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Precision Medicine and Imaging

Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma

François Audenet, Sumit Isharwal, Eugene K. Cha, Mark T.A. Donoghue, Esther N. Drill, Irina Ostrovnaya, Eugene J. Pietzak, John P. Sfakianos, Aditya Bagrodia, Paari Murugan, Guido Dalbagni, Timothy F. Donahue, Jonathan E. Rosenberg, Dean F. Bajorin, Maria E. Arcila, Jaclyn F. Hechtman, Michael F. Berger, Barry S. Taylor, Hikmat Al-Ahmadie, Gopa Iyer, Bernard H. Bochner, Jonathan A. Coleman and David B. Solit
François Audenet
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for François Audenet
  • For correspondence: francois.audenet@gmail.comcolemanj@mskcc.orgsolitd@mskcc.org
Sumit Isharwal
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Eugene K. Cha
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Mark T.A. Donoghue
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Esther N. Drill
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Irina Ostrovnaya
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Eugene J. Pietzak
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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John P. Sfakianos
Department of Urology, Mount Sinai Hospital, New York, New York.
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Aditya Bagrodia
Department of Urology, UT Southwestern Medical Center, Dallas, Texas.
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Paari Murugan
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota.
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Guido Dalbagni
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Timothy F. Donahue
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jonathan E. Rosenberg
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Dean F. Bajorin
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Maria E. Arcila
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jaclyn F. Hechtman
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Michael F. Berger
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Barry S. Taylor
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Hikmat Al-Ahmadie
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Gopa Iyer
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.Weil Cornell Medical College, New York, New York.
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Bernard H. Bochner
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.Weil Cornell Medical College, New York, New York.
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Jonathan A. Coleman
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: francois.audenet@gmail.comcolemanj@mskcc.orgsolitd@mskcc.org
David B. Solit
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.Weil Cornell Medical College, New York, New York.
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  • For correspondence: francois.audenet@gmail.comcolemanj@mskcc.orgsolitd@mskcc.org
DOI: 10.1158/1078-0432.CCR-18-2039 Published February 2019
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Abstract

Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.

Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.

Results: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.

Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.

This article is featured in Highlights of This Issue, p. 897

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received June 27, 2018.
  • Revision received August 20, 2018.
  • Accepted October 19, 2018.
  • Published first October 23, 2018.
  • ©2018 American Association for Cancer Research.
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Clinical Cancer Research: 25 (3)
February 2019
Volume 25, Issue 3
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Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma
François Audenet, Sumit Isharwal, Eugene K. Cha, Mark T.A. Donoghue, Esther N. Drill, Irina Ostrovnaya, Eugene J. Pietzak, John P. Sfakianos, Aditya Bagrodia, Paari Murugan, Guido Dalbagni, Timothy F. Donahue, Jonathan E. Rosenberg, Dean F. Bajorin, Maria E. Arcila, Jaclyn F. Hechtman, Michael F. Berger, Barry S. Taylor, Hikmat Al-Ahmadie, Gopa Iyer, Bernard H. Bochner, Jonathan A. Coleman and David B. Solit
Clin Cancer Res February 1 2019 (25) (3) 967-976; DOI: 10.1158/1078-0432.CCR-18-2039

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Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma
François Audenet, Sumit Isharwal, Eugene K. Cha, Mark T.A. Donoghue, Esther N. Drill, Irina Ostrovnaya, Eugene J. Pietzak, John P. Sfakianos, Aditya Bagrodia, Paari Murugan, Guido Dalbagni, Timothy F. Donahue, Jonathan E. Rosenberg, Dean F. Bajorin, Maria E. Arcila, Jaclyn F. Hechtman, Michael F. Berger, Barry S. Taylor, Hikmat Al-Ahmadie, Gopa Iyer, Bernard H. Bochner, Jonathan A. Coleman and David B. Solit
Clin Cancer Res February 1 2019 (25) (3) 967-976; DOI: 10.1158/1078-0432.CCR-18-2039
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