Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder

Philip H. Kim, Eugene K. Cha, John P. Sfakianos, Gopa Iyer, Emily C. Zabor, Sasinya N. Scott, Irina Ostrovnaya, Ricardo Ramirez, Arony Sun, Ronak Shah, Alyssa M. Yee, Victor E. Reuter, Dean F. Bajorin, Jonathan E. Rosenberg, Nikolaus Schultz, Michael F. Berger, Hikmat A. Al-Ahmadie, David B. Solit, Bernard H. Bochner

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


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. Patient summary 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.

Original languageEnglish
Pages (from-to)198-201
Number of pages4
JournalEuropean Urology
Issue number2
StatePublished - 1 Feb 2015
Externally publishedYes


  • Bladder cancer
  • Clinical outcomes
  • Genomics
  • Mutation
  • PIK3CA


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