Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets

Eugene J. Pietzak, Aditya Bagrodia, Eugene K. Cha, Esther N. Drill, Gopa Iyer, Sumit Isharwal, Irina Ostrovnaya, Priscilla Baez, Qiang Li, Michael F. Berger, Ahmet Zehir, Nikolaus Schultz, Jonathan E. Rosenberg, Dean F. Bajorin, Guido Dalbagni, Hikmat Al-Ahmadie, David B. Solit, Bernard H. Bochner

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Background Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. Objective To identify genetic alterations with potential clinical implications in NMIBC. Design, setting, and participants Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. Outcome measurements and statistical analysis Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. Results and limitations TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p < 0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval: 1.51–6.51, p = 0.002). Conclusions Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. Patient summary Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests. High-grade nonmuscle invasive bladder cancer has high rates of DNA damage repair gene alterations, mutational burden, and actionable alterations, making trials of novel targeted agents and immunotherapies warranted. ARID1A mutations are associated with recurrence after bacillus Calmette-Guérin therapy and may be a predictive biomarker and a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)952-959
Number of pages8
JournalEuropean Urology
Volume72
Issue number6
DOIs
StatePublished - Dec 1 2017

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Urinary Bladder Neoplasms
Biomarkers
Bacillus
Therapeutics
DNA Repair
DNA Damage
Mutation
Genes
Recurrence
Immunotherapy
Neoplasms
Research Ethics Committees
Chromatin
Exons
Carcinogenesis
Regression Analysis

Keywords

  • AT-Rich interaction domain 1A
  • Bacillus Calmette-Guérin
  • DNA damage repair
  • Genomics
  • Immunotherapy
  • Nonmuscle invasive bladder cancer
  • Targeted therapy

ASJC Scopus subject areas

  • Urology

Cite this

Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. / Pietzak, Eugene J.; Bagrodia, Aditya; Cha, Eugene K.; Drill, Esther N.; Iyer, Gopa; Isharwal, Sumit; Ostrovnaya, Irina; Baez, Priscilla; Li, Qiang; Berger, Michael F.; Zehir, Ahmet; Schultz, Nikolaus; Rosenberg, Jonathan E.; Bajorin, Dean F.; Dalbagni, Guido; Al-Ahmadie, Hikmat; Solit, David B.; Bochner, Bernard H.

In: European Urology, Vol. 72, No. 6, 01.12.2017, p. 952-959.

Research output: Contribution to journalArticle

Pietzak, EJ, Bagrodia, A, Cha, EK, Drill, EN, Iyer, G, Isharwal, S, Ostrovnaya, I, Baez, P, Li, Q, Berger, MF, Zehir, A, Schultz, N, Rosenberg, JE, Bajorin, DF, Dalbagni, G, Al-Ahmadie, H, Solit, DB & Bochner, BH 2017, 'Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets', European Urology, vol. 72, no. 6, pp. 952-959. https://doi.org/10.1016/j.eururo.2017.05.032
Pietzak, Eugene J. ; Bagrodia, Aditya ; Cha, Eugene K. ; Drill, Esther N. ; Iyer, Gopa ; Isharwal, Sumit ; Ostrovnaya, Irina ; Baez, Priscilla ; Li, Qiang ; Berger, Michael F. ; Zehir, Ahmet ; Schultz, Nikolaus ; Rosenberg, Jonathan E. ; Bajorin, Dean F. ; Dalbagni, Guido ; Al-Ahmadie, Hikmat ; Solit, David B. ; Bochner, Bernard H. / Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. In: European Urology. 2017 ; Vol. 72, No. 6. pp. 952-959.
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abstract = "Background Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. Objective To identify genetic alterations with potential clinical implications in NMIBC. Design, setting, and participants Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. Outcome measurements and statistical analysis Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Gu{\'e}rin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. Results and limitations TERT promoter mutations (73{\%}) and chromatin-modifying gene alterations (69{\%}) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57{\%} of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30{\%} (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p < 0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95{\%} confidence interval: 1.51–6.51, p = 0.002). Conclusions Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. Patient summary Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests. High-grade nonmuscle invasive bladder cancer has high rates of DNA damage repair gene alterations, mutational burden, and actionable alterations, making trials of novel targeted agents and immunotherapies warranted. ARID1A mutations are associated with recurrence after bacillus Calmette-Gu{\'e}rin therapy and may be a predictive biomarker and a potential therapeutic target.",
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TY - JOUR

T1 - Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets

AU - Pietzak, Eugene J.

AU - Bagrodia, Aditya

AU - Cha, Eugene K.

AU - Drill, Esther N.

AU - Iyer, Gopa

AU - Isharwal, Sumit

AU - Ostrovnaya, Irina

AU - Baez, Priscilla

AU - Li, Qiang

AU - Berger, Michael F.

AU - Zehir, Ahmet

AU - Schultz, Nikolaus

AU - Rosenberg, Jonathan E.

AU - Bajorin, Dean F.

AU - Dalbagni, Guido

AU - Al-Ahmadie, Hikmat

AU - Solit, David B.

AU - Bochner, Bernard H.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Background Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. Objective To identify genetic alterations with potential clinical implications in NMIBC. Design, setting, and participants Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. Outcome measurements and statistical analysis Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. Results and limitations TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p < 0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval: 1.51–6.51, p = 0.002). Conclusions Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. Patient summary Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests. High-grade nonmuscle invasive bladder cancer has high rates of DNA damage repair gene alterations, mutational burden, and actionable alterations, making trials of novel targeted agents and immunotherapies warranted. ARID1A mutations are associated with recurrence after bacillus Calmette-Guérin therapy and may be a predictive biomarker and a potential therapeutic target.

AB - Background Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. Objective To identify genetic alterations with potential clinical implications in NMIBC. Design, setting, and participants Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. Outcome measurements and statistical analysis Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses. Results and limitations TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p < 0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval: 1.51–6.51, p = 0.002). Conclusions Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation. Patient summary Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests. High-grade nonmuscle invasive bladder cancer has high rates of DNA damage repair gene alterations, mutational burden, and actionable alterations, making trials of novel targeted agents and immunotherapies warranted. ARID1A mutations are associated with recurrence after bacillus Calmette-Guérin therapy and may be a predictive biomarker and a potential therapeutic target.

KW - AT-Rich interaction domain 1A

KW - Bacillus Calmette-Guérin

KW - DNA damage repair

KW - Genomics

KW - Immunotherapy

KW - Nonmuscle invasive bladder cancer

KW - Targeted therapy

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