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

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

Simeon U Springer #  1   2 , Chung-Hsin Chen #  3 , Maria Del Carmen Rodriguez Pena #  4   5 , Lu Li  6 , Christopher Douville  7 , Yuxuan Wang  1   2 , Joshua David Cohen  1   2 , Diana Taheri  4   8 , Natalie Silliman  1   2 , Joy Schaefer  1   2 , Janine Ptak  1   2 , Lisa Dobbyn  1   2 , Maria Papoli  1   2 , Isaac Kinde  1   2 , Bahman Afsari  9   10 , Aline C Tregnago  4 , Stephania M Bezerra  11 , Christopher VandenBussche  4 , Kazutoshi Fujita  12 , Dilek Ertoy  13 , Isabela W Cunha  11 , Lijia Yu  5 , Trinity J Bivalacqua  14 , Arthur P Grollman  15   16 , Luis A Diaz  17 , Rachel Karchin  7   9 , Ludmila Danilova  10   13 , Chao-Yuan Huang  3 , Chia-Tung Shun  18 , Robert J Turesky  19   20 , Byeong Hwa Yun  19   20 , Thomas A Rosenquist  15 , Yeong-Shiau Pu  3 , Ralph H Hruban  4 , Cristian Tomasetti  6   10 , Nickolas Papadopoulos  1   2 , Ken W Kinzler  1   2 , Bert Vogelstein  1   2 , Kathleen G Dickman  15   16 , George J Netto  4   5
Affiliations

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

Simeon U Springer et al. Elife. .

Erratum in

  • Correction: Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy.
    Springer SU, Chen CH, Rodriguez Pena MDC, Li L, Douville C, Wang Y, Cohen JD, Taheri D, Silliman N, Schaefer J, Ptak J, Dobbyn L, Papoli M, Kinde I, Afsari B, Tregnago AC, Bezerra SM, VandenBussche C, Fujita K, Ertoy D, Cunha IW, Yu L, Bivalacqua TJ, Grollman AP, Diaz LA, Karchin R, Danilova L, Huang CY, Shun CT, Turesky RJ, Yun BH, Rosenquist TA, Pu YS, Hruban RH, Tomasetti C, Papadopoulos N, Kinzler KW, Vogelstein B, Dickman KG, Netto GJ. Springer SU, et al. Elife. 2018 Nov 12;7:e43237. doi: 10.7554/eLife.43237. Elife. 2018. PMID: 30418154 Free PMC article.

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.

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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.

Figures

Figure 1.
Figure 1.. Schematic of the approach used to evaluate urinary cells in this study.
UroSEEK assay is designed to detect urothelial neoplasms that are in direct contact with urine (A) of variable pathologic stages originating in upper urinary tract (B) or bladder (C).
Figure 2.
Figure 2.. Flow diagram indicating the number of patients in the three cohorts evaluated in this study and summarizing the salient findings.
Cytology was performed on only a subset of the patients (see main text).
Figure 3.
Figure 3.. Fraction of mutations found in the ten-gene panel in 231 urinary cell samples assessed in the BC early detection cohort, 56 urinary cell samples assessed in the UTUC cohort, and 132 urinary cell samples assessed in the BC surveillance cohort.
Figure 4.
Figure 4.. Venn diagram showing the distribution of positive results for each of the three UroSEEK assays for the (A) BC early detection (B) UTUC and (C) BC surveillance cohorts.
URO = Ten gene panel, TERT = TERT promoter region, ANEU = Aneuploidy test.
Figure 5.
Figure 5.. Bar graphs of the lead time between a positive UroSEEK test and the detection of disease at the clinical level in the (A) BC early detection and (B) BC surveillance cohorts.
Figure 6.
Figure 6.. Bar graphs representing the performance of Cytology vs. UroSEEK in diagnosis of low- and high-grade urothelial neoplasms in the early detection and surveillance BC cohorts and the UTUC cohort.
See this image and copyright information in PMC

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