Title |
Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets
|
---|---|
Published in |
European Urology, June 2017
|
DOI | 10.1016/j.eururo.2017.05.032 |
Pubmed ID | |
Authors |
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 |
Abstract |
Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies. To identify genetic alterations with potential clinical implications in NMIBC. 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. 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. 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). 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 15 | 38% |
Germany | 2 | 5% |
Turkey | 2 | 5% |
United Kingdom | 2 | 5% |
Brazil | 2 | 5% |
France | 1 | 3% |
Pakistan | 1 | 3% |
Mexico | 1 | 3% |
Belgium | 1 | 3% |
Other | 2 | 5% |
Unknown | 11 | 28% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 20 | 50% |
Scientists | 10 | 25% |
Practitioners (doctors, other healthcare professionals) | 8 | 20% |
Science communicators (journalists, bloggers, editors) | 2 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Korea, Republic of | 1 | <1% |
Unknown | 228 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 39 | 17% |
Student > Ph. D. Student | 33 | 14% |
Student > Master | 23 | 10% |
Student > Bachelor | 21 | 9% |
Student > Doctoral Student | 17 | 7% |
Other | 40 | 17% |
Unknown | 56 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 77 | 34% |
Biochemistry, Genetics and Molecular Biology | 53 | 23% |
Agricultural and Biological Sciences | 21 | 9% |
Immunology and Microbiology | 3 | 1% |
Business, Management and Accounting | 2 | <1% |
Other | 6 | 3% |
Unknown | 67 | 29% |