Trends in urine biomarker discovery for urothelial bladder cancer: DNA, RNA, or protein?

Abstract

Urothelial bladder cancer is a complex disease displaying a landscape of heterogenous molecular subtypes, mutation profiles and clinical presentations. Diagnosis and surveillance rely on flexible cystoscopy which has high accuracy, albeit accompanied by a high-cost burden for healthcare providers and discomfort for patients. Advances in "omic" technologies and computational biology have provided insights into the molecular pathogenesis of bladder cancer and provided powerful tools to identify markers for disease detection, risk stratification, and predicting responses to therapy. To date, numerous attempts have been made to discover and validate diagnostic biomarkers that could be deployed as an adjunct to the cystoscopic diagnosis and long-term surveillance of bladder cancer. We report a comprehensive literature analysis using PubMed to assess the changing trends in investigating DNA, RNA, or proteins as diagnostic urinary biomarkers over a period of 5 decades: 1970-2020. A gradual shift has been observed in research away from protein biomarkers to nucleic acids including different classes of RNA, and DNA methylation and mutation markers. Until 2000, publications involving protein biomarker discovery constituted 87% of the total number of research articles with DNA comprising 6% and RNA 7%. Since 2000 the proportion of protein biomarker articles has fallen to 40%, and DNA and RNA studies increased to 32% and 28%, respectively.Clearly research focus, perhaps driven by technological innovation, has shifted from proteins to nucleic acids. We optimistically hypothesise that, following thorough validation, a clinically useful detection test for bladder cancer based on a panel of DNA or RNA markers could become reality within 5-10 years.

Urine biomarkers in cancer detection: A systematic review of preanalytical parameters and applied methods

“…The most common urological cancers are prostate cancer (PCa) and bladder cancer (mostly, urothelial cancer) 21 (Table 1). Previous literature reviews clearly demonstrate the clinical utility of urine‐based biomarkers for urothelial and PCa 22‐26 . Several FDA‐approved or CLIA tests are available for urothelial and PCa (Table 3).…”

“…Previous literature reviews clearly demonstrate the clinical utility of urine-based biomarkers for urothelial and PCa. [22][23][24][25][26] Several FDA-approved or CLIA tests are available for urothelial and PCa (Table 3). Therefore, only findings about preanalytics will be further discussed in more detail.…”

Biomarkers of Bladder Cancer: Cell-Free DNA, Epigenetic Modifications and Non-Coding RNAs

“…As presented in the further examples, seen in Table 4 ., most miRNA gene expressions have been found to initiate and promote tumor progression. miRNAs may serve as potential diagnostic and prognostic indicators [ 115 , 116 ]. In quantitative reverse transcriptase polymerase chain reaction, microarray can be used as prognostic analysis.…”

“…A novel class of RNA is a single-stranded circRNA that is stable, with a long half-life, and can be found in urine [ 116 ]. Their role is in the regulation of gene expression via microRNA inhibition.…”

Use of Multiple Machine Learning Approaches for Selecting Urothelial Cancer-Specific DNA Methylation Biomarkers in Urine

“…Due to the direct contact of urine and urothelium, urothelial cancer cells or cancer cell components are released into the urine. Numerous approaches have been carried out to identify UCa by the use of urinary molecular biomarkers [5][6][7][8][9][10][11]. However, none of the used approaches or identified biomarkers have been included in a clinical routine or even in guidelines, possibly due to the complex nature of molecular signatures that, in part, require a specialized readout software [10,11].…”