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Published on: January 5, 2017
Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer
Gopa Iyer1, Hikmat Al-Ahmadie, Nikolaus Schultz
1Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY, USA.
Purpose:
We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery.
Patients And Methods:
An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing.
Results:
Sixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G1-S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P < .001 and P < .003, respectively).
Conclusion:
High-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization.
Insights
High-grade bladder cancer shows significant genomic diversity, with most tumors having actionable alterations. Pretreatment genomic profiling is crucial for developing targeted therapies.
Area of Science:
- Genomics
- Oncology
- Drug Discovery
Background:
- High-grade bladder cancer is a complex disease with limited targeted treatment options.
- Understanding its genomic landscape is key to developing novel therapeutic strategies.
Purpose of the Study:
- To determine the prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer.
- To establish a foundation for therapeutic drug discovery targeting these alterations.
Main Methods:
- Integrative analysis of 97 high-grade bladder tumors.
- Identification of actionable drug targets based on clinical validation or investigational inhibitors.
- DNA copy number alterations (CNAs) assessed via array comparative genomic hybridization.
- Mutation profiling using mass spectroscopy-based genotyping and Sanger sequencing.
Main Results:
- Sixty-one percent of tumors exhibited potentially actionable genomic alterations.
- Distinct patterns of mutations were observed in RTK-RAS-RAF and PI3K/AKT/mTOR pathways, and cell cycle regulators.
- Two distinct tumor classes emerged based on CNA burden, with TP53 and RB1 mutations more frequent in high-CNA tumors.
Conclusions:
- High-grade bladder cancer displays considerable genomic heterogeneity.
- A majority of tumors possess tractable genomic alterations that may indicate response to targeted agents.
- Pretreatment genomic characterization is essential for effective development of target-specific therapies due to genomic diversity.