EURURO Vol. 72 No. 3

366 476

Platinum Priority – Editorial
Referring to the article published on pp. 354–365 of this issue
Seeking the Molecular Truth in Bladder Cancer:
Biology = Genome T (Transcriptome)2
Peter C. Black
Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
The greatest single advance in our understanding of bladder
cancer in the past 5 yr has been the description of molecular
subtypes. The first major contribution came from the Lund
group in 2012 and was followed by almost simulta-
neous publication of three subtyping systems by three
different groups in 2014 . Some 3 yr later, in 2017, we
are grappling with two principal challenges: how to utilize
this molecular framework for further scientific discovery,
and how to define the clinical utility of subtyping. The lack
of a consensus subtyping system confounds both chal-
lenges.
The Cancer Genome Atlas (TCGA) has become the
foundation for molecular analysis of bladder cancer. Almost
every manuscript on bladder cancer can refer back to the
TCGA for validation of a novel concept, a critical pathway, or
a gene of interest. The natural application of this
comprehensive molecular characterization of bladder
cancer is to develop a paradigm of precision oncology
based on markers of response to therapy and the
identification of novel targets of therapy, recognizing that
the only therapy uniformly delivered to patients in the
TCGA cohort was radical cystectomy. Nonetheless, this data
set is key to our understanding of the disease, and findings
derived from it can be applied to independent cohorts
receiving specific therapies.
Molecular subtyping of bladder cancer is based primarily
on RNA expression, yet most forays into precision oncology
in bladder cancer, as in most cancers, are based on genomic
alterations. An integrative analysis of molecular subtypes
and genomic alterations is critical to advance our insight
into bladder cancer pathogenesis. In this issue of European
Urology, the scientists who developed the different methods
of molecular subtyping have joined forces to review the key
genomic alterations in bladder cancer in the context of RNA-
based subtypes in the TCGA cohort .
A strength of this analysis is not only cooperation among
the top experts in this field but also their use of all the
subtyping methods. In the absence of a consensus of
molecular subtypes, the TCGA clusters have been used in
some scenarios as representative, but there is currently no
reason to prioritize this method over the other methods.
TCGA clustering has been applied in two immunotherapy
trials to date, with disparate results . Unfortunately,
neither trial described the subtyping methodology ade-
quately, and the transcriptomic data have not been made
publicly available. This particular clinical application of
subtyping therefore remains uninterpretable to the scien-
tific community, and a comparison to other subytping
methods is not possible.
The analysis by Choi et al builds on previous studies
and shows that the dichotomous University of North
Carolina (UNC) classification into basal and luminal is most
easily recapitulated across subtyping methods, and the
molecular differences are greatest between these two
subtypes. However, the UNC group subsequently intro-
duced the claudin-low subtype which [4_TD$DIFF]is not included in
the analysis by Choi et al. Surprisingly, a correlation with
the four TCGA clusters is also not reported.
As a result, the analysis focuses mostly on the MD
Anderson and Lund classifications. Although the
differences between basal and luminal tumors are again
seen clearly here, the degree of correlation of genomic
alterations to the additional subtypes in each model is quite
variable. The p53-like subtype in the MD Anderson
available at
journal homepage:
DOI of original article: .
* Department of Urologic Sciences, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada. Tel. +1 604 8754301;
Fax: +1 604 8755604.
E-mail address:
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.