EURURO Vol. 72 No. 3

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The subdivision in the UNC/MD Anderson/TCGA luminal
tumors that is created by the Lund classifier also appears to
be extremely important. It is very interesting that the GU
and uroA tumors are enriched with somewhat mutually
exclusive patterns of mutations and CNAs involving key
luminal genes (PPARG/GATA3 vs FGFR3). Overall, more of the
top genes in the GU tumors were affected by CNAs than they
were in the other molecular subtypes. The fact that GU
tumors are enriched with ERCC2 mutations is also
noteworthy. It will be interesting to determine their
relationships to cigarette smoking [19_TD$DIFF] and relative
sensitivities to NAC [32_TD$DIFF] Given that ERCC2, RB1 [33_TD$DIFF] , and
ERBB2 [74_TD$DIFF] mutations and CNA levels in general [32_TD$DIFF] have
been linked to chemosensitivity, it seems likely that
patients with GU tumors will obtain greater direct clinical
benefit from NAC than those who have uroA tumors.
It should be emphasized that our understanding of the
biological and clinical properties of the molecular subtypes
of bladder cancer is still fairly limited. Most of the available
genomic and associated clinical data were obtained
retrospectively, and the clinical follow-up is fairly short.
Although the total number of profiled bladder cancers is
increasing, it is relatively small, and challenges associated
with merging the data that have been and continue to be
generated on different genomic platforms make generating
meta-datasets difficult. Preclinical studies implicating
different cells of origin in the formation of papillary [75_TD$DIFF]
and nonpapillary [76_TD$DIFF] cancers provide possible explana-
tions for the origins of basal and luminal bladder cancers,
but their relevance to human carcinogenesis remains
unclear. The specific effects of most of the DNA alterations
that have been identified in bladder cancers need to be
explored much more deeply, presumably in preclinical
models, to determine whether subtype context is important
for their effects. The new information provided by TCGA and
other groups will enable laboratory scientists to create
models that more accurately capture important aspects of
the genomic heterogeneity observed in patients.
We do not yet know whether molecular subtype
membership is a stable, ‘‘intrinsic’’ feature of a given
tumor. Bioinformatic analyses have already demonstrated
that membership in the p53-like/infiltrated/TCGA cluster II
subtype is relatively unstable, and we have demonstrated
that luminal tumors often become p53-like after NAC
[58_TD$DIFF] . These observations could explain why TCGA cluster II
membership is not even more strongly associated with
response to immune checkpoint blockade than has been
observed in recently completed clinical trials [65_TD$DIFF] In
addition, as noted above, the uroB subtype may establish
a precedent for luminal-to-basal subtype ‘‘switching’’ in
bladder cancer. Muscle-invasive tumors can be multifocal,
and our collaborators are currently performing whole-
organ mapping studies to determine whether all these
multifocal tumors belong to the same subtype (B. Czerniak,
personal communication). NMIBCs are prone to recurrence,
and it will be important to perform longitudinal studies to
determine how often subtype membership is maintained in
these recurrences. Ongoing studies are performing deep
genomic characterizations of metastases, and it will be
interesting to see whether primary tumors and metastases
always belong to the same subtype. Finally, additional
comparisons of the DNA alterations in and subtype
membership of tumors collected before and after neoadju-
vant therapies, and where possible, systemic therapy for
metastatic disease, must still be performed to determine
whether subtype membership is stable. This information
has important implications for prognostication and sub-
type-based therapy.
Author contributions: David J. McConkey 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: Choi, Ochoa, McConkey.
Acquisition of data: Choi, Aine, Ho¨glund, Kim.
Analysis and interpretation of data: Choi, Ochoa, McConkey.
Drafting of the manuscript: Choi, Ochoa, McConkey.
Critical revision of the manuscript for important intellectual content: Aine,
Ho¨glund, Kim, Real, Kiltie, Lerner, Milsom, Dyrskjøt.
Statistical analysis: Choi, Ochoa.
Obtaining funding: McConkey.
Administrative, technical, or material support: None.
Supervision: McConkey.
Other: None.
Financial disclosures: David J. McConkey 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 supported by the
MD Anderson Bladder SPORE (CA091846), the Cancer Prevention and
Research Institute of Texas (CPRIT) (RP140542), and V foundation[2_TD$DIFF].
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
.
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