Abstract
BackgroundLower urinary tract symptoms (LUTS) and prostate specific antigen-based parameters seem to have only a limited utility for the differential diagnosis of prostate cancer (PCa). MALDI-TOF/MS peptidomic profiling could be a useful diagnostic tool for biomarker discovery, although reproducibility issues have limited its applicability until now. The current study aimed to evaluate a new MALDI-TOF/MS candidate biomarker.MethodsWithin- and between-subject variability of MALDI-TOF/MS-based peptidomic urine and serum analyses were evaluated in 20 and 15 healthy donors, respectively. Normalizations and approaches for accounting below limit of detection (LOD) values were utilized to enhance reproducibility, while Monte Carlo experiments were performed to verify whether measurement error can be dealt with LOD data. Post-prostatic massage urine and serum samples from 148 LUTS patients were analysed using MALDI-TOF/MS. Regression-calibration and simulation and extrapolation methods were used to derive the unbiased association between peptidomic features and PCa.ResultsAlthough the median normalized peptidomic variability was 24.9%, the within- and between-subject variability showed that median normalization, LOD adjustment, and log2 data transformation were the best combination in terms of reliability; in measurement error conditions, intraclass correlation coefficient was a reliable estimate when the LOD/2 was substituted for below LOD values. In the patients studied, 43 peptides were shared by the urine and serum, and several features were found to be associated with PCa. Only few serum features, however, show statistical significance after the multiple testing procedures were completed. Two serum fragmentation patterns corresponded to the complement C4-A.ConclusionsMALDI-TOF/MS serum peptidome profiling was more efficacious with respect to post-prostatic massage urine analysis in discriminating PCa.
Highlights
Lower urinary tract symptoms (LUTS) and prostate specific antigen-based parameters seem to have only a limited utility for the differential diagnosis of prostate cancer (PCa)
That this marker shared with f/total PSA (tPSA) a good sensitivity (67.7% for free to total PSA (f/tPSA) and 69.1% for prostate cancer antigen 3 (PCA3)), but with respect to f/tPSA it is less specific for LUTS patients (71.7% for f/tPSA and 48.4% for PCA3)
We found in a previous study that the analytical variability of urine peptidomic profiling was high, but we demonstrated that combining bioinformatics strategies and new approaches to the problem of signal limit of detection (sLOD) can reduce features’ variability, improving the reproducibility of results [12]
Summary
Lower urinary tract symptoms (LUTS) and prostate specific antigen-based parameters seem to have only a limited utility for the differential diagnosis of prostate cancer (PCa). MALDI-TOF/MS peptidomic profiling could be a useful diagnostic tool for biomarker discovery, reproducibility issues have limited its applicability until now. Lower urinary tract symptoms (LUTS) can be caused by prostate-related [e.g. benign prostatic hyperplasia (BPH)] and non prostaterelated conditions [e.g. bladder dysfunction] [1]. The association between LUTS and prostate cancer (PCa) has been extensively debated in light of the fact that LUTS has long been considered a potential early clinical manifestation of PCa. Currently no reliable biomarkers are capable of discriminating between PCa and benign conditions in patients with LUTS. Prostate cancer antigen 3 (PCA3), which is based on the quantification of both PCA3 and PSA mRNA expression in urine samples, has been shown to outperform PSA in identifying patients at risk for PCa at the first biopsy and to be useful in predicting the outcome of re-biopsy after the first biopsy [5]
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