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.
Highlights
Prostate cancer is the most frequently diagnosed neoplasm and the third leading cause of cancer mortality in men
To facilitate our diagnostic strategy, we considered as candidates only secreted and membrane-bound proteins which were previously identified in our seminal plasma (SP) proteome of more than 3,000 proteins [14,15,28]
We assumed that different -omics approaches may have certain limitations
Summary
Prostate cancer is the most frequently diagnosed neoplasm and the third leading cause of cancer mortality in men. Its incidence rate has continued to increase rapidly during the past two decades, especially in men over the age of 50 years. Close to 260,000 men die from prostate cancer every year [1]. The most commonly used prostate cancer biomarker, prostate-specific antigen (PSA), is secreted by both normal prostate cells and prostate cancer cells. There is no question that the introduction of PSA testing over the last two decades revolutionized the practice of urology. As a result of PSA screening, most men today with prostate cancer present with localized disease and serum PSA values
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