title: Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder.
abstract: Urothelial carcinoma of the bladder (UCB) is genomically heterogeneous, with frequent alterations in genes regulating chromatin state, cell cycle control, and receptor kinase signaling. To identify prognostic genomic markers in high-grade UCB, we used capture-based massively parallel sequencing to analyze 109 tumors. Mutations were detected in 240 genes, with 23 genes mutated in ≥5% of cases. The presence of a recurrent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation was associated with improved recurrence-free survival (RFS) (hazard ratio [HR]: 0.35; p=0.014) and improved cancer-specific survival (CSS) (HR: 0.35; p=0.040) in patients treated with radical cystectomy (RC). In multivariable analyses controlling for pT and pN stages, PIK3CA mutation remained associated with RFS (HR: 0.39; p=0.032). The most frequent alteration, TP53 mutation (57%), was more common in extravesical disease (69% vs 32%, p=0.005) and lymph node-positive disease (77% vs 56%, p=0.025). Patients with cyclin-dependent kinase inhibitor 2A (CDKN2A)-altered tumors experienced worse RFS (HR: 5.76; p<0.001) and worse CSS (HR: 2.94; p=0.029) in multivariable analyses. Mutations in chromatin-modifying genes were highly prevalent but not associated with outcomes. In UCB patients treated with RC, PIK3CA mutations are associated with favorable outcomes, whereas TP53 and CDKN2A alterations are associated with poor outcomes. Genomic profiling may aid in the identification of UCB patients at highest risk following RC.
  
  
  RESULTS
  Using next-generation sequencing, we identified genomic subsets of high-grade urothelial bladder cancer associated with favorable and unfavorable outcomes. These findings may aid in the selection of patients most likely to benefit from novel combined modality approaches.
authors.affiliation: Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Kim
authors.affiliation: Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Eugene K
authors.initials: EK
authors.lastname: Cha
authors.affiliation: Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: John P
authors.initials: JP
authors.lastname: Sfakianos
authors.affiliation: Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill Medical College of Cornell University, New York, NY.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Zabor
authors.affiliation: Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.affiliation: Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ramirez
authors.affiliation: Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Arony
authors.initials: A
authors.lastname: Sun
authors.affiliation: Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ronak
authors.initials: R
authors.lastname: Shah
authors.affiliation: Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Yee
authors.affiliation: Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill Medical College of Cornell University, New York, NY.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.affiliation: Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill Medical College of Cornell University, New York, NY.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.affiliation: Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill Medical College of Cornell University, New York, NY.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.affiliation: Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Hikmat A
authors.initials: HA
authors.lastname: Al-Ahmadie
authors.affiliation: Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill Medical College of Cornell University, New York, NY.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.|Weill Medical College of Cornell University, New York, NY.
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Bochner
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D058534:Class I Phosphatidylinositol 3-Kinases; D015653:Cystectomy; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008207:Lymphatic Metastasis; D015999:Multivariate Analysis; D009154:Mutation; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011237:Predictive Value of Tests; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D019459:Urothelium / Q000473:pathology* / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: Bladder cancer; Clinical outcomes; Genomics; Mutation; PIK3CA
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