Application of Proteogenomics to Urine Analysis towards the Identification of Novel Biomarkers of Prostate Cancer: An Exploratory Study

Abstract

To identify new protein targets for PCa detection, first, a shotgun discovery experiment was performed to characterize the urinary proteome of PCa patients. This revealed 18 differentially abundant urinary proteins in PCa patients. Second, selected targets were clinically tested by immunoblot, and the soluble E-cadherin fragment was detected for the first time in the urine of PCa patients. Third, the proteogenome landscape of these PCa patients was characterized, revealing 1665 mutant protein isoforms. Statistical analysis revealed 6 differentially abundant mutant protein isoforms in PCa patients. Analysis of the likely effects of mutations on protein function and PPIs involving the dysregulated mutant protein isoforms suggests a protective role of mutations HSPG2*Q1062H and VASN*R161Q and an adverse role of AMBP*A286G and CD55*S162L in PCa patients. This work originally characterized the urinary proteome, focusing on the proteogenome profile of PCa patients, which is usually overlooked in the analysis of PCa and body fluids. Combined analysis of mass spectrometry data using two different software packages was performed for the first time in the context of PCa, which increased the robustness of the data analysis. The application of proteogenomics to urine proteomic analysis can be very enriching in mutation-related diseases such as cancer.

Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach

“…Most of them are involved in binding processes (mostly protein binding) and originate from the circulating immunoglobulin complex, the external side of the plasma membrane and extracellular space (according to String-db.org, accessed on 7 April 2022, v11.5), as expected in a body fluid. To consolidate these results, we compared them with recent human urinary proteomics data from the literature ( Table S4 ) [ 15 , 16 , 17 ]. With respect to PCa1 vs. Cont1, four of six proteins have already been identified in the urine of PCa patients, namely retinol-binding protein 4 (RBP4).…”

“…Thus, RBP4 content may reflect an attempt by epithelial cells to counteract prostate carcinogenesis when testosterone acts as a promotor (as is the case in this study). The increase in RBP4 levels has already been detected in the urine of patients with PCa [ 15 ]. RBP4 levels decreased with age, likely indicating age-related hormonal changes that may have contributed to the lack of a significant correlation between RBP4 levels and prostate lesion score.…”

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

“…HSPG2 was also reported to regulate immune and stromal infiltration in glioma [ 19 ] and prostate cancer [ 20 ]. Lima et al performed a proteogenomics analysis and found that HSPG2-specific mutations played a protective role in prostate cancer [ 21 ]. So far, no studies have revealed the correlation of HSPG2 mutations with immunological features and ICI treatment efficacy in cancers.…”

Editorial: The Application of Proteogenomics to Urine Analysis for the Identification of Novel Biomarkers of Prostate Cancer: An Exploratory Study

“…Lima et al [ 3 ] used a combination of mass spectrometry and genomic data to identify proteins and genomic mutations that were co-expressed in urine samples from patients with prostate cancer compared with healthy controls. They identified several potential biomarkers that could be used for the early detection of PCa.…”