94 96
Clinical
Trial Update
The
Cancer
Genome Atlas
Project
on Muscle-invasive
Bladder
Cancer
Seth
P.
Lerner
a , * ,John Weinstein
b ,David Kwiatkowski
c , d ,Jaegil
Kim
d ,Gordon
Robertson
e ,Katherine
A. Hoadley
f ,Rehan
Akbani
b ,Chad
Creighton
a ,on
behalf
of
the
TCGA Muscle
Invasive
Bladder
Cancer
Analysis Working
Group
a
Baylor
College
of Medicine,
Houston,
TX,
USA;
b
MD
Anderson
Cancer
Center,
Houston,
TX,
USA;
c
Dana
Farber
Cancer
Center,
Boston, MA,
USA;
d
Broad
Institute,
Boston, MA, USA;
e
British
Columbia
Cancer
Agency,
Vancouver,
Canada;
f
University
of North
Carolina,
Chapel Hill, NC, USA
The
Cancer Genome Atlas
(TCGA)
project
in
bladder
cancer
reported
the
integrated
genomic
analysis
of
the
first
131 patients
in 2014
[1]. We analyzed
chemotherapy-naive,
muscle-invasive
urothelial
cancers
for
somatic
mutation,
DNA copynumber variants,mRNAandmicroRNA expression,
protein and phosphorylated protein expression
(RPPA), DNA
methylation,
integrated
with
comprehensive
clinical
and
pathologic data.
This muscle-invasive
cohort has
one
of
the
highest
somatic
mutation
rates,
with
mean
and
median
somatic
mutation
rates
of
7.7
and
5.5
per
megabase,
respectively,
similar
to
adenocarcinoma
and
squamous
cell
carcinoma
of
the
lung
and
melanoma.
We
reported
32
significantly mutated
genes
(SMGs)
involved
in multiple
pathways
including
cell
cycle
regulation
(93%
of
tumors),
chromatin
remodeling
(76%),
DNA
damage
response,
tran-
scription
factors,
and
RAS/RTK/PI3K
(72%)
signaling
path-
ways.
Four
SMGs—ARID1a, MLL2,
KDM6a,
and
EP300—are
involved
in epigenetic
regulation and were mutated
in up
to
one-quarter
of
the
tumors.
One-third
of
the
tumors were
characterized by
cancer-specific DNA hypermethylation. An
additional 281
tumors
are
in
the pipeline, and
the
complete
data
set will be
analyzed beginning
in
early
2015. We have
preliminary mutation
data
on
238
samples
(including
the
first
131),
and
six
additional
SMGs
have
been
identified.
Several of the 38 SMGs have not been described previously
in
bladder
cancer.
Combining
copy
number
variation
and
somatic muta-
tions,
69%
of
tumors
harbor
one
potentially
actionable
target or more. Three mutation cluster
(I)
‘‘
Focally amplified
’’
–
enriched
in
focal
copy
number
alterations
(eg.
3p
loss/
PPARG) and MLL2 mutations;
(II)
Enriched
for TP53 and RB1
mutations, E2F3 amplifications;
and
(III)
Papillary histology
,
FGFR3 mutant
CDKN2A-deficient
Unsupervised
clustering
of
mRNA,
miRNA,
and
RPPA
suggests
four
expression
clusters,
three
of which were
fully
characterized
as
follows.
Cluster
I
showed
papillary mor-
phology and FGFR3 dysregulation. Clusters
I and
II expressed
high
HER2
(
ERBB2
)
and
estrogen
receptor-
b
signaling
signature,
sharing
features
with
luminal
A
breast
cancer.
Cluster
III
showed
similarities
to
basal-like
breast
and
squamous
cell
head
and
neck
carcinomas.
Cluster
III
had
a
high cancer stem cell content, similar
to
the basal phenotype
reported
earlier by Volkmer
et
al
[2]and Ho
and
colleagues
[3] .Cluster
III was
also
enriched with
tumors with mixed
squamous
histology,
similar
to
the
subtype
described
by
Sjodahl
et
al
[4] ,which
had
the worst
prognosis.
Cluster
III
also
correlated with
other
TCGA
subtypes
including
basal-
like
breast
carcinoma,
head
and
neck
squamous
cell
carcinoma,
and
lung
squamous
cell
carcinoma
[1] .This
has
been
confirmed with
a
recent
cluster
of
cluster
TGCA
pan-
cancer
analysis, which
stratified
the
bladder
cancer
cohort
into
three subtypes. Two were similar
to
lung adenocarcino-
ma
and
head
and
neck
and
lung
squamous
carcinoma,
and
the
third,
which
contained
the
majority
of
tumors,
was
unique
to
bladder
cancer
and
had
the
best
prognosis
compared with
the
two
other
subtypes
[5].
We have now
integrated
the mutation
subtypes
and
the
expression
clusters
for
234
tumors.
Expression
cluster
I
is
E U R O P E A N U R O L O G Y F O C U S 1 ( 2 0 1 5 ) 9 4 – 9 5available
at
www.sciencedirect.comjournal
homepage:
www.europeanurology.com* Scott Department
of Urology,
Baylor
College
of Medicine Medical
Center,
7200
Cambridge, MC
BCM380, Houston,
TX
77030, USA.
address:
slerner@bcm.edu(S.P.
Lerner).
http://dx.doi.org/10.1016/j.euf.2014.11.0022405-4569/
#
2015
European
Association
of Urology.
Published
by
Elsevier
B.V.
All
rights
reserved.