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 IyerBernard H. Bochner, Jonathan A. Coleman, David B. Solit

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)967-976
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number3
DOIs
StatePublished - Feb 1 2019

Fingerprint

Urinary Bladder
Carcinoma
Neoplasms
Urinary Bladder Neoplasms
Hereditary Nonpolyposis Colorectal Neoplasms
Recurrence
Tumor Burden
Research Design
Mutation
DNA
N-methylsuccinimide

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Audenet, F., Isharwal, S., Cha, E. K., Donoghue, M. T. A., Drill, E. N., Ostrovnaya, I., ... Solit, D. B. (2019). Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clinical Cancer Research, 25(3), 967-976. https://doi.org/10.1158/1078-0432.CCR-18-2039

Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. / Audenet, François; Isharwal, Sumit; Cha, Eugene K.; Donoghue, Mark T.A.; Drill, Esther N.; Ostrovnaya, Irina; Pietzak, Eugene J.; Sfakianos, John P.; Bagrodia, Aditya; Murugan, Paari; Dalbagni, Guido; Donahue, Timothy F.; Rosenberg, Jonathan E.; Bajorin, Dean F.; Arcila, Maria E.; Hechtman, Jaclyn F.; Berger, Michael F.; Taylor, Barry S.; Al-Ahmadie, Hikmat; Iyer, Gopa; Bochner, Bernard H.; Coleman, Jonathan A.; Solit, David B.

In: Clinical Cancer Research, Vol. 25, No. 3, 01.02.2019, p. 967-976.

Research output: Contribution to journalArticle

Audenet, F, Isharwal, S, Cha, EK, Donoghue, MTA, Drill, EN, Ostrovnaya, I, Pietzak, EJ, Sfakianos, JP, Bagrodia, A, Murugan, P, Dalbagni, G, Donahue, TF, Rosenberg, JE, Bajorin, DF, Arcila, ME, Hechtman, JF, Berger, MF, Taylor, BS, Al-Ahmadie, H, Iyer, G, Bochner, BH, Coleman, JA & Solit, DB 2019, 'Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma', Clinical Cancer Research, vol. 25, no. 3, pp. 967-976. https://doi.org/10.1158/1078-0432.CCR-18-2039
Audenet, François ; Isharwal, Sumit ; Cha, Eugene K. ; Donoghue, Mark T.A. ; Drill, Esther N. ; Ostrovnaya, Irina ; Pietzak, Eugene J. ; Sfakianos, John P. ; Bagrodia, Aditya ; Murugan, Paari ; Dalbagni, Guido ; Donahue, Timothy F. ; Rosenberg, Jonathan E. ; Bajorin, Dean F. ; Arcila, Maria E. ; Hechtman, Jaclyn F. ; Berger, Michael F. ; Taylor, Barry S. ; Al-Ahmadie, Hikmat ; Iyer, Gopa ; Bochner, Bernard H. ; Coleman, Jonathan A. ; Solit, David B. / Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 3. pp. 967-976.
@article{87d62c79da4a41bd9d51d5de07f26ad8,
title = "Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma",
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.",
author = "Fran{\cc}ois Audenet and Sumit Isharwal and Cha, {Eugene K.} and Donoghue, {Mark T.A.} and Drill, {Esther N.} and Irina Ostrovnaya and Pietzak, {Eugene J.} and Sfakianos, {John P.} and Aditya Bagrodia and Paari Murugan and Guido Dalbagni and Donahue, {Timothy F.} and Rosenberg, {Jonathan E.} and Bajorin, {Dean F.} and Arcila, {Maria E.} and Hechtman, {Jaclyn F.} and Berger, {Michael F.} and Taylor, {Barry S.} and Hikmat Al-Ahmadie and Gopa Iyer and Bochner, {Bernard H.} and Coleman, {Jonathan A.} and Solit, {David B.}",
year = "2019",
month = "2",
day = "1",
doi = "10.1158/1078-0432.CCR-18-2039",
language = "English (US)",
volume = "25",
pages = "967--976",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma

AU - Audenet, François

AU - Isharwal, Sumit

AU - Cha, Eugene K.

AU - Donoghue, Mark T.A.

AU - Drill, Esther N.

AU - Ostrovnaya, Irina

AU - Pietzak, Eugene J.

AU - Sfakianos, John P.

AU - Bagrodia, Aditya

AU - Murugan, Paari

AU - Dalbagni, Guido

AU - Donahue, Timothy F.

AU - Rosenberg, Jonathan E.

AU - Bajorin, Dean F.

AU - Arcila, Maria E.

AU - Hechtman, Jaclyn F.

AU - Berger, Michael F.

AU - Taylor, Barry S.

AU - Al-Ahmadie, Hikmat

AU - Iyer, Gopa

AU - Bochner, Bernard H.

AU - Coleman, Jonathan A.

AU - Solit, David B.

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060149623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060149623&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-2039

DO - 10.1158/1078-0432.CCR-18-2039

M3 - Article

C2 - 30352907

AN - SCOPUS:85060149623

VL - 25

SP - 967

EP - 976

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -