title: Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, Cornell University, New York, NY, USA.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Aphrothiti J
authors.initials: AJ
authors.lastname: Hanrahan
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Arjun V
authors.initials: AV
authors.lastname: Balar
authors.forename: Philip H
authors.initials: PH
authors.lastname: Kim
authors.forename: Oscar
authors.initials: O
authors.lastname: Lin
authors.forename: Nils
authors.initials: N
authors.lastname: Weinhold
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Emily C
authors.initials: EC
authors.lastname: Zabor
authors.forename: Manickam
authors.initials: M
authors.lastname: Janakiraman
authors.forename: Ilana R
authors.initials: IR
authors.lastname: Garcia-Grossman
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Bochner
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations; D050699:E2F3 Transcription Factor / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D016158:Genes, p53; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
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