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J Urol. 2016 Jun;195(6):1684-1689. doi: 10.1016/j.juro.2016.01.006. Epub 2016 Jan 14.

Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma.

Author information

1
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY.
2
Weill Medical College of Cornell University, New York, NY.
3
Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY.
4
Department of Epidemiology and Biostatistics; Memorial Sloan Kettering Cancer Center, New York, NY.
5
Department of Pathology; Memorial Sloan Kettering Cancer Center, New York, NY.
6
Department of Medicine, Genitourinary Oncology Service; Memorial Sloan Kettering Cancer Center, New York, NY.
7
Human Oncology & Pathogenesis Program; Memorial Sloan Kettering Cancer Center, New York, NY.
#
Contributed equally

Abstract

PURPOSE:

Genomic characterization of radical nephroureterectomy specimens in patients with upper tract urothelial carcinoma may allow for thoughtful integration of systemic and targeted therapies. We sought to determine whether genomic alterations in upper tract urothelial carcinoma are associated with adverse pathological and clinical outcomes.

MATERIALS AND METHODS:

Next generation exon capture sequencing of 300 cancer associated genes was performed in 83 patients with upper tract urothelial carcinoma. Genomic alterations were assessed individually and also grouped into core signal transduction pathways or canonical cell functions for association with clinicopathological outcomes. Binary outcomes, including grade (high vs low), T stage (pTa/T1/T2 vs pT3/T4) and organ confined status (pT2 or less and N0/Nx vs greater than pT2 or N+) were assessed with the Kruskal-Wallis and Fisher exact tests as appropriate. Associations between alterations and survival were estimated using the Kaplan-Meier method and Cox regression.

RESULTS:

Of the 24 most commonly altered genes in 9 pathways TP53/MDM2 alterations and FGFR3 mutations were the only 2 alterations uniformly associated with high grade, advanced stage, nonorgan confined disease, and recurrence-free and cancer specific survival. TP53/MDM2 alterations were associated with adverse clinicopathological outcomes whereas FGFR3 mutations were associated with favorable outcomes. We created a risk score using TP53/MDM2 and FGFR3 status that was able to discriminate between adverse pathological and clinical outcomes, including in the subset of patients with high grade disease. The study is limited by small numbers and lack of validation.

CONCLUSIONS:

Our data indicate that specific genomic alterations in radical nephroureterectomy specimens correlate with tumor grade, stage and cancer specific survival outcomes.

KEYWORDS:

biological markers; carcinoma; genomics; kidney; ureter

PMID:
26778714
PMCID:
PMC4871772
DOI:
10.1016/j.juro.2016.01.006
[Indexed for MEDLINE]
Free PMC Article

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