Unlocking the potential of tumor-derived DNA in urine for cancer detection: methodological challenges and opportunities

High cancer mortality rates and the rising cancer burden worldwide drive the development of innovative methods in order to advance cancer diagnostics. Urine contains a viable source of tumor material and allows for self-collection from home. Biomarker testing in this liquid biopsy represents a novel approach that is convenient for patients and can be effective in detecting cancer at a curable stage. Here, we set out to provide a detailed overview of the rationale behind urine-based cancer detection, with a focus on non-urological cancers, and its potential for cancer diagnostics. Moreover, evolving methodological challenges and untapped opportunities for urine biomarker testing are discussed, particularly emphasizing DNA methylation of tumor-derived cell-free DNA. We also provide future recommendations for technical advancements in urine-based cancer detection and elaborate on potential mechanisms involved in the transrenal transport of cell-free DNA.