Format

Send to

Choose Destination
Eur Urol. 2015 Feb;67(2):198-201. doi: 10.1016/j.eururo.2014.06.050. Epub 2014 Aug 1.

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

Author information

1
Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
2
Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
3
Weill Medical College of Cornell University, New York, NY.
4
Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
5
Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
6
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
7
Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY.
#
Contributed equally

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.

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.

KEYWORDS:

Bladder cancer; Clinical outcomes; Genomics; Mutation; PIK3CA

PMID:
25092538
PMCID:
PMC4312739
DOI:
10.1016/j.eururo.2014.06.050
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center