Urinary marker panels for aggressive prostate cancer detection

Abstract

Majority of patients with indolent prostate cancer (PCa) can be managed with active surveillance. Therefore, finding biomarkers for classifying patients between indolent and aggressive PCa is essential. In this study, we investigated urinary marker panels composed of urinary glycopeptides and/or urinary prostate-specific antigen (PSA) for their clinical utility in distinguishing non-aggressive (Grade Group 1) from aggressive (Grade Group ≥ 2) PCa. Urinary glycopeptides acquired via data-independent acquisition mass spectrometry (DIA-MS) were quantitatively analyzed, where prostatic acid phosphatase (ACPP), clusterin (CLU), alpha-1-acid glycoprotein 1 (ORM1), and CD antigen 97 (CD97) were selected to be evaluated in various combinations with and without urinary PSA. Targeted parallel reaction monitoring (PRM) assays of the glycopeptides from urinary ACPP and CLU were investigated along with urinary PSA for the ability of aggressive PCa detection. The multi-urinary marker panels, combined via logistic regression, were statistically evaluated using bootstrap resampling and validated by an independent cohort. Majority of the multi-urinary marker panels (e.g., a panel consisted of ACPP, CLU, and Urinary PSA) achieved area under the curve (AUC) ranged from 0.70 to 0.85. Thus, multi-marker panels investigated in this study showed clinically meaningful results on aggressive PCa detection to separate Grade Group 1 from Grade Group 2 and above warranting further evaluation in clinical setting in future.

Figure 1

Experimental workflow of the study.

Figure 2

Urinary marker panels composed of ACPP, CLU (using quantitative analysis of DIA-MS), and/or urinary PSA. (a) ROC analysis of CLU, ACPP, urinary PSA, and multi-signature panels. (b) and (c) Comparison between real models and randomly generated models from label permutation based on bootstrap resampling. For simplicity, only protein names are used.

Figure 3

Evaluation of urinary marker panels. (a) Performance of the urinary marker panels composed of ACPP + CLU and ACPP + CLU + urinary PSA at different serum PSA levels in comparison to serum PSA. (b) Other multi-urinary marker panels with good performance compared to random models from label permutation.

Figure 4

Urinary marker panels composed of PRM assays of the urinary glycopeptides from ACPP, CLU, and/or urinary PSA. (a) ROC analysis of CLU, ACPP, urinary PSA, and multi-signature panels. (b) and (c) Comparison between real models and randomly generated models from label permutation based on bootstrap resampling.