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

Author:

Springer Simeon U12ORCID,Chen Chung-Hsin3,Rodriguez Pena Maria Del Carmen45ORCID,Li Lu6ORCID,Douville Christopher7ORCID,Wang Yuxuan12ORCID,Cohen Joshua David12ORCID,Taheri Diana48,Silliman Natalie12,Schaefer Joy12,Ptak Janine12,Dobbyn Lisa12,Papoli Maria12,Kinde Isaac12,Afsari Bahman910,Tregnago Aline C4,Bezerra Stephania M11,VandenBussche Christopher4,Fujita Kazutoshi12,Ertoy Dilek13,Cunha Isabela W11,Yu Lijia5ORCID,Bivalacqua Trinity J14,Grollman Arthur P1516,Diaz Luis A17,Karchin Rachel79,Danilova Ludmila1013,Huang Chao-Yuan3,Shun Chia-Tung18,Turesky Robert J1920,Yun Byeong Hwa1920,Rosenquist Thomas A15,Pu Yeong-Shiau3,Hruban Ralph H4,Tomasetti Cristian610,Papadopoulos Nickolas12,Kinzler Ken W12,Vogelstein Bert12ORCID,Dickman Kathleen G1516ORCID,Netto George J45ORCID

Affiliation:

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

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.

Funder

National Science Council

National Institutes of Health

Henry and Marsha Laufer

John Templeton Foundation

Conrad N. Hilton Foundation

Ludwig Institute for Cancer Research

Sol Goldman Pancreatic Research Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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