Urine as an emerging liquid biopsy for prostate cancer biomarker detection

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Urine as an emerging liquid biopsy for prostate cancer biomarker detection

Current methods for PCa detection lack specificity

Prostate cancer (PCa) is the second most frequently diagnosed cancer and a major cause of death in men worldwide. Testing for prostate-specific antigen (PSA) in blood, the current gold standard for PCa screening has limitations. Other non-cancerous conditions can also result in elevated serum PSA levels. Manipulations of the prostate through DRE, biopsy, catheterization, and ejaculation can also result in increased PSA levels, resulting in poor specificity (1).

Prostate cancer facts

To improve detection and reduce the high death rate among PCa patients, finding new and specific biomarkers are necessary for early detection.

Urine as a promising sample type

Urine is an attractive sample type for PCa detection, as the sample contains information from several areas of the body. Studies have shown that there are various biomarker candidates for PCa in urine, including prostate cells, DNA, RNA, proteins, exosomes and other small molecules (1). One study concluded that first-void urine (initial urine flow) after DRE resulted in a clear increase in PCa biomarker levels of both cell pellets and exosomes (1).

PCa biomarkers definitions

Epigenomics - DNA methylation markers are attractive for PCa

Epigenomics is the study of reversible modifications of DNA or DNA-associated proteins, such as DNA methylation (2). Changes in DNA methylation are among the most frequent molecular alterations in human cancer. The most common (>90%) genetic alteration reported to date in PCa is the epigenetic silencing of the glutathione-S transferase P1 (GSTP1) gene, as a result of promotor hypermethylation (1). Other epigenetic alterations are also being investigated as biomarkers for PCa. DNA methylation is particularly interesting as the alterations remain stable in body fluids, such as urine and occur in well-defined regions, making it easier to detect by sensitive PCR-based assays (1).

Transcriptomics - miRNAs are exciting in cancer research

Urine based RNA-based biomarkers, including coding and non-coding transcripts and regulatory RNAs, such as miRNAs, are promising in cancer research. The most common urinary marker is Prostate cancer antigen 3 (PCA3), a prostate-specific long noncoding mRNA. The PCA3 gene is overexpressed in 95% of all primary PCa specimens and absent in benign prostate tissue and other tumor types, making it a relatively specific biomarker for the cancer type (1). Another highly specific RNA-based urinary biomarker for PCa is the TMPRSS2-ERG (transmembrane protease, serine 2 – E26 transformation specific (ETS) related oncogene ERG) fusion gene (1). Commercially available tests are available for PCA3 and TMPRSS2-ERG. While miRNAs are very stable and are detectable in body fluids such as urine, more studies need to be performed to investigate the connection between other RNA markers and PCa.

Proteomics – a novel approach for PCa research

The study of proteins, especially urinary proteins, has shown to be promising for non-invasive PCa detection. Many proteins have been suggested as candidate biomarkers, but no protein biomarkers have entered clinical use yet (1). Additional studies must be performed to better understand the potential and accuracy of proteins as a diagnostic biomarker for PCa.

Conclusion

The study of ''omics'' has great potential in PCa research. Several biomarker candidates have been identified in urine, offering new ways to screen for the cancer type. Urine sampling also presents advantages to other current testing methods as the process is easy, quick and non-invasive. To date, four urinary tests for PCa are commercially available:

PCa biomarkers graphics table

However, to use urine for clinical applications, the pre-analytical variation, including collection, transport and storage must be limited. Additionally, first-void urine has shown to be valuable for PCa detection, highlighting the potential need to accurately collect this fraction of urine. Novosanis' urine collection device, Colli-Pee®, allows for volumetric and standardize collection of firstvoid urine. The device architecture also enables immediate mixing with a preservative, improving sample stability.

Reference:

  1. Jordaens et. al, White Paper- Urine as an emerging liquid biopsy for prostate cancer biomarkers, May 2020
  2. PMID: 28476144