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. 2016 Aug;24(8):1167-74.
doi: 10.1038/ejhg.2015.281. Epub 2016 Jan 13.

Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA

Fiona S Togneri  1 , Douglas G Ward  2 , Joseph M Foster  3 , Adam J Devall  2 , Paula Wojtowicz  1 , Sofia Alyas  1 , Fabiana Ramos Vasques  1 , Assa Oumie  3 , Nicholas D James  4 , K K Cheng  5 , Maurice P Zeegers  6 , Nayneeta Deshmukh  2 , Brendan O'Sullivan  7 , Philippe Taniere  7 , Karen G Spink  3 , Dominic J McMullan  1 , Mike Griffiths  1 , Richard T Bryan  2
Affiliations

Genomic complexity of urothelial bladder cancer revealed in urinary cfDNA

Fiona S Togneri et al. Eur J Hum Genet. 2016 Aug.

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.

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Conflict of interest statement

RTB has previously contributed to an advisory board for Olympus Medical Systems with regard to narrow band imaging cystoscopy. JMF, AO and KGS are all paid employees of Affymetrix UK Ltd and hold shares in Affymetrix (NASDAQ: AFFX). The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Example of genomic profiles from DNAs extracted from FFPE and cellular and cfDNA from the urine from patient 23 with a stage G2 pT1 NMIBC. Comparison of profiles shows consistent aberrations identified in all three samples (red=loss, blue=gain and yellow=LOH). Aberrations from all three sources show homozygous loss at 9p21.3 including CDKN2A/B; listed in the TARGET database. Biallelic inactivation of CDKN2A/B may predict response to CDK4/6 inhibitors for this patient.
Figure 2
Figure 2
By examining the BAF plots of the SNP probes for patient 13, the highest aberrant cell load for this patient is observed in cfDNA (greatest separation in bottom plots). The number of TARGET aberrations (3; amplifications of CCND1 (may predict sensitivity to CDK4/6 inhibitors), MDM2 (may predict sensitivity to Nutlins and MDM2 inhibitors) and CDK4 (may predict sensitivity to CDK4/6 inhibitors)) is consistent across all sample types. A degree of tumour heterogeneity is also clear.
Figure 3
Figure 3
Patient 7. DNAs extracted from urine provide improved quality genomic data and clearer characterisation of the tumour profile than DNA from FFPE tumour material, despite repeat slides being cut and extracted. Two TARGET aberrations (CCND1 amplification (may predict sensitivity to CDK4/6 inhibitors) and CCNE1 amplification (may predict sensitivity to CDK2 inhibitors)) were observed in both cfDNA and urinary cellular DNA however none of these aberrations were independently called in two separate DNAs from FFPE tumour material.
Figure 4
Figure 4
Genomic profile from urinary cfDNA of non-UBC patient with prostatic duct carcinoma confirms that detection of a tumour genome in urinary DNA is not bladder cancer specific. Red lines highlight regions of CN loss with resulting loss of heterozygosity indicated by yellow colouring of the chromosomal regions. Blue and red arrows indicate sub-microscopic germline CN gains and losses, respectively.
See this image and copyright information in PMC

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