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Elife. 2018 Mar 20;7. pii: e32143. doi: 10.7554/eLife.32143.

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy.

Author information

1
Howard Hughes Medical Institute, Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, United States.
2
Sidney Kimmel Comprehensive Cancer Center, Baltimore, United States.
3
Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
4
Department of Pathology, Johns Hopkins University, Baltimore, United States.
5
Department of Pathology, University of Alabama at Birmingham, Birmingham, United States.
6
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States.
7
Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, United States.
8
Department of Pathology, Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
9
Department of Oncology, Johns Hopkins University, Baltimore, United States.
10
Division of Biostatistics and Bioinformatics, Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, United States.
11
Department of Pathology, AC Camargo Cancer Center, Sao Paulo, Brazil.
12
Department of Pathology, Osaka University, Osaka, Japan.
13
Department of Pathology, Hacettepe University, Ankara, Turkey.
14
Department of Urology, Johns Hopkins University, Baltimore, United States.
15
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, United States.
16
Department of Medicine, Stony Brook University, Stony Brook, United States.
17
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States.
18
Department of Forensic Medicine and Pathology, National Taiwan University Hospital, Taipei, Taiwan.
19
Masonic Cancer Center, University of Minnesota, Minneapolis, United States.
20
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, United States.
#
Contributed equally

Abstract

Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.

KEYWORDS:

bladder; cancer; cancer biology; chromosomes; genes; human; liquid biopsy; renal pelvis; ureter; urine

Conflict of interest statement

SS, CC, MR, LL, CD, YW, JC, DT, NS, JS, JP, LD, MP, IK, BA, AT, SB, CV, KF, DE, IC, LY, TB, AG, LD, RK, LD, CH, CS, RT, BY, TR, YP, RH, CT, KD, GN No competing interests declared, NP Founder of Personal Genome Diagnostics and PapGene and advises Sysmex-Inostics. These companies and others have licensed technologies from Johns Hopkins, of which BV, KK, and NP are inventors on a patent (U.S. 20140227705 A1) and receive royalties. The terms of these arrangements are managed by the university in accordance with its conflict of interest policies. Luis A Diaz: Member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. LAD holds equity in PapGene, Personal Genome Diagnostics (PGDx) and Phoremost. He is a paid consultant for Merck, PGDx and Phoremost. LAD is an inventor of licensed intellectual property related to technology for ctDNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University. These licenses and relationships are associated with equity or royalty payments to LAD. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. In addition, in the past 5 years, LAD has participated as a paid consultant for one-time engagements with Caris, Lyndra, Genocea Biosciences, Illumina and Cell Design Labs. KK Ken W Kinzler: Founder of Personal Genome Diagnostics and PapGene and advises Sysmex-Inostics. These companies and others have licensed technologies from Johns Hopkins, of which BV, KK, and NP are inventors on a patent (U.S. 20140227705 A1) and receive royalties. The terms of these arrangements are managed by the university in accordance with its conflict of interest policies. BV Bert Vogelstein: Founder of Personal Genome Diagnostics and PapGene and advises Sysmex-Inostics. These companies and others have licensed technologies from Johns Hopkins, of which BV, KK, and NP are inventors on a patent (U.S. 20140227705 A1) and receive royalties. The terms of these arrangements are managed by the university in accordance with its conflict of interest policies.

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