Trans-Renal Cell-Free Tumor DNA for Urine-Based Liquid Biopsy of Cancer

Abstract

Cancer biomarkers are a promising tool for cancer detection, personalization of therapy, and monitoring of treatment response or recurrence. "Liquid biopsy" commonly refers to minimally invasive or non-invasive sampling of a bodily fluid (i.e., blood, urine, saliva) for detection of cancer biomarkers such as circulating tumor cells or cell-free tumor DNA (ctDNA). These methods offer a means to collect frequent tumor assessments without needing surgical biopsies. Despite much progress with blood-based liquid biopsy approaches, there are limitations-including the limited amount of blood that can be drawn from a person and challenges with collecting blood samples at frequent intervals to capture ctDNA biomarker kinetics. These limitations are important because ctDNA is present at extremely low levels in plasma and there is evidence that measuring ctDNA biomarker kinetics over time can be useful for clinical prediction. Additionally, blood-based assays require access to trained phlebotomists and often a trip to a healthcare facility. In contrast, urine is a body fluid that can be self-collected from a patient's home, at frequent intervals, and mailed to a laboratory for analysis. Multiple reports indicate that fragments of ctDNA pass from the bloodstream through the kidney's glomerular filtration system into the urine, where they are known as trans-renal ctDNA (TR-ctDNA). Accumulating studies indicate that the limitations of blood based ctDNA approaches for cancer can be overcome by measuring TR-ctDNA. Here, we review current knowledge about TR-ctDNA in urine as a cancer biomarker approach, and discuss its clinical potential and open questions in this research field.

Keywords: biomarker; cancer; cell-free DNA; circulating tumor DNA; ctDNA; liquid biopsy; trans-renal; urine.

FIGURE 1

Current model of formation of trans-renal ctDNA. The drawing on the left provides a conceptualized overview of the process of ctDNA generation and its transit to the urine. The drawing on the right provides a more detailed conceptualization of the presumed transit of cell-free DNA through the glomerular barrier of the kidney. Abbreviation used in the drawing: cfDNA, cell-free DNA. The artwork in this figure was created by Mesa Schumacher, M.A.