Multi-omics Biomarker Pipeline Reveals Elevated Levels of Protein-glutamine Gamma-glutamyltransferase 4 in Seminal Plasma of Prostate Cancer Patients
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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.
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AI in multi-omics analysis in cancer
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Recent Advances of Ultrasound-Based Nano-Delivery Systems in Prostate Cancer Imaging and TreatmentPreprint
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Recent advances of ultrasound-based nano-delivery systems in prostate cancer imaging and treatment
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Self-citation
- 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)
- University of Calgary (CA)
- Corresponding author
- Drabovich, Andrei P.
- Jarvi, Keith
- Diamandis, Eleftherios P.
- ORCID
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 18
- Issue
- 9
- Pages
- 1807-1823
- ISSN
- 1535-9476 (ISSN-L)
- PMC
- PMC6731075
- OpenAlex
- W2954232647
- Cited by
- 40
- References
- 83
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 7 · 2020: 7
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular & Cellular Proteomics (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gouvernement du Canada | Canadian Institutes of Health Research (CIHR) (285693)
- Prostate Cancer Canada (PCC) (RS2015–01)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- prostate cancer, seminal plasma, tumor markers, non-invasive diagnosis, PSA, multiple reaction monitoring, secretomics, multimarker panels, cancer grading
- MeSH terms
- Machine Learning, Adult, Aged, Enzyme-Linked Immunosorbent Assay, Humans, Male, Middle Aged, Prostatic Neoplasms, Transglutaminases, Semen, Biomarkers, Tumor, Prostate-Specific Antigen, Seminal Plasma Proteins, Proteomics
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