Deregulated molecular genetic pathways in urinary bladder cancer with the importance of molecular biomarkers in diagnosis and follow-up- A comprehensive and updated review

Abstract

This article reviews and compares various currently available non-invasive, molecular biomarker-based tests for bladder cancer (BC) detection, and evaluates other potential molecules that may be used for BC diagnosis and surveillance. Currently, urinary cytology and periodic cystoscopies are clinically recommended for the diagnosis and monitoring of BC. Though highly specific, urinary cytology lacks sensitivity, whereas cystoscopies are invasive tests that are uncomfortable for the patient. Molecular biomarkers associated with BC progression form the basis for various available non-invasive tests. Urinary proteins like NMP22, MCM5 and Human complement factor-H related protein (BTA) are detected by ELISA/Immunochromatographic assay devices (NMP22, BTA, ADXBLADDER). Chromosomal abnormalities reported in BC -aneuploidy in chromosomes 3, 7, and 17 and deletions in chromosome 9- are detected by the Fluorescence in situ Hybridization based UroVysion test. Tumor antigens like sulfated mucin glycoproteins and glycosylated CEA help to light up urothelial carcinoma cells exfoliated into urine (uCyt+). Mutations in TERTp, FGFR3, KRAS, HRAS, TP53, CDKN2A, ERBB2 and PIK3CA contribute to BC progression and these are detected in tumor DNA by RT-qPCR, NGS and/or Sanger sequencing-based assays (Uromonitor, UroSEEK, AssureMDX). mRNA levels of genomic markers frequently deregulated in BC like IGFBP5, HOXA13, MDK, CDC2, CXCR5, IGF2, ABL1, CRH, UPK1B and ANXA10 are assesed by CxBladder and Xpert Bladder Cancer Monitor. BC associated changes in DNA methylation are detected by real time PCR and NGS based assays (EpiCheck, UroMark, AssureMDX). These tests have not yet been formally indicted into clinical practice but can serve as sensitive indicators for early diagnosis, disease monitoring, and treatment response in BC. Keywords: bladder cancer, biomarkers, non-invasive tests, molecular events in bladder cancer, genetic changes in bladder cancer