Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer Journal Article

Authors: Iyer, G.; Al-Ahmadie, H.; Schultz, N.; Hanrahan, A. J.; Ostrovnaya, I.; Balar, A. V.; Kim, P. H.; Lin, O.; Weinhold, N.; Sander, C.; Zabor, E. C.; Janakiraman, M.; Garcia-Grossman, I. R.; Heguy, A.; Viale, A.; Bochner, B. H.; Reuter, V. E.; Bajorin, D. F.; Milowsky, M. I.; Taylor, B. S.; Solit, D. B.
Article Title: Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer
Abstract: 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. 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. 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). 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.
Keywords: adult; aged; aged, 80 and over; middle aged; genetics; mutation; cancer staging; neoplasm staging; proto oncogene; gene amplification; phosphatidylinositol 3 kinase; bladder tumor; urinary bladder neoplasms; tumor suppressor gene; genes, erbb-2; genes, p53; dna copy number variations; copy number variation; transcription factor e2f3; phosphatidylinositol 3-kinases; e2f3 transcription factor; very elderly; e2f3 protein, human; pik3ca protein, human
Journal Title: Journal of Clinical Oncology
Volume: 31
Issue: 25
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2013-09-01
Start Page: 3133
End Page: 3140
Language: English
DOI: 10.1200/jco.2012.46.5740
PUBMED: 23897969
PROVIDER: scopus
PMCID: PMC3753703
Notes: --- - "Export Date: 2 December 2013" - "Source: Scopus"
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MSK Authors
  1. Adriana Heguy
    85 Heguy
  2. Dean Bajorin
    388 Bajorin
  3. David Solit
    421 Solit
  4. Oscar Lin
    231 Lin
  5. Gopakumar Vasudeva Iyer
    122 Iyer
  6. Emily Craig Zabor
    119 Zabor
  7. Arjun Vasant Balar
    8 Balar
  8. Bernard Bochner
    315 Bochner
  9. Agnes Viale
    203 Viale
  10. Chris Sander
    196 Sander
  11. Victor Reuter
    892 Reuter
  12. Philip Hyunwoo Kim
    39 Kim
  13. Nikolaus D Schultz
    193 Schultz