220 Chapter 8 Transrenal transport and direct local shedding of tumor-derived material Tumor-derived cfDNA Copy number aberrations Fragmentation profiles (Hydroxy)methylation Mutations Tumor-derived cfRNA Long noncoding RNAs Messenger RNAs Circular RNAs MicroRNAs Circulating nucleosomes Nucleosome positioning Histone modifications Cancer-associated proteins Protein levels Metabolites Glycosaminoglycans Exfoliated tumor cells Histological examination Molecular profiling Release of tumor-derived material in the bloodsream 2 1 Non-invasive cancer detection using urine biomarkers 3 Figure 2: Schematic illustration of urine as a rich source of biomarkers for cancer detection. Tumor-derived material is released into the bloodstream and ends up in the urine by transrenal transport. Locally shedded tumor-derived material also contributes to the total pool of urine biomarkers. Urine can easily be collected from individuals, allowing non-invasive cancer detection. cfDNA = cell-free DNA; cfRNA = cell-free RNA. Created with BioRender.com. 8.4.2 Cell-free DNA fragmentation patterns In both plasma and urine, circulating cfDNA predominantly exists in a bound state to histone proteins, since naked DNA is quickly degraded by DNA nucleases (85). The structural properties of cleaved cfDNA, such as fragment size distributions or fragmentend sequences, are non-random and associated with cancer (44, 86, 87). Characteristic fragmentation patterns can be measured in liquid biopsies (44), including urine (80, 88-90), as also described in Chapter 5. The analysis of fragmentation patterns allows the detection of a wide variety of cancer types within a single assay, as shown in plasma using the ‘DNA evaluation of fragments for early interception’ (DELFI) approach (91). Moreover, the tissue of origin can be identified by inferring nucleosome positioning near transcription start sites from the start and end points of cfDNA fragments (92). Using
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