Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets Journal Article
| Authors: | Pietzak, E. J.; Bagrodia, A.; Cha, E. K.; Drill, E. N.; Iyer, G.; Isharwal, S.; Ostrovnaya, I.; Baez, P.; Li, Q.; Berger, M. F.; Zehir, A.; Schultz, N.; Rosenberg, J. E.; Bajorin, D. F.; Dalbagni, G.; Al-Ahmadie, H.; Solit, D. B.; Bochner, B. H. |
| Article Title: | Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets |
| 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. © 2017 European Association of Urology |
| Keywords: | adult; controlled study; treatment response; aged; cancer surgery; major clinical study; promoter region; missense mutation; mutation; cancer recurrence; comparative study; cancer staging; follow up; dna damage; bcg vaccine; cancer immunotherapy; epidermal growth factor receptor 2; cohort analysis; fibroblast growth factor receptor 3; immunotherapy; tumor recurrence; cystectomy; genomics; targeted therapy; mitomycin; recurrence free survival; bcg vaccination; nonmuscle invasive bladder cancer; next generation sequencing; bacillus calmette-guerin; non muscle invasive bladder cancer; dna damage repair; human; male; female; priority journal; article; at-rich interaction domain 1a |
| Journal Title: | European Urology |
| Volume: | 72 |
| Issue: | 6 |
| ISSN: | 0302-2838 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2017-12-01 |
| Start Page: | 952 |
| End Page: | 959 |
| Language: | English |
| DOI: | 10.1016/j.eururo.2017.05.032 |
| PROVIDER: | scopus |
| PUBMED: | 28583311 |
| PMCID: | PMC6007852 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
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