Genomic Characterization of Upper Tract Urothelial Carcinoma.
BACKGROUND
Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.


OBJECTIVE
To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.


METHODS
Tumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.


METHODS
We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).


CONCLUSIONS
Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.


CONCLUSIONS
High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.


RESULTS
Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
John P
JP
Sfakianos
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: chae@mskcc.org.
Eugene K
EK
Cha
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA.
Gopa
G
Iyer
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sasinya N
SN
Scott
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Emily C
EC
Zabor
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ronak H
RH
Shah
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Qinghu
Q
Ren
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Aditya
A
Bagrodia
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Philip H
PH
Kim
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
A Ari
AA
Hakimi
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Irina
I
Ostrovnaya
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ricardo
R
Ramirez
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Aphrothiti J
AJ
Hanrahan
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Neil B
NB
Desai
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Arony
A
Sun
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Patrizia
P
Pinciroli
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA.
Jonathan E
JE
Rosenberg
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA.
Guido
G
Dalbagni
Department of Epidemiology and Biostatistics, Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nikolaus
N
Schultz
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA.
Dean F
DF
Bajorin
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA.
Victor E
VE
Reuter
Weill Medical College of Cornell University, New York, NY, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Michael F
MF
Berger
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA.
Bernard H
BH
Bochner
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Hikmat A
HA
Al-Ahmadie
Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
David B
DB
Solit
Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA.
Jonathan A
JA
Coleman
D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D005260:Female; D023281:Genomics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014516:Ureteral Neoplasms / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
Bladder cancer; Genomics; Targeted therapy; Upper tract urothelial carcinoma