Current and emerging bladder cancer biomarkers with an emphasis on urine biomarkers

ABSTRACT

Introduction: Bladder cancer detection typically requires unpleasant and costly cystoscopy, a procedure potentially harmful and often accompanied by variable adverse effects. The use of urine analysis as a noninvasive method is of great scientific interest since it is enriched in tumor-related proteins, DNA and RNA which can provide a molecular landscape with multiple alterations identified in bladder cancer.

Areas covered: Current sensitivity, specificity and diagnostic accuracy of FDA approved urine-based assays are still suboptimal with none of them routinely used by clinics. The recent introduction of RNA/DNA based bladder cancer tests, some of them commercially available, establishes a promising new horizon of clinical applicability.

Expert opinion: There is growing evidence toward the use of minimally invasive ‘liquid biopsies’ to identify biomarkers in urothelial malignancy. Urine has been identified as an optimal noninvasive source of proteins, DNA and RNA; therefore, it has been identified as a type of liquid biopsy likely to soon be routine clinical practice. Cell-free proteins and peptides, exosomes, cell-free DNA, methylated DNA and DNA mutations, circulating tumor cells, miRNA, lncRNA, rtRNA and mRNAs, have been assessed in urine specimens. However, lack of well-designed multicenter clinical studies remain as important limitation, and therefore, precludes their use in clinical practice.

KEYWORDS:

• Urinary biomarkers
• bladder cancer
• liquid biopsy
• microRNA
• exosomes
• cell-free DNA
• artificial intelligence

Article highlights

• Relevant studies investigating the diagnostic role of urinary biomarkers are reviewed in the context of either primary or recurrent bladder cancer management.

• Protein-derived urinary biomarkers but also those originated in tumor DNA or RNA shed by tumor cells into the urine are currently gaining clinical relevance.

• DNA and RNA derived genetic material released by tumor cells into the urine harbors a wide range of mutations and other molecular alterations identified in the original tumor.

• Most urinary biomarkers have been developed to monitor bladder tumor recurrences after standard therapy, and therefore are surveillance related.

• The expanded research landscape based on the analysis of urinary DNA and RNA alterations open unprecedented potential clinical applications, from the surveillance of a recurrent tumor to primary diagnosis, prognosis or to assess potential therapeutic targets.

• The rationale for urine-derived ‘liquid biopsy’ lies in the understanding of molecular biology and pathway alterations in bladder cancer, which results in the identification of multiple genetic steps that define the disease.

Author Contributions

ALB, LC, TG, RM, AC, MS, FM conception and design. ALB, LC, RM, AC drafting the manuscript. ALB, LC, RM, AC, MS, FM, AB, MS, MRR critical revision of the manuscript. All authors have approved the final version of the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.