Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA

Abstract

Urothelial bladder cancers (UBCs) have heterogeneous clinical characteristics that are mirrored in their diverse genomic profiles. Genomic profiling of UBCs has the potential to benefit routine clinical practice by providing prognostic utility above and beyond conventional clinicopathological factors, and allowing for prediction and surveillance of treatment responses. Urinary DNAs representative of the tumour genome provide a promising resource as a liquid biopsy for non-invasive genomic profiling of UBCs. We compared the genomic profiles of urinary cellular DNA and cell-free DNA (cfDNA) from the urine with matched diagnostic formalin-fixed paraffin-embedded tumour DNAs for 23 well-characterised UBC patients. Our data show urinary DNAs to be highly representative of patient tumours, allowing for detection of recurrent clinically actionable genomic aberrations. Furthermore, a greater aberrant load (indicative of tumour genome) was observed in cfDNA over cellular DNA (P<0.001), resulting in a higher analytical sensitivity for detection of clinically actionable genomic aberrations (P<0.04) when using cfDNA. Thus, cfDNA extracted from the urine of UBC patients has a higher tumour genome burden and allows greater detection of key genomic biomarkers (90%) than cellular DNA from urine (61%) and provides a promising resource for robust whole-genome tumour profiling of UBC with potential to influence clinical decisions without invasive patient interventions.

Cell-free DNA as a diagnostic marker for cancer: current insights

“…These studies are important because they demonstrated the feasibility of NGS approaches on cfDNA in urine,85 even presenting a higher tumor genome burden in the cell-free fraction than in the cell sediment 84. All these results indicate further applications of ucfDNA in tumors.…”

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer

“…However, even when excluding clinically metastatic patients likely to have a very low or absent tumor burden (e.g., those with pathologic lymph node disease), there remained some plasma cfDNA samples from patients with metastasis that yielded no ctDNA evidence. Our assay was also relatively uninformative in the localized setting, although the availability of tumor tissue collected at transurethral resection (or cystectomy) and urinebased biomarkers reduce the rationale for pursuing plasma ctDNA in this setting (27,41). Nevertheless, future studies seeking to capture somatic information from all patients with metastasis could augment targeted panel sequencing with ddPCR for patient-specific mutations identified through archival tissue analyses or for recurrent hotspot mutations (e.g., in PI3KCA or TERT), as has been applied successfully to patients with clinically localized bladder cancer (27,29).…”

A field guide for cancer diagnostics using cell‐free DNA: From principles to practice and clinical applications

“…Of note, analyzing tyrosine kinase inhibitor‐resistance in NSCLC patients indicated by the EGFR p.T790M mutation is currently the only application for liquid biopsy in routine diagnostics. The general feasibility of this approach was demonstrated not only in clinical studies, but also in first studies related to routine diagnostics, and some reports showed that the resistance‐conferring mutation was often detectable in ctDNA prior to clinical progression . Although a low amount of ctDNA copies may be close to noise, data in osimertinib treated, EGFR p.T790M‐positive NSCLC patients indicated response even with less than 10 DNA copies per milliliter plasma .…”