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.
Highlights
Urine tests looking at genomic copy number (CN) include the FISH-based UroVysion test (Abbott, Des Plaines, IL, USA; FDA-approved Urothelial bladder cancer (UBC) diagnosis),12 which uses individual exfoliated tumour cells isolated from urine, and the CGH-based BCA-1 test, which uses DNA extracted from these exfoliated cells
We demonstrate that the complex genomics and important clinically actionable aberrations that are evident in formalin-fixed paraffin-embedded (FFPE) tumour material are echoed in urinary DNAs, and that the tumour genome is enriched in cell-free DNA (cfDNA) compared with cellular DNA
We demonstrate the clinical utility of urinary DNA from UBC patients and support the hypothesis that cfDNA from urine provides an improved resource for non-invasive genomic profiling of UBC when compared with urine cellular DNA
Summary
Urothelial bladder cancer (UBC) is the seventh most common cancer in Western societies with a rising global incidence. Disease management poses numerous challenges because of the following: (i) the propensity for non-muscle-invasive bladder cancer (NMIBC) to recur, necessitating long-term surveillance; (ii) a variable risk of NMIBC progression, associated with poor 5-year survival; (iii) a lack of proven biomarker prognosticators to identify those subsets of patients who will suffer tumour recurrence, progression and death; and (iv) the radical therapies required to treat muscle-invasive disease (MIBC). UBCs are highly heterogeneous in their clinical characteristics and this is mirrored in their genomics, characteristics of which traverse conventional grade and stage groupings.5Typically, genomic aberrations in tumours have been characterised using formalin-fixed paraffin-embedded (FFPE) or fresh-frozen tumour tissue, with such analyses elucidating promising biomarkers and suggesting genomic signatures with potential to influence future therapeutic interventions. Identifying such genomic complexity in a non-invasive manner could be highly advantageous for facilitating the diagnosis, treatment and surveillance of patients with NMIBC or MIBC.9,10Genetic changes in UBCs have previously been investigated noninvasively using genetic material present in the urine. Genomic aberrations in tumours have been characterised using formalin-fixed paraffin-embedded (FFPE) or fresh-frozen tumour tissue, with such analyses elucidating promising biomarkers and suggesting genomic signatures with potential to influence future therapeutic interventions.. Genomic aberrations in tumours have been characterised using formalin-fixed paraffin-embedded (FFPE) or fresh-frozen tumour tissue, with such analyses elucidating promising biomarkers and suggesting genomic signatures with potential to influence future therapeutic interventions.6–8 Identifying such genomic complexity in a non-invasive manner could be highly advantageous for facilitating the diagnosis, treatment and surveillance of patients with NMIBC or MIBC.. A small number of studies have investigated urinary cfDNA for UBC analysis with mixed results, and it has previously been suggested that due to its origin, cfDNA may be enriched for tumour-specific biomarkers with reduced contamination from germline DNA of non-cancerous cells.
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