TY - JOUR
T1 - The origin of tumor DNA in urine of urogenital cancer patients
T2 - Local shedding and transrenal excretion
AU - Hentschel, Anouk E.
AU - van den Helder, Rianne
AU - van Trommel, Nienke E.
AU - van Splunter, Annina P.
AU - van Boerdonk, Robert A.A.
AU - van Gent, Mignon D.J.M.
AU - Nieuwenhuijzen, Jakko A.
AU - Steenbergen, Renske D.M.
N1 - Funding Information: This research was funded by the Hanarth Foundation and Weijerhorst Foundation, who provided financial support for the conduct of the research. The funders had no role in the design of the study; in the collection, analysis or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.The authors would like to thank Birgit I. Lissenberg-Witte for providing statistical support. Funding Information: Funding: This research was funded by the Hanarth Foundation and Weijerhorst Foundation, who provided financial support for the conduct of the research. The funders had no role in the design of the study; in the collection, analysis or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Liquid biopsy
KW - Methylation
KW - Molecular diagnostics
KW - Mutation
KW - Urine
KW - Urogenital neoplasms
UR - http://www.scopus.com/inward/record.url?scp=85100030299&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers13030535
DO - https://doi.org/10.3390/cancers13030535
M3 - Article
C2 - 33572525
SN - 2072-6694
VL - 13
SP - 1
EP - 11
JO - Cancers
JF - Cancers
IS - 3
M1 - 535
ER -