Integrative analysis of 1q23.3 copy-number gain in metastatic urothelial carcinoma.
OBJECTIVE
Metastatic urothelial carcinoma of the bladder is associated with multiple somatic copy-number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy.


METHODS
We obtained overall survival (OS) and array DNA copy-number data from patients with metastatic urothelial carcinoma in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by NanoString nCounter to identify transcripts from the region that are associated with copy-number gain. In addition, expression data from an independent cohort were used to identify candidate genes.


RESULTS
Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in both cohorts [adjusted HR, 2.96; 95% confidence interval (CI), 1.35-6.48; P = 0.01 and adjusted HR, 5.03; 95% CI, 1.43-17.73; P < 0.001]. The F11R, PFDN2, PPOX, USP21, and DEDD genes, all located on 1q23.3, were closely associated with poor outcome.


CONCLUSIONS
1q23.3 copy-number gain displayed association with poor survival in two cohorts of metastatic urothelial carcinoma. The identification of the target of this copy-number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of patients with poor-risk urothelial carcinoma. Prospective validation of the survival association is necessary to demonstrate clinical relevance.
Authors' Affiliations: Departments of Biostatistics and Computational Biology, and Medical Oncology; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute; Department of Biostatistics, Harvard School of Public Health; Department of Pathology; Translational Medicine Division, Brigham and Women's Hospital, Boston; Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Sidney Kimmel Cancer Center; Department of Pathology, Johns Hopkins University, Baltimore, Maryland; Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York; and Hospital del Mar Research Institute-IMIM, Barcelona; and Hospital Parc Tauli, Sabadell, Spain.
Markus
M
Riester
Lillian
L
Werner
Joaquim
J
Bellmunt
Shamini
S
Selvarajah
Elizabeth A
EA
Guancial
Barbara A
BA
Weir
Edward C
EC
Stack
Rachel S
RS
Park
Robert
R
O'Brien
Fabio A B
FA
Schutz
Toni K
TK
Choueiri
Sabina
S
Signoretti
Josep
J
Lloreta
Luigi
L
Marchionni
Enrique
E
Gallardo
Federico
F
Rojo
Denise I
DI
Garcia
Yvonne
Y
Chekaluk
David J
DJ
Kwiatkowski
Bernard H
BH
Bochner
William C
WC
Hahn
Azra H
AH
Ligon
Justine A
JA
Barletta
Massimo
M
Loda
David M
DM
Berman
Philip W
PW
Kantoff
Franziska
F
Michor
Jonathan E
JE
Rosenberg
D000328:Adult; D000368:Aged; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D014571:Urologic Neoplasms / Q000235:genetics* / Q000473:pathology