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. 2021 Jan 31;13(3):535.
doi: 10.3390/cancers13030535.

The Origin of Tumor DNA in Urine of Urogenital Cancer Patients: Local Shedding and Transrenal Excretion

Anouk E Hentschel  1   2 , Rianne van den Helder  1   3 , Nienke E van Trommel  3 , Annina P van Splunter  1 , Robert A A van Boerdonk  1 , Mignon D J M van Gent  4 , Jakko A Nieuwenhuijzen  2 , Renske D M Steenbergen  1
Affiliations

The Origin of Tumor DNA in Urine of Urogenital Cancer Patients: Local Shedding and Transrenal Excretion

Anouk E Hentschel et al. Cancers (Basel). .

Abstract

In urogenital cancers, urine as a liquid biopsy for non-invasive cancer detection holds great promise for future clinical application. Their anatomical position allows for the local shedding of tumor DNA, but recent data indicate that tumor DNA in urine might also result from transrenal excretion. This study aims to assess the origin of tumor-associated DNA in the urine of 5 bladder and 25 cervical cancer patients. Besides natural voided urine, paired urine samples were collected in which contact with the local tumor was circumvented to bypass local shedding. The latter concerned nephrostomy urine in bladder cancer patients, and catheter urine in cervical cancer patients. Methylation levels of GHSR, SST, and ZIC1 were determined using paired bladder tumor tissues and cervical scrapes as a reference. Urinary methylation levels were compared to natural voided urine of matched controls. To support methylation results, mutation analysis was performed in urine and tissue samples of bladder cancer patients. Increased methylation levels were not only found in natural voided urine from bladder and cervical cancer patients, but also in the corresponding nephrostomy and catheter urine. DNA mutations detected in bladder tumor tissues were also detectable in all paired natural voided urine as well as in a subset of nephrostomy urine. These results provide the first evidence that the suitability of urine as a liquid biopsy for urogenital cancers relies both on the local shedding of tumor cells and cell fragments, as well as the transrenal excretion of tumor DNA into the urine.

Keywords: biomarkers; liquid biopsy; methylation; molecular diagnostics; mutation; urine; urogenital neoplasms.

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Conflict of interest statement

Renske D.M. Steenbergen has a minority share in Self-screen BV, a spin-off company of Amsterdam UMC, location VUmc.

Figures

Figure 1
Figure 1
DNA methylation levels of markers GHSR (A), SST (B), and ZIC1 (C) in paired bladder tumor tissues (tissue, □), natural voided urine (bladder, ○), and nephrostomy urine (kidney, ∆) from five muscle-invasive bladder cancer patients, compared to natural voided urine from 25 gender- and age-matched controls. DNA methylation levels are represented by the log2-transformed Ct ratios. Boxplots show medians with the 25th and 75th percentile and whiskers range from the smallest to the largest value.
Figure 2
Figure 2
DNA methylation levels of markers GHSR (A), SST (B), and ZIC1 (C) in paired cervical scrapes, natural voided urine, and catheter urine from 25 cervical cancer patients, as well as in natural voided urine from 25 healthy female controls. DNA methylation levels are represented by the log2-transformed Ct ratios. Boxplots show medians with the 25th and 75th percentile and whiskers range from the smallest to the largest value.
Figure 3
Figure 3
Presence of DNA mutations in paired bladder tumor tissues (tissue), natural voided urine (bladder), and nephrostomy urine (kidney) from five muscle-invasive bladder cancer patients. The percentage (%) indicates the variant allele fraction.
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