EURURO Vol. 72 No. 4

641 656

Urothelial Cancer
Comprehensive Genomic Characterization of Upper Tract
Urothelial Carcinoma
Tyler J. Moss Yuan Qi Liu Xi Bo Peng Tae-Beom Kim Nader E. Ezzedine
Maribel E. Mosqueda Charles C. Guo Bogdan A. Czerniak Michael Ittmann
David A. Wheeler Seth P. Lerner Surena F. Matin
a Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; b Department of
Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; c Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX,
USA; d Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;
e Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; f Department of Pathology, Baylor College of Medicine,
Houston, TX, USA; g Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA; hDepartment of Urology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA
ava ilable at
journal homepage:
Article info
Article history:
Accepted May 25, 2017
Associate Editor:
James Catto
Statistical Editor:
Melissa Assel
Keywords:
Upper tract urothelial carcinoma
Genomics
Ureteral cancer
Renal pelvic cancer
Abstract
Background: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic
and genomic factors compared to bladder cancer.
Objective: To characterize the genomic landscape of UTUC and provide insights into its
biology using comprehensive integrated genomic analyses.
Design, setting, and participants: We collected 31 untreated snap-frozen UTUC samples
from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA
sequencing (RNAseq), and protein analysis.
Outcome measurements and statistical analysis: Adjusting for batch effects, consensus
mutation calls from independent pipelines identified DNA mutations, gene expression
clusters using unsupervised consensus hierarchical clustering (UCHC), and protein
expression levels that were correlated with relevant clinical variables, The Cancer
Genome Atlas, and other published data.
Results and limitations: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60%
high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were
the most common mutational signatures. UCHC of RNAseq data segregated samples into
four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA muta-
tions, nonsmokers, high-grade <pT2 tumors, high recurrences. Cluster 2: 100% FGFR3
mutations, low-grade tumors, tobacco use, noninvasive disease, no bladder recurrences.
Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations, five bladder recur-
rences, tobacco use, tumors all <pT2. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%)
mutations, no PIK3CA mutations, high-grade pT2+ disease, tobacco use, carcinoma in
situ, shorter survival. We identified a novel SH3KBP1-CNTNAP5 fusion.
Conclusions: Mutations in UTUC occur at differing frequencies from bladder cancer,
with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK
signaling. Further studies are needed to validate the described subtypes, explore their
responses to therapy, and better define the novel fusion mutation.
* Corresponding author. Scott Department of Urology, Baylor College of Medicine, 7200 Cambridge,
Houston, TX 77030, USA. Tel. +1 713 7986841; Fax: +1 713 7987900.
E-mail address: (S.P. Lerner).
** Corresponding author. Department of Urology, The University of Texas MD Anderson Cancer
Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel. +1 713 7923250;
Fax: +1 713 7944894.
E-mail address: (S.F. Matin).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.