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PreprintCited by 0Prostate Cancer Diagnosis and TreatmentProstate Cancer Treatment and ResearchAdvanced Proteomics Techniques and Applications

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Multi-omics biomarker pipeline reveals elevated levels of protein-glutamine gamma-glutamyltransferase 4 in seminal plasma of prostate cancer patients

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Drabovich, Andrei P., Saraon, Punit, Drabovich, Mikalai, Karakosta, Theano D., Dimitromanolakis, Apostolos, Hyndman, M. Eric, Jarvi, Keith, Diamandis, Eleftherios P.·2017·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/120873

Preprint — published as 10.1074/mcp.ra119.001612 · Paper page

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Abstract

Purpose: Prostate-specific antigen, a blood serum biomarker of prostate cancer, lacks specificity and prognostic significance, so considerable efforts are devoted to developing novel biomarkers. Seminal plasma, due to its proximity to prostate, is a promising fluid for biomarker discovery and non-invasive diagnostics. In this study, we investigated if seminal plasma proteins could increase specificity of detecting primary prostate cancer and discriminate between high- and low-grade cancers. Experimental Design: To select 148 most promising biomarker candidates, we combined proteins identified through five independent data mining or experimental approaches: tissue transcriptomics, seminal plasma proteomics, cell secretomics, tissue specificity and androgen regulation. A rigorous biomarker development pipeline based on targeted proteomics assays was designed to evaluate the most promising candidates. Results: We qualified 77 and verified 19 proteins in seminal plasma of 67 negative biopsy and 155 prostate cancer patients. Verification revealed a prostate-specific, secreted and androgen-regulated protein-glutamine gamma-glutamyltransferase 4 (TGM4), which could predict prostate cancer on biopsy and outperformed age and serum PSA. Machine-learning approaches also revealed improved multi-marker combinations for diagnosis and prognosis. In the independent verification set measured by an inhouse ELISA, TGM4 was up-regulated 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. Low levels of TGM4 (median 120 pg/mL) were detected in blood serum, but could not differentiate between negative biopsy, prostate cancer or prostate inflammation. Conclusions: Performance of TGM4 warrants its further investigation within the distinct genomic subtypes and evaluation for the inclusion into emerging multi-biomarker panels.

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Metadata

Authors
Drabovich, A. P., Saraon, P., Drabovich, M., Karakosta, T. D., Dimitromanolakis, A., Hyndman, M. E., Jarvi, K., & Diamandis, E. P.
Affiliations
  • Mount Sinai Hospital (CA)
  • University of Toronto (CA)
  • University Health Network (CA)
  • Rockyview General Hospital (CA)
Corresponding author
  • Drabovich, Andrei P.
  • Jarvi, Keith
  • Diamandis, Eleftherios P.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2017-03-26
DOI
10.1101/120873
OpenAlex
W2609592944
Cited by
0
References
1
Type
posted content
Language
en
Open access
Licence
Locations
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
Funders
Prostate Cancer Canada (RS2015–01)
Topics
  • Health Sciences › Medicine › Urology › Prostate Cancer Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
prostate cancer, seminal plasma, tumor markers, non-invasive diagnosis, targeted proteomics, multimarker panels, cancer grading, prostate-specific antigen

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