkers
  • serum/plasma
  • selected reaction monitoring
  • absolute quantification
  • assay development
  • machine learning
  • protein-glutamine gamma-glutamyltransferase 4
  • seminal plasma
  • TGM4
  • XGBoost

Footnotes

  • Author contributions: A.P.D., K.J., and E.P.D. designed research; A.P.D., P.S., and T.K. performed research; A.P.D. contributed new reagents/analytic tools; A.P.D., M.D., and A.D. analyzed data; A.P.D. wrote the paper; M.E.H. and K.J. provided clinical samples and clinical expertise.

  • ↵* This work was supported by grants from the Canadian Institute of Health Research (#285693) to E.P.D., K.J., and A.P.D, and Prostate Cancer Canada (RS2015-01) to A.P.D.

  • ↵Embedded Image This article contains supplemental material.

  • Received June 4, 2019.
  • © 2019 Drabovich et al.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

View Full Text

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on Molecular & Cellular Proteomics.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Multi-omics Biomarker Pipeline Reveals Elevated Levels of Protein-glutamine Gamma-glutamyltransferase 4 in Seminal Plasma of Prostate Cancer Patients
(Your Name) has sent you a message from Molecular & Cellular Proteomics
(Your Name) thought you would like to see the Molecular & Cellular Proteomics web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Multi-omics Biomarker Pipeline Reveals Elevated Levels of Protein-glutamine Gamma-glutamyltransferase 4 in Seminal Plasma of Prostate Cancer Patients
Andrei P. Drabovich, Punit Saraon, Mikalai Drabovich, Theano D. Karakosta, Apostolos Dimitromanolakis, M. Eric Hyndman, Keith Jarvi, Eleftherios P. Diamandis
Molecular & Cellular Proteomics September 1, 2019, First published on June 27, 2019, 18 (9) 1807-1823; DOI: 10.1074/mcp.RA119.001612

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Request Permissions

Share
Multi-omics Biomarker Pipeline Reveals Elevated Levels of Protein-glutamine Gamma-glutamyltransferase 4 in Seminal Plasma of Prostate Cancer Patients
Andrei P. Drabovich, Punit Saraon, Mikalai Drabovich, Theano D. Karakosta, Apostolos Dimitromanolakis, M. Eric Hyndman, Keith Jarvi, Eleftherios P. Diamandis
Molecular & Cellular Proteomics September 1, 2019, First published on June 27, 2019, 18 (9) 1807-1823; DOI: 10.1074/mcp.RA119.001612
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

In this issue

Molecular & Cellular Proteomics: 18 (9)
Molecular & Cellular Proteomics
Vol. 18, Issue 9
1 Sep 2019
  • Table of Contents
  • Table of Contents (PDF)
  • Cover (PDF)
  • About the Cover
  • Index by author
  • Ed Board (PDF)

View this article with LENS

Jump to section

  • Article
    • Graphical Abstract
    • Abstract
    • EXPERIMENTAL PROCEDURES
    • RESULTS
    • DISCUSSION
    • Data Availability
    • Acknowledgments
    • Footnotes
    • REFERENCES
  • Figures & Data
  • eLetters
  • Info & Metrics
  • PDF

  • Follow MCP on Twitter
  • RSS feeds
  • Email

Articles

  • Current Issue
  • Papers in Press
  • Archive

For Authors

  • Submit a Manuscript
  • Info for Authors

Guidelines

  • Proteomic Identification
  • Clinical Proteomics
  • Glycomic Identification
  • Targeted Proteomics
  • Frequently Asked Questions

About MCP

  • About the Journal
  • Permissions and Licensing
  • Advertisers
  • Subscribers

ASBMB Publications

  • Molecular & Cellular Proteomics
  • Journal of Biological Chemistry
  • Journal of Lipid Research
  • ASBMB Today

© 2019 American Society for Biochemistry and Molecular Biology | Privacy Policy

MCP Print ISSN 1535-9476 Online ISSN 1535-9484

Powered by HighWire