Abstract
In many cancer types, the expression and function of ∼22 nucleotide-long microRNAs (miRNA) is deregulated. Mature miRNAs can be stably detected in extracellular vesicles (EVs) in biofluids, therefore they are considered to have great potential as biomarkers. In the present study, we investigated whether miRNAs have a distinct expression pattern in urine-EVs of prostate cancer (PCa) patients compared to control males. By next generation sequencing, we determined the miRNA expression in a discovery cohort of 4 control men and 9 PCa patients. miRNAs were validated by using a stemloop RT-PCR in an independent cohort of 74 patients (26 control and 48 PCa-patients). Whereas standard mapping protocols identified > 10 PCa associated miRNAs in urinary EVs, miR-21, miR-375 and miR-204 failed to robustly discriminate for disease in a validation study with RT-PCR-detection of mature miRNA sequences. In contrast, we observed that miRNA isoforms (isomiRs) with 3′ end modifications were highly discriminatory between samples from control men and PCa patients. Highly differentially expressed isomiRs of miR-21, miR-204 and miR-375 were subsequently validated in an independent group of 74 patients. Receiver-operating characteristic analysis was performed to evaluate the diagnostic performance of three isomiRs, resulting in a 72.9% sensitivity with a high (88%) specificity and an area under the curve (AUC) of 0.866. In comparison, prostate specific antigen had an AUC of 0.707 and measuring the mature form of these miRNAs yielded a lower 70.8% sensitivity and 72% specificity (AUC 0.766). We propose that isomiRs may carry discriminatory information which is useful to generate stronger biomarkers.
Highlights
Prostate cancer is the most common form of human cancer, with the second cancer related cause of death in Western males [1]
The most abundant miRNA in urinary extracellular vesicles (EVs) of all patients was miR‐10b‐5p (Supplementary Table S1). miR‐10b is highly expressed in various tissues, including kidney and has previously been observed by others in urine EVs, and in EVs secreted by the PC‐3 prostate cancer cell line [25, 26]
In the present study we demonstrate that urine EVs can be used for minimally invasive tests to detect prostate cancer (PCa) in suspect individuals
Summary
Prostate cancer is the most common form of human cancer, with the second cancer related cause of death in Western males [1]. While elevated serum PSA levels above 4.0 ng/ml increases the risk of PCa significantly [3], increased PSA levels is not specific for PCa. As a consequence, about 70–80% of the prostate‐tissue biopsies are unnecessary [4, 5]. Due to the multifocal growth of PCa within the prostate, there is a chance that PCa is not detected even when multiple prostate‐tissue biopsies are taken and accurately examined. Apart from the highly invasive nature of taking tumor biopsies, patients may develop infection (sepsis) as a consequence of the procedure [7]. This is becoming a concern regarding the increased antimicrobial resistance, despite the use of pre‐biopsy antimicrobial prophylaxis [7]. Minimally‐invasive alternatives for accurate detection of PCa are needed
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