Novel Urine-Based DNA Methylation Biomarkers for Urothelial Bladder Carcinoma Detection in Patients With Hematuria

According to GLOBOCAN data, bladder cancer (BC) is considered a major health problem that represents 3% of all cancer diagnoses. Urothelial bladder carcinoma (UBC) accounts for the vast majority (>90%) of BC cases with predominance of non-muscle invasive disease (Ta, Tis or T1) in 75% of patients while others show muscle invasion (T2-4).

In refereed population, UBC is usually diagnosed as a result of work-up for hematuria at a rate of 2-5% following an evaluation of asymptomatic microscopic hematuria, and, up to 5-15% of patients with macroscopic hematuria. Therefore, a timely prompt evaluation of hematuria can give to earlier diagnosis and better survival of UBC.

Currently, cystoscopy /cross sectional imaging are the gold standard tools for UBC diagnosis in patients with hematuria. Unfortunately, these costly, invasive and painful diagnostics could miss early, small/flat bladder lesions. Urine cytology has been proposed as a non-invasive alternative test with high specificity, however, it lacks sensitivity for diagnosis of low grade (LG) tumors.

Over the last decades, multiple researches have output different markers for UBC diagnosis. Based on their target of assessment, these markers include screening for soluble antigens (BTA-Stat, NMP-22, surviving, etc.), cell surface antigens (Cytokeratins and UroVysion), genomic markers (Cxbladder and Xpert) and urinary metabolomics (CRAT and SLC25A20). However, most of these markers are limited by unsatisfying diagnostic performance, high cost or lack of validation.

Several preliminary studies have shown that DNA methylation, a critical step in transcription regulation, is chemically stable and can be precisely quantified, making it an attractive marker for UBC detection. Both local and global DNA hypermethylation in BC specimens are usually associated with inactivation of tumor suppressor genes. These methylations changes could be effectively identified in urine sediments as well as tumor tissues.