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genes. The frequency of the characteristic mutations was
quite different in these subtypes, all of which had unique
features compared to bladder cancer. For example,
both clusters 2 and 3 have 100% FGFR3 mutations, yet
cluster 2 patients had no bladder recurrences, while cluster
3 patients had high rates of bladder recurrence.
Similar to the study by Sfakianos et al , we report a
high frequency of FGFR3 mutations in low-grade tumors and
of TP53 mutations in high-grade tumors, and confirm the
prevalence of chromatin-modifying gene mutations such as
the KMT family (Supplementary Tables 2 and 3).
We observed comparable mutation rates in UTUC (mean
5.8 /Mb, median 3.4 /Mb) and TCGA bladder cancer (mean
7.7 /Mb, median 5.5 /Mb ) with strong APOBEC signature
in a large proportion of the patients. FGFR3, KMT2D, and
CDKN2A were mutated at a higher frequency in UTUC than
in TCGA bladder cancer and the TP53 mutation
frequency was lower (Supplementary Table 6).
Along with the previously identified FGFR3-TACC3 fusion
, we observed a novel SH3KBP1-CNTNAP5 fusion.
Annotation of this novel fusion gene suggests a role in
signaling receptor recycling and/or degradation, and under-
lines the importance of growth factor signaling in UTUC.
Our study supports a rationale for pursuit of several
druggable targets in the clinic, most notably FGFR3. With
phase 1 data showing promising tolerability and overall
response rates for erdafitinib in metastatic urothelial cancer
, our data provide compelling justification for evalua-
tion of FGFR3 inhibitors in patients with both low- and
high-grade UTUC, with a pilot clinical trial currently in
development. Immune checkpoint inhibitor therapies such
as nivolumab (anti-PD1), ipilimumab (anti-CTLA4), and
pembrolizumab (anti-PDL1) might be effective in a subset
of the patients, especially those in cluster 4.
Limitations of this study include the relatively small
sample size, owing to constraints of the availability of
untreated frozen tissue and germline tissue, and tissue
quality/quantity for such a large number of analyses.
However our observations serve as important hypothesis-
generating findings that can be explored in future studies.
Tissues were obtained from two different institutions, and
despite clinical similarities, pathologic review by fellowship-
trained genitourinary pathologists, interindependent pipe-
line analyses, correction for batch effects, and consensus
calls from both institutions, there may be other unquantified
preanalytic variables that could affect outcomes.
5. Conclusions
Comprehensive genomic characterization of UTUC revealed
novel mutations and mutation frequencies in comparison to
bladder cancer, and identified four expression subtypes
with unique molecular profiles and clinical correlates. WES
analyses demonstrated that DNA repair and chromatin-
modifying genes play a critical role in this disease.
Expression analyses confirmed the additional critical
role of FGFR3 in both low- and high-grade tumors, and
validate this as a rational therapeutic target, along with
immune checkpoint therapies for a subset of patients with
the most adverse molecular and clinical features.
Author contributions: Surena F. Matin and Seth P. Lerner had full access to
all the data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study concept and design: Matin, Lerner.
Acquisition of data: Ezzedine, Mosqueda, Guo, Czerniak, Ittmann, Lerner,
Matin.
Analysis and interpretation of data: Moss, Qi, Xi, Wheeler.
Drafting of the manuscript: Moss, Qi, Xi, Mosqueda, Wheeler, Lerner,
Matin.
Critical revision of the manuscript for important intellectual content: Moss,
Qi, Xi, Peng, Kim, Ezzedine, Mosqueda, Guo, Czerniak, Ittmann, Wheeler,
Lerner, Matin.
Statistical analysis: Moss, Qi, Xi, Peng, Kim, Wheeler.
Obtaining funding: Lerner, Matin.
Administrative, technical, or material support: None.
Supervision: Matin, Lerner, Wheeler.
Other: None.
Financial disclosures: Surena F. Matin certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: This work was funded in part by
the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, the Khalifa Bin
Zayed Al Nahyan Foundation, the Monteleone Family Foundation for
Research in Kidney and Bladder Cancer, and the Eleanor and Scott Petty
Fund for UTUC Research, University of Texas MD Anderson Cancer
Center. This work was also funded in part by the Partnership for Bladder
Cancer Research, Scott Department of Urology, Dan L. Duncan Cancer
Center Baylor College of Medicine. Sequencing was performed for MD
Anderson Cancer Center samples in the Sequencing and Microarray
Facility and RPPA data produced by the Reverse Phase Protein Array core,
both funded by NCI Grant CA016672. The sponsors played no direct role
in the study.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
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